氟西汀改善脑缺血引起的空间学习记忆缺陷及其机制研究
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摘要
脑卒中(俗称中风)为脑部血管阻塞或破裂引起脑部血流受阻所致病症,是中老年人的常见病、多发病。流行病学调查显示脑卒中存活者中有近30%的患者出现不同形式和程度的认知功能障碍,主要表现为记忆障碍、定向力障碍、空间结构能力障碍、推理思维能力障碍等。其中,记忆障碍者占45.4%。空间学习记忆障碍直接影响脑血管病的康复,已成为脑卒中研究的重点。
近年来,动物实验和临床研究均已经证实成年哺乳动物神经元再生对缺血后脑功能的重建至关重要。空间学习记忆主要依赖于海马,因此海马齿状回(dentate gyrus,DG)的神经元再生对于学习记忆至关重要。大量的文献已经证实局灶性脑缺血能够激发成年哺乳动物侧脑室室管膜下区(subventricular zone,SVZ)以及海马DG区神经元再生,新生神经元能向损伤的脑区迁移而且可以整合到已有的神经回路中形成一定的突触联系,这有利于改善缺血引起的神经功能缺陷及海马依赖性的学习记忆能力。这些研究均提示缺血后空间认知损害可能通过增强海马部位的神经元再生得到改善。
氟西汀被广泛应用于抗抑郁的治疗,其主要作用是抑制中枢神经系统突触间隙的5-羟色胺(5-hydroxytryptamine,5-HT)再摄取。近年来的研究显示,慢性的氟西汀治疗在生理状态下可以促进哺乳动物海马新生细胞的增殖和存活,然而,在脑缺血后慢性氟西汀治疗能否增强神经元再生从而改善空间学习记忆功能?为了探讨这一问题,我们研究了小鼠局灶性脑缺血后慢性氟西汀治疗对海马DG区神经元再生及空间学习记忆缺陷的影响,为中风后空间认知障碍提供了一个安全有效的治疗方法。本文采用成年小鼠大脑中动脉阻塞(middlecerebral artery occlusion,MCAO)制备局灶性脑缺血再灌注模型,为研究脑缺血后学习记忆障碍提供一种较理想的实验动物模型。
为了研究氟西汀对脑缺血后感觉运动功能及空间学习记忆能力的影响,实验共分为3组:假手术组—给予生理盐水;溶剂对照组—MCAO造模后给予生理盐水;氟西汀组—MCAO造模后给予氟西汀,在MCAO造模后第8天开始给予氟西汀(10 mg/kg,腹腔注射,每日一次),连续给药28天至MCAO造模后第35天结束,同时假手术组及溶剂对照组给予相同体积的生理盐水。
在脑缺血造模后第7,14,21,28,35,42,49及59天分别进行神经损伤严重程度评分(Neurological severity scores,NSS)和足失误测试(foot fault tests,FFT)未评价感觉运动功能。实验结果显示:NSS实验中,各个测量时间点溶剂对照组小鼠神经损伤严重程度评分显著高于假手术组,说明局灶性脑缺血能显著损害小鼠的感觉运动功能;但在氟西汀组和溶剂对照组之间神经损伤严重程度评分没有统计学差异,说明慢性氟西汀治疗对脑缺血后感觉运动功能的恢复没有影响。FFT实验是对小鼠运动中左右两侧前肢放置的协调性进行评估,结果显示各个时间点假手术组小鼠左右两侧前肢的失足率各约50%,氟西汀组及溶剂对照组小鼠缺血对侧前肢失足比例均显著增高,但这两组之间没有显著性差异,这同样说明慢性氟西汀治疗对脑缺血后运动协调功能的恢复没有影响。
在MCAO造模后第22-28天、50-59天即氟西汀治疗两周、四周后分别进行MorriS水迷宫实验(Morris water maze,MWM)检测氟西汀对空间学习记忆能力的影响。
在氟西汀治疗两周时,MWM隐蔽平台试验氟西汀组和溶剂对照组逃避潜伏期及游泳路线的长度均显著长于假手术组;但氟西汀组和溶剂对照组之间没有显著性差异,同样空间探索试验中氟西汀组和溶剂对照组小鼠在原平台象限的停留时间及穿越原平台位置的次数亦均没有统计学差异。说明局灶性脑缺血导致空间学习记忆能力明显受到损害,但氟西汀治疗两周对脑缺血引起的空间学习记忆损害没有改善作用。
氟西汀治疗四周并停药两周后,MWM隐蔽平台试验氟西汀组逃避潜伏期和游泳路线的长度显著短于溶剂对照组,接近假手术组,说明慢性氟西汀治疗能改善脑缺血后的空间学习记忆损害;并且在三组之间游泳速度没有显著差异,排除了动物体力差异对空间学习记忆能力的影响;空间探索试验中氟西汀组在原平台象限的停留时间及穿越原平台位置的次数均显著多于溶剂对照组。为了排除视觉对空间学习记忆的影响进行可视平台试验,结果显示三组的逃避潜伏期没有统计学差异,因此排除了视觉障碍对动物空间学习记忆能力的影响。
行为学实验结束后取小鼠脑组织进行TTC染色显示溶剂对照组与氟西汀组脑组织梗死面积的大小没有显著差异,以上研究结果说明慢性氟西汀治疗对脑缺血后感觉运动功能的恢复没有影响,但能改善脑缺血后的空间学习记忆损害,且不是由于梗死面积的缩小引起的。
为了研究海马神经元再生与氟西汀改善脑缺血后空间学习记忆功能之间的相互关系。
首先,我们观察了氟西汀给药对脑缺血后神经元再生的影响,我们在MCAO造模后19-21天(氟西汀给药后第12-14天)给予5-溴脱氧尿核苷(5-bromo-2'-deoxyuridine,BrdU:一种公认的新生细胞标记物)50mg/kg,连续给药6次,给药间隔为12小时,标记新生细胞。最后一次BrdU注射24h和28天后处死动物,观察氟西汀是否调控海马DG区细胞的增殖和存活。BrdU阳性细胞计数结果表明:三组之间缺血侧及对侧新生细胞的数目均没有显著差异,但氟西汀组缺血侧及对侧存活的细胞数与溶剂对照组相比,均显著增多,对照组和假手术组之间存活的细胞数没有差异,说明慢性氟西汀治疗对缺血后海马DG区神经元的增殖没有影响,但能促进新生细胞的存活。
其次,为了进一步探讨氟西汀改善脑缺血后空间学习记忆功能是否依赖于海马神经元再生,我们运用端粒酶抑制剂3-叠氮脱氧胸苷(3'-azido-3'-deoxythymidine,AZT)阻断海马神经元再生。本实验室前期研究表明,在生理状态下,端粒酶抑制剂AZT显著抑制了小鼠海马齿状回神经元的增殖及存活。造模后实验动物共分为三组:溶剂对照组—MCAO造模后给予生理盐水;氟西汀组(FLX组)—MCAO造模后给予氟西汀;FLX+AZT组—MCAO造模后先给予AZT半小时后再给予氟西汀,小鼠氟西汀给药前半小时(MCAO后8-35天)腹腔注射AZT(100mg/kg,给药28次,间隔24小时),第19-21天给予BrdU(50mg/kg,连续给药6次,给药间隔为12小时)标记新生细胞。末次BrdU注射28天后检测海马神经元再生,并进行Morris水迷宫实验。
结果显示:氟西汀治疗前半小时给予AZT,能够削弱氟西汀诱导的缺血后DG区神经元再生的上调,FLX+AZT组缺血侧及对侧Brdu阳性细胞数分别比FLX组减少了46%和37%接近溶剂对照组。且在水迷宫实验中,隐蔽平台试验中与FLX组、溶剂对照组相比,FLX+AZT组逃避潜伏期及游泳路线的长度均显著延长,以上结果说明AZT能够削弱氟西汀诱导的缺血后DG区神经元再生的上调,且此时氟西汀改善缺血后空间记忆损害的效应消失。
结论:慢性氟西汀治疗对脑缺血后感觉运动功能的恢复没有影响;脑缺血后慢性氟西汀治疗不影响海马DG区神经元的增殖,但能够促进新生细胞的存活,并逆转缺血引起的空间学习记忆损害。海马神经元再生的上调是氟西汀改善缺血后空间学习记忆损害所必需的。
Stroke is a devastating injury caused by interruption of the blood supply to the brain. Spatial cognitive deficits including spatial memory impairment are very common after ischemic stroke. About 30% of the stroke survivors suffer spatial cognitive deficits. However, there is no effective pharmacotherapy at present.
Recent advances in the study of neural regeneration suggest that neurogenesis may be a critical element in brain repair. Spatial memory is largely dependent on hippocampal formation. Neurogenesis in the adult dentate gyrus (DG) is important in learning and memory processes. In adult rodents, experimental cerebral ischemia enhances neurogenesis in the brain's neuroproliferative zones, the subgranular zone (SGZ) of the hippocampal DG and the subventricular zone (SVZ) of the lateral ventricle. There is also evidence for stroke-induced neurogenesis in the human brain. Recently, these newborn neurons after ischemic injury were shown to migrate to injured brain regions, become actively integrated into the existing circuitry, and form appropriate synapses, which contributed to ameliorate neurological deficits and form hippocampal-dependent memory. These studies raise the possibility that spatial cognitive deficits after ischemic stroke may be improved through enhancing hippocampal neurogenesis.
Fluoxetine is a widely used antidepressant compound, whose primary action is based on the inhibition of serotonin-reuptake in the central nervous system (CNS). Recent studies have shown that chronic fluoxetine treatment can promote the proliferation as well as the survival and differentiation of newborn cells in the hippocampus of the adult mammalian brain and in some neurological diseases, such as depression. It is important to determine whether chronic fluoxetine treatment can enhance neurogenesis and neuronal remodeling in the hippocampus and improve spatial cognitive functional recovery after ischemic stroke, as this question remains to be answered. Aiming to determine the contribution of fluoxetine on ischemic stroke, we examined the effects of a chronic fluoxetine regimen on hippocampal neurogenesis and functional recovery, especially spatial cognitive function after focal cerebral ischemia.
To determine whether fluoxetine treatment improves sensorimotor functional recovery and attenuates spatial memory impairment, mice received i.p. injections of fluoxetine (dissolved in 0.9% NaCl and administered at a dose of 10 mg·kg~(-1)) daily starting on day 8 after ischemia induction and continuing to 35 days after MCAO (28 days). Vehicle control mice and sham-operated mice were given an equivalent volume of vehicle (saline). Neurological severity scores and foot fault tests were performed 7, 14, 21, 28, 35, 42, 49 and 59 days after MCAO, and spatial cognitive performance was tested in the Morris water maze during day 22-28 and day 50-59 after MCAO. The animals subjected to MCAO exhibited significant and sustained neurological deficits compared with sham-operated mice, while the mean modified neurological severity scores showed no significant difference between fluoxetine- and vehicle-treated mice throughout the testing period. Unilateral foot faults were expressed by the number of contralateral foot faults as a percentage of the total errors made, and a value of 50% represents an equal number of errors made by both sides. In sham-operated animals, no functional deficit was observed as they made approximately the same number of errors on the contralateral side as they did on the ipsilateral side. In the mice subjected to MCAO, there was a significant increase in the number of contralateral errors. However, fluoxetine treatment did not significantly reduce this functional deficit compared with vehicle. These results suggest that chronic fluoxetine treatment does not significantly improve sensorimotor functional recovery after stroke. In the test of Morris water maze, we first exposed animals to water maze task after fluoxetine treatment for 14-20 days (day 22-28 after MCAO). In the hidden platform trials, with regard to escape latency, repeated-measures two-way ANOVA revealed a group difference. Post hoc analysis using LSD test revealed that sham-operated group had a significantly reduced escape latency compared with the two ischemic groups, with vehicle and with fluoxetine. However, there was no significant difference between fluoxetine- and vehicle-treated mice in escape latency. Ischemic groups had significantly prolonged swimming length also compared with sham-operated mice. Repeated-measures two-way ANOVA of the swimming speed showed that there were no differences between three groups, suggesting that the impaired spatial cognitive ability of ischemic mice on the water maze task is not caused by motor ability changes. During the spatial probe trials, in which the platform was removed, ischemic mice exhibited reduced time spent in the target quadrant and number of crossing platform position compared with sham-operated mice. Therefore, fluoxetine treatment for 14 days does not ameliorate the MCAO-induced spatial learning and memory impairment. When animals were exposed to the water maze task after 28 days of fluoxetine treatment and 14 days of drug withdrawal, however, the escape latency in fluoxetine-treated group was significantly shorter than that in vehicle-treated group, and was similar to that in sham-operated group. Similarly, fluoxetine-treated mice had significantly reduced swimming length compared with vehicle-treated mice. Swimming speed was also measured, and there were no significant differences between each group. In the spatial probe trials, Sham-operated and fluoxetine-treated mice exhibited markedly increased time spent in the target quadrant) and number of crossing the platform position compared with vehicle-treated mice. To exclude the possibility that the improved memory by chronic fluoxetine treatment was confounded by motivational or sensorimotor factors, we performed a water maze task with visible platform in which the platform was elevated 0.5 cm above the water level. Repeated-measures two-way ANOVA of escape latency demonstrated no significant differences between each group, suggesting that the improved memory by fluoxetine is spatial memory. At the end of behavioral tests, the infarct volume was determined in mice from the three groups by TTC staining. Fluoxetine treatment for 4 weeks starting day 8 after MCAO did not lessen infarct volume, suggesting that the improved memory by fluoxetine is not due to infarct volume reduction.
To examine whether fluoxetine increases neurogenesis, mice received i.p. injections of 5-bromo-2'-deoxyuridine (BrdU; Sigma) 50 mg·kg~(-1) twice daily during day 19-21 after MCAO. For the cellular proliferation study, animals were sacrificed 24 hours after the last BrdU injection to examine the number of newly formed cells in the DG. To determine the survival of the newly born cells, animals were sacrificed 28 days after the last BrdU injection. The number of newborn cells in the DG of fluoxetine-treated mice did not differ from that of vehicle both in ipsilateral and contralalteral, suggesting that chronic fluoxetine treatment has no effect on progenitor cell proliferation in the DG of ischemic mice. Neither fluoxetine nor vehicle treatment changed the number of newborn cells in the DG of ischemic mice compared with sham-operated mice in both the ipsilateral and contralalteral region. Moreover, there was no significant difference in the numbers of BrdU-positive cells between the ipsilateral and contralateral sides in fluoxetine-, vehicle-treated and sham-operated groups. However, chronic fluoxetine treatment facilitated the survival of newborn cells in the DG, the number of BrdU-positive cells both in the ipsilateral and contralateral DG was significantly increased in the animals treated with fluoxetine compared with vehicle or sham-operated mice, suggesting that chronic fluoxetine treatment increased the survival of newly born cells in the hippocampus after stroke. There was no significant difference in the numbers of BrdU-positive cells between vehicle-treated mice and sham-operated mice both in the ipsilateral and contralateral DG.
To determine whether hippocampal neurogenesis is necessary for the effect of fluoxetine on spatial cognitive performance after MCAO, we used a telomerase inhibitor, 3'-azido-deoxythymidine (AZT), to disrupt neurogenesis. The mice were treated with 100 mg/kg AZT per day i.p. during the period of fluoxetine treatment (from day 8 to day 35 after MCAO). Spatial cognitive performance and hippocampal neurogenesis were tested 49 d after MCAO (28 d after the last BrdU administration) by the same approach as was mentioned previously. In the mice treated with fluoxetine combined with AZT, the number of BrdU-positive cells in the DG was significantly fewer than that in the mice treated with fluoxetine alone, and similar to that in vehicle-treated animals, suggesting that the increased neurogenesis by fluoxetine treatment was neutralized by the negative action of AZT. In water maze task, AZT completely abolished the effects of fluoxetine on escape latency and swimming length, compared with fluoxetine alone group, even the speeds of fluoxetine and AZT treatment mice were rapid than fluoxetine-treated and vehicle-treated mice. Thus, hippocampal neurogenesis is required for the beneficial effect of fluoxetine on ischemia-induced spatial cognitive deficits.
Thus, our data suggest that although chronic fluoxetine treatment does not significantly improve sensorimotor functional recovery after stroke and has no effect on progenitor cell proliferation in the DG of ischemic mice, it benefits spatial cognitive function recovery following ischemic insult, and the improved cognitive function is associated with enhanced newborn cell survival in the hippocampus. Moreover, hippocampal neurogenesis is essential for fluoxetine-improved spatial cognitive deficits.
近年来,动物实验和临床研究均已经证实成年哺乳动物神经元再生对缺血后脑功能的重建至关重要。空间学习记忆主要依赖于海马,因此海马齿状回(dentate gyrus,DG)的神经元再生对于学习记忆至关重要。大量的文献已经证实局灶性脑缺血能够激发成年哺乳动物侧脑室室管膜下区(subventricular zone,SVZ)以及海马DG区神经元再生,新生神经元能向损伤的脑区迁移而且可以整合到已有的神经回路中形成一定的突触联系,这有利于改善缺血引起的神经功能缺陷及海马依赖性的学习记忆能力。这些研究均提示缺血后空间认知损害可能通过增强海马部位的神经元再生得到改善。
氟西汀被广泛应用于抗抑郁的治疗,其主要作用是抑制中枢神经系统突触间隙的5-羟色胺(5-hydroxytryptamine,5-HT)再摄取。近年来的研究显示,慢性的氟西汀治疗在生理状态下可以促进哺乳动物海马新生细胞的增殖和存活,然而,在脑缺血后慢性氟西汀治疗能否增强神经元再生从而改善空间学习记忆功能?为了探讨这一问题,我们研究了小鼠局灶性脑缺血后慢性氟西汀治疗对海马DG区神经元再生及空间学习记忆缺陷的影响,为中风后空间认知障碍提供了一个安全有效的治疗方法。本文采用成年小鼠大脑中动脉阻塞(middlecerebral artery occlusion,MCAO)制备局灶性脑缺血再灌注模型,为研究脑缺血后学习记忆障碍提供一种较理想的实验动物模型。
为了研究氟西汀对脑缺血后感觉运动功能及空间学习记忆能力的影响,实验共分为3组:假手术组—给予生理盐水;溶剂对照组—MCAO造模后给予生理盐水;氟西汀组—MCAO造模后给予氟西汀,在MCAO造模后第8天开始给予氟西汀(10 mg/kg,腹腔注射,每日一次),连续给药28天至MCAO造模后第35天结束,同时假手术组及溶剂对照组给予相同体积的生理盐水。
在脑缺血造模后第7,14,21,28,35,42,49及59天分别进行神经损伤严重程度评分(Neurological severity scores,NSS)和足失误测试(foot fault tests,FFT)未评价感觉运动功能。实验结果显示:NSS实验中,各个测量时间点溶剂对照组小鼠神经损伤严重程度评分显著高于假手术组,说明局灶性脑缺血能显著损害小鼠的感觉运动功能;但在氟西汀组和溶剂对照组之间神经损伤严重程度评分没有统计学差异,说明慢性氟西汀治疗对脑缺血后感觉运动功能的恢复没有影响。FFT实验是对小鼠运动中左右两侧前肢放置的协调性进行评估,结果显示各个时间点假手术组小鼠左右两侧前肢的失足率各约50%,氟西汀组及溶剂对照组小鼠缺血对侧前肢失足比例均显著增高,但这两组之间没有显著性差异,这同样说明慢性氟西汀治疗对脑缺血后运动协调功能的恢复没有影响。
在MCAO造模后第22-28天、50-59天即氟西汀治疗两周、四周后分别进行MorriS水迷宫实验(Morris water maze,MWM)检测氟西汀对空间学习记忆能力的影响。
在氟西汀治疗两周时,MWM隐蔽平台试验氟西汀组和溶剂对照组逃避潜伏期及游泳路线的长度均显著长于假手术组;但氟西汀组和溶剂对照组之间没有显著性差异,同样空间探索试验中氟西汀组和溶剂对照组小鼠在原平台象限的停留时间及穿越原平台位置的次数亦均没有统计学差异。说明局灶性脑缺血导致空间学习记忆能力明显受到损害,但氟西汀治疗两周对脑缺血引起的空间学习记忆损害没有改善作用。
氟西汀治疗四周并停药两周后,MWM隐蔽平台试验氟西汀组逃避潜伏期和游泳路线的长度显著短于溶剂对照组,接近假手术组,说明慢性氟西汀治疗能改善脑缺血后的空间学习记忆损害;并且在三组之间游泳速度没有显著差异,排除了动物体力差异对空间学习记忆能力的影响;空间探索试验中氟西汀组在原平台象限的停留时间及穿越原平台位置的次数均显著多于溶剂对照组。为了排除视觉对空间学习记忆的影响进行可视平台试验,结果显示三组的逃避潜伏期没有统计学差异,因此排除了视觉障碍对动物空间学习记忆能力的影响。
行为学实验结束后取小鼠脑组织进行TTC染色显示溶剂对照组与氟西汀组脑组织梗死面积的大小没有显著差异,以上研究结果说明慢性氟西汀治疗对脑缺血后感觉运动功能的恢复没有影响,但能改善脑缺血后的空间学习记忆损害,且不是由于梗死面积的缩小引起的。
为了研究海马神经元再生与氟西汀改善脑缺血后空间学习记忆功能之间的相互关系。
首先,我们观察了氟西汀给药对脑缺血后神经元再生的影响,我们在MCAO造模后19-21天(氟西汀给药后第12-14天)给予5-溴脱氧尿核苷(5-bromo-2'-deoxyuridine,BrdU:一种公认的新生细胞标记物)50mg/kg,连续给药6次,给药间隔为12小时,标记新生细胞。最后一次BrdU注射24h和28天后处死动物,观察氟西汀是否调控海马DG区细胞的增殖和存活。BrdU阳性细胞计数结果表明:三组之间缺血侧及对侧新生细胞的数目均没有显著差异,但氟西汀组缺血侧及对侧存活的细胞数与溶剂对照组相比,均显著增多,对照组和假手术组之间存活的细胞数没有差异,说明慢性氟西汀治疗对缺血后海马DG区神经元的增殖没有影响,但能促进新生细胞的存活。
其次,为了进一步探讨氟西汀改善脑缺血后空间学习记忆功能是否依赖于海马神经元再生,我们运用端粒酶抑制剂3-叠氮脱氧胸苷(3'-azido-3'-deoxythymidine,AZT)阻断海马神经元再生。本实验室前期研究表明,在生理状态下,端粒酶抑制剂AZT显著抑制了小鼠海马齿状回神经元的增殖及存活。造模后实验动物共分为三组:溶剂对照组—MCAO造模后给予生理盐水;氟西汀组(FLX组)—MCAO造模后给予氟西汀;FLX+AZT组—MCAO造模后先给予AZT半小时后再给予氟西汀,小鼠氟西汀给药前半小时(MCAO后8-35天)腹腔注射AZT(100mg/kg,给药28次,间隔24小时),第19-21天给予BrdU(50mg/kg,连续给药6次,给药间隔为12小时)标记新生细胞。末次BrdU注射28天后检测海马神经元再生,并进行Morris水迷宫实验。
结果显示:氟西汀治疗前半小时给予AZT,能够削弱氟西汀诱导的缺血后DG区神经元再生的上调,FLX+AZT组缺血侧及对侧Brdu阳性细胞数分别比FLX组减少了46%和37%接近溶剂对照组。且在水迷宫实验中,隐蔽平台试验中与FLX组、溶剂对照组相比,FLX+AZT组逃避潜伏期及游泳路线的长度均显著延长,以上结果说明AZT能够削弱氟西汀诱导的缺血后DG区神经元再生的上调,且此时氟西汀改善缺血后空间记忆损害的效应消失。
结论:慢性氟西汀治疗对脑缺血后感觉运动功能的恢复没有影响;脑缺血后慢性氟西汀治疗不影响海马DG区神经元的增殖,但能够促进新生细胞的存活,并逆转缺血引起的空间学习记忆损害。海马神经元再生的上调是氟西汀改善缺血后空间学习记忆损害所必需的。
Stroke is a devastating injury caused by interruption of the blood supply to the brain. Spatial cognitive deficits including spatial memory impairment are very common after ischemic stroke. About 30% of the stroke survivors suffer spatial cognitive deficits. However, there is no effective pharmacotherapy at present.
Recent advances in the study of neural regeneration suggest that neurogenesis may be a critical element in brain repair. Spatial memory is largely dependent on hippocampal formation. Neurogenesis in the adult dentate gyrus (DG) is important in learning and memory processes. In adult rodents, experimental cerebral ischemia enhances neurogenesis in the brain's neuroproliferative zones, the subgranular zone (SGZ) of the hippocampal DG and the subventricular zone (SVZ) of the lateral ventricle. There is also evidence for stroke-induced neurogenesis in the human brain. Recently, these newborn neurons after ischemic injury were shown to migrate to injured brain regions, become actively integrated into the existing circuitry, and form appropriate synapses, which contributed to ameliorate neurological deficits and form hippocampal-dependent memory. These studies raise the possibility that spatial cognitive deficits after ischemic stroke may be improved through enhancing hippocampal neurogenesis.
Fluoxetine is a widely used antidepressant compound, whose primary action is based on the inhibition of serotonin-reuptake in the central nervous system (CNS). Recent studies have shown that chronic fluoxetine treatment can promote the proliferation as well as the survival and differentiation of newborn cells in the hippocampus of the adult mammalian brain and in some neurological diseases, such as depression. It is important to determine whether chronic fluoxetine treatment can enhance neurogenesis and neuronal remodeling in the hippocampus and improve spatial cognitive functional recovery after ischemic stroke, as this question remains to be answered. Aiming to determine the contribution of fluoxetine on ischemic stroke, we examined the effects of a chronic fluoxetine regimen on hippocampal neurogenesis and functional recovery, especially spatial cognitive function after focal cerebral ischemia.
To determine whether fluoxetine treatment improves sensorimotor functional recovery and attenuates spatial memory impairment, mice received i.p. injections of fluoxetine (dissolved in 0.9% NaCl and administered at a dose of 10 mg·kg~(-1)) daily starting on day 8 after ischemia induction and continuing to 35 days after MCAO (28 days). Vehicle control mice and sham-operated mice were given an equivalent volume of vehicle (saline). Neurological severity scores and foot fault tests were performed 7, 14, 21, 28, 35, 42, 49 and 59 days after MCAO, and spatial cognitive performance was tested in the Morris water maze during day 22-28 and day 50-59 after MCAO. The animals subjected to MCAO exhibited significant and sustained neurological deficits compared with sham-operated mice, while the mean modified neurological severity scores showed no significant difference between fluoxetine- and vehicle-treated mice throughout the testing period. Unilateral foot faults were expressed by the number of contralateral foot faults as a percentage of the total errors made, and a value of 50% represents an equal number of errors made by both sides. In sham-operated animals, no functional deficit was observed as they made approximately the same number of errors on the contralateral side as they did on the ipsilateral side. In the mice subjected to MCAO, there was a significant increase in the number of contralateral errors. However, fluoxetine treatment did not significantly reduce this functional deficit compared with vehicle. These results suggest that chronic fluoxetine treatment does not significantly improve sensorimotor functional recovery after stroke. In the test of Morris water maze, we first exposed animals to water maze task after fluoxetine treatment for 14-20 days (day 22-28 after MCAO). In the hidden platform trials, with regard to escape latency, repeated-measures two-way ANOVA revealed a group difference. Post hoc analysis using LSD test revealed that sham-operated group had a significantly reduced escape latency compared with the two ischemic groups, with vehicle and with fluoxetine. However, there was no significant difference between fluoxetine- and vehicle-treated mice in escape latency. Ischemic groups had significantly prolonged swimming length also compared with sham-operated mice. Repeated-measures two-way ANOVA of the swimming speed showed that there were no differences between three groups, suggesting that the impaired spatial cognitive ability of ischemic mice on the water maze task is not caused by motor ability changes. During the spatial probe trials, in which the platform was removed, ischemic mice exhibited reduced time spent in the target quadrant and number of crossing platform position compared with sham-operated mice. Therefore, fluoxetine treatment for 14 days does not ameliorate the MCAO-induced spatial learning and memory impairment. When animals were exposed to the water maze task after 28 days of fluoxetine treatment and 14 days of drug withdrawal, however, the escape latency in fluoxetine-treated group was significantly shorter than that in vehicle-treated group, and was similar to that in sham-operated group. Similarly, fluoxetine-treated mice had significantly reduced swimming length compared with vehicle-treated mice. Swimming speed was also measured, and there were no significant differences between each group. In the spatial probe trials, Sham-operated and fluoxetine-treated mice exhibited markedly increased time spent in the target quadrant) and number of crossing the platform position compared with vehicle-treated mice. To exclude the possibility that the improved memory by chronic fluoxetine treatment was confounded by motivational or sensorimotor factors, we performed a water maze task with visible platform in which the platform was elevated 0.5 cm above the water level. Repeated-measures two-way ANOVA of escape latency demonstrated no significant differences between each group, suggesting that the improved memory by fluoxetine is spatial memory. At the end of behavioral tests, the infarct volume was determined in mice from the three groups by TTC staining. Fluoxetine treatment for 4 weeks starting day 8 after MCAO did not lessen infarct volume, suggesting that the improved memory by fluoxetine is not due to infarct volume reduction.
To examine whether fluoxetine increases neurogenesis, mice received i.p. injections of 5-bromo-2'-deoxyuridine (BrdU; Sigma) 50 mg·kg~(-1) twice daily during day 19-21 after MCAO. For the cellular proliferation study, animals were sacrificed 24 hours after the last BrdU injection to examine the number of newly formed cells in the DG. To determine the survival of the newly born cells, animals were sacrificed 28 days after the last BrdU injection. The number of newborn cells in the DG of fluoxetine-treated mice did not differ from that of vehicle both in ipsilateral and contralalteral, suggesting that chronic fluoxetine treatment has no effect on progenitor cell proliferation in the DG of ischemic mice. Neither fluoxetine nor vehicle treatment changed the number of newborn cells in the DG of ischemic mice compared with sham-operated mice in both the ipsilateral and contralalteral region. Moreover, there was no significant difference in the numbers of BrdU-positive cells between the ipsilateral and contralateral sides in fluoxetine-, vehicle-treated and sham-operated groups. However, chronic fluoxetine treatment facilitated the survival of newborn cells in the DG, the number of BrdU-positive cells both in the ipsilateral and contralateral DG was significantly increased in the animals treated with fluoxetine compared with vehicle or sham-operated mice, suggesting that chronic fluoxetine treatment increased the survival of newly born cells in the hippocampus after stroke. There was no significant difference in the numbers of BrdU-positive cells between vehicle-treated mice and sham-operated mice both in the ipsilateral and contralateral DG.
To determine whether hippocampal neurogenesis is necessary for the effect of fluoxetine on spatial cognitive performance after MCAO, we used a telomerase inhibitor, 3'-azido-deoxythymidine (AZT), to disrupt neurogenesis. The mice were treated with 100 mg/kg AZT per day i.p. during the period of fluoxetine treatment (from day 8 to day 35 after MCAO). Spatial cognitive performance and hippocampal neurogenesis were tested 49 d after MCAO (28 d after the last BrdU administration) by the same approach as was mentioned previously. In the mice treated with fluoxetine combined with AZT, the number of BrdU-positive cells in the DG was significantly fewer than that in the mice treated with fluoxetine alone, and similar to that in vehicle-treated animals, suggesting that the increased neurogenesis by fluoxetine treatment was neutralized by the negative action of AZT. In water maze task, AZT completely abolished the effects of fluoxetine on escape latency and swimming length, compared with fluoxetine alone group, even the speeds of fluoxetine and AZT treatment mice were rapid than fluoxetine-treated and vehicle-treated mice. Thus, hippocampal neurogenesis is required for the beneficial effect of fluoxetine on ischemia-induced spatial cognitive deficits.
Thus, our data suggest that although chronic fluoxetine treatment does not significantly improve sensorimotor functional recovery after stroke and has no effect on progenitor cell proliferation in the DG of ischemic mice, it benefits spatial cognitive function recovery following ischemic insult, and the improved cognitive function is associated with enhanced newborn cell survival in the hippocampus. Moreover, hippocampal neurogenesis is essential for fluoxetine-improved spatial cognitive deficits.
引文
[1] Kidwell CS, Liebeskind DS, Starkman S, Saver JL. 2001. Trends in acute ischemic stroke trials through the 20th century. Stroke 32:1349-1359.
[2] Tatemichi TK, Desmond DW, Mayeux R, et al. Dementia after stroke: baseline frequency, risks, and clinical features in a hosp italized cohort. Neurology, 1992, 42:1185293.
[3] Hagek VE. Brief assessment of cognitive impairment in patients with stroke. Arch physMed. Rehabic, 1989, 70: 114.
[4] Asplund K, Stegmayr B, Pelltonen M. 1998. From the twentieth to the twenty-first century: A public health perspective on stroke. In: Ginsberg MD, Bogousslavsky J (Eds). Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management. Blackwell Science, Maiden, MA, p901-908.
[5] Temple S. (2001) The develompment of neural stem cells. Nature 414: 112-117.
[6] Gage FH. (2002) Mammalian neural stem cells. Science 287:1433-1438.
[7] Song H, Stevens CF, Gage FH. (2002) Astroglia induce neurogenesis from adult neural stem cells. Nature 417: 39-44.
[8] Macklis JD. (2001) New memories from new neurons. Nature 314-317.
[9] Van Praag H, Schinder AF, Christie BR et al. (2002) Functional neurogenesis in the adult hippocampus. Nature 2002: 415: 1030-1034.
[10]Kornack DR and Rakic P. (2001) Cell proliferation without neurogenesis in adult primate neocortex. Science 294: 2127-2130.
[11]Magavi SS, Leavitt BR, Macklis JD. (2000) Induction of neurogenesis in the neocortex of adult mice. Nature 405: 951-955.
[12] Gould E, Reeves AJ, Graziano MS, Gross CG. (1999) Science 286: 548-552.
[13]Horner PJ, Gage FH. (2000) Regenerating the damaged central nervous system. Nature 407: 963-970.
[14]Shors TJ, Miesegaes G, Beylin A et al. (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410: 372-376.
[15] Altaian J (1969). Autoradiographic and histological studies of postnatal neurogenesis: IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 137: 433-458.
[16] Lois and Alvarez-Buylla A. (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264: 1145-1148.
[17] Lois C, Garcia-Verdugo JM, Alvarez-Buylla A.(1996) Chain migration of neuronal precursors. Science 271:978-981.
[18]Gheusi G, Cremer H, McLean H, et al. (2000) Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc Natl Acad Sci U S A 97: 1823-1828.
[19]Raineteau O, Rietschin L, Gradwohl G, Guillemot F and Gahwiler BH. (2004) Neurogenesis in hippocampal slice cultures. Mol Cell Neurosci 26 (2): 241-50.
[20] Dam M, Tonin P, De Boni A, Pizzolato G, Casson S, Ermani M, Freo U, Piron L, Battistin L. 1996. Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke 27: 1211-1214.
[21] Morris RG, Garrud P, Rawlins JN, O'keefe J. 1982. Place navigation impaired in rats with hippocampal lesions. Nature 297: 681-683.
[22] Squire LR. 1992. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99: 195-231.
[23]Tsien JZ, Huerta PT, Tonegawa S. 1996. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87: 1327-1338.
[24]Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN. 2003. Spatial memory performance of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci U S A 100: 14385-14390.
[25]Kempermann G, Kuhn HG, Gage FH. 1997. More hippocampal neurons in adult mice living in an enriched environment. Nature 386: 493-495.
[26] Kuhn HG, Dickinson-Anson H, Gage FH. (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027-2033.
[27] Perfilieva E, Risedal A, Nyberg J, et al. (2001) Gender and strain influence on neurogenesis in dentate gyros of young rats. J Cereb Blood Flow Metab 21: 211-217.
[28] Jin K, Minami M, Lan JQ, et al. (2001) Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci USA 98:4710-4715.
[29] Liu J, Solway K, Messing RO, et al. (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci, 18: 7768-7778.
[30]Tham TN, Lazarini F, Franceschini IA, et al. (2001) Developmental pattern of expression of the alpha chemokine stromal cell-derived factor 1 in the rat central nervous system. Eur J Neurosci 13: 845-856.
[31]Nacher J, Rosell D, Alonso2Llosa G, et al. (2001) NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci 13: 512-520.
[32]Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104-10.
[33]Brezun JM, Daszuta A (1999) Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89: 999-1002.
[34] Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805-9.
[35]Sairanen M, Lucas G, Ernfors P, Castren M, Castren E. 2005. Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25: 1089-1094.
[36]Horsfield SA, Rosse RB, Tomasino V, Schwartz BL, Mastropaolo J, Deutsch SI. 2002. Fluoxetine's effects on cognitive performance in patients with traumatic brain injury. Int J Psychiatry Med 32: 337-344.
[37]Tiraboschi E, Tardito D, Kasahara J, Moraschi S, Pruneri P, Gennarelli M, Racagni G, Popoli M. 2004. Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. Neuropsychopharmacology 29:1831-1840.
[38]Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW. 2000. Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 101: 305-312.
[39]Tamura A, Graham D I, McCulloch J, et al. Focal cerebral ischemia in the rat: 1. Descrip tion of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab, 1981,1: 53260.
[40] 程明,朱熊兆. 学习记忆的行为学研究方法. 中国行为医学科学, 2005,14: 65266.
[41]Z Longa EZ,Weinstein PR, Carlson S, et al. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke, 1989, 20: 84291.
[42]Kollmar R, SchabitzWR, Heiland S, et al. Neurop rotective effect of delayed moderate hypothermia after focal cerebral ischemia: anMR I study. Stroke, 2002, 33: 189921904.
[43]TamuraM, Aoki Y, Seto T, et al. Cerebrop rotective action of a Na + /Ca2 + channel blockerNS27. II. Effect on the cerebral infarction, behavioral and cognitive impairments at the chronic stage of permanent middle cerebral artery occlusion in rats. Brain Res, 2001, 890: 1702176.
[44] Aoki Y, TamuraM, Itoh Y, et al. Cerebrop rotective action of a Na+ /Ca2+ channel blockerNS27. I. Effect on the cerebral infarction and edema at the acute stage of permanentmiddle cerebral artery occlusion in rats. Brain Res, 2001, 890: 1622169.
[45] Sun YJ, Jin KL, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA. 2003. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 11:1843-1851.
[46]Takasawa K, Kitagawa K, Yagita Y, Sasaki T, Tanaka S, Matsushita K, Ohstuki T, Miyata T, Okano H, Hori M, Matsumoto M. 2002. Increased proliferation of neural progenitor cells but reduced survival of newborn cells in the contralateral hippocampus after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 22:299-307.
[47] Jolkkonen J, Puurunen K, Rantakomi S, Sirvio J, Haapalinna A, Sivenius J. 2000. Effects-of fluoxetine on sensorimotor and spatial learning deficits following focal cerebral ischemia in rats. Restor Neurol Neurosci 17: 211-216.
[48]Zhao CS, Puurunen K, Schallert T, Sivenius J, Jolkkonen J. 2005. Behavioral and histological effects of chronic antipsychotic and antidepressant drug treatment in aged rats with focal ischemic brain injury. Behav Brain Res 158: 211-220.
[49] Windle V, Corbett D. 2005. Fluoxetine and recovery of motor function after focal ischemia in rats. Brain Res 1044: 25-32.
[50] Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M. 2001. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32: 1005-1011.
[51]Gibson CL, Bath PM, Murphy SP. 2005. G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 25: 431-439.
[52] Morris R. 1984. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11: 47-60.
[53]Zhu DY, Liu SH, Sun HS, Lu YM. 2003. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J Neurosci 23: 223-229.
[54] Cipriani A, Brambilla P, Furukawa T, Geddes J, Gregis M, Hotopf M, Malvini L, Barbui C. 2005. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev 4: CD004185.
[55]Pariente J, Loubinoux I, Carel C, Albucher JF, Leger A, Manelfe C, Rascol O, Chollet F. 2001. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann Neurol 50: 718-729.
[56] Chang YC, Tzeng SF, Yu L, Huang AM, Lee HT, Huang CC, Ho CJ. 2006. Early-life fluoxetine exposure reduced functional deficits after hypoxic-ischemia brain injury in rat pups. Neurobiol Dis 24 : 101-113.
[57]Mowla A, Mosavinasab M, Pani A. 2007. Does fluoxetine have any effect on the cognition of patients with mild cognitive impairment? A double-blind, placebo-controlled, clinical trial. J Clin Psychopharmacol 27: 67-70.
[58]Raber J, Fan Y, Matsumori Y, Liu Z, Weinstein PR, Fike JR, Liu J. 2004. Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. Ann Neurol 55: 381-389.
[59] Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L, Weinstein PR, Liu J. 2007. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 38: 146-152.
[60]Luo CX, Jiang J, Zhou QG, Zhu XJ, Wang W, Zhang ZJ, Han X, Zhu DY. 2007. Voluntary exercise-induced neurogenesis in the postischemic dentate gyrus is associated with spatial memory recovery from stroke. J Neurosci Res 85: 1637-1646.
[61]Chiou SH, Chen SJ, Peng CH, Chang YL, Ku HH, Hsu WM, Ho LL, Lee CH. 2006. Fluoxetine up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-induced apoptosis in hippocampus-derived neural stem cell. Biochem Biophys Res Commun 343: 391-400.
[62] Chen H, Pandey G N and Dwivedi Y. 2006. Hippocampal cell proliferation regulation by repeated stress and antidepressants. Neuroreport 17: 863-867.
[63]Dranovsky A and Hen R. 2006. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol. Psychiatry 59: 1136-1143.
[64]Robinson RG. 1998. Treatment issues in poststroke depression. Depress Anxiety 8: 85-90.
[65] Endres M, Gertz K, Lindauer U, Katchanov J, Schultze J, Schrock H, Nickenig G, Kuschinsky W, Dirnagl U, Laufs U. 2003. Mechanisms of stroke protection by physical activity. Ann Neurol 54: 582-590.
[66] Malberg JE, Duman RS. 2003. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28: 1562-1571.
[67] van Praag H, Christie BR, Sejnowski TJ, Gage FH. 1999. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A. 96:13427-13431.
[68] Lee TH, Yang JT, Kato H, Wu JH, Chen ST. 2004. Expression of brain-derived neurotrophic factor immunoreactivity and mRNA in the hippocampal CA1 and cortical areas after chronic ischemia in rats.J Neurosci Res. 76:705-712.
[69] Choi YS, Cho KO, Kim SY. 2007.Fluoxetine does not affect the ischemia-induced increase of neurogenesis in the adult rat dentate gyrus. Arch PharmRes.30:641-645.
[70]Lonze and Ginty, 2002; Lonze BE, Ginty DD. 2002. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35: 605-623.
[71]Mizuno K, Giese KP. 2005. Hippocampus-dependent memory formation: do memory type-specific mechanisms exist? J Pharmacol Sci 98: 191-197.
[72]Nakagawa S, Kim J-E, Lee R, Malberg JE, Chen J, Steffen C, Zhang Y-J, Nestler EJ, Duman RS. 2002. Regulation of neurogenesis in adult mouse hippocampus by cAMP and cAMP response element-binding protein. J Neurosci 22: 3673-3682.
[73]Zhu DY, Lau L, Liu SH, Wei JS, Lu YM. 2004. Activation of cAMP-response element-binding protein (CREB) after focal cerebral ischemia stimulates neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 101: 9453-9457.
[74] Dowlatshahi D, MacQueen GM, Wang JF, Young LT. 1998. Increased temporal cortex CREB concentrations and antidepressant treatment in major depression. Lancet 352: 1754-1755.
[75] Kim do H, Li H, Yoo KY, Lee BH, Hwang IK, Won MH. 2007. Effects of fluoxetine on ischemic cells and expressions in BDNF and some antioxidants in the gerbil hippocampal CA1 region induced by transient ischemia. Exp Neurol 204: 748-758.
[76]Abdel-Salam OM, Baiuomy AR, Arbid MS. 2004. Studies on the anti-inflammatory effect of fluoxetine in the rat. Pharmacol Res 49: 119-131.
[77] Kwon YT ,Balogh SA ,Davydov IV ,et al . Altered activity ,social behavior ,and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the N-end rule pathway.Mol CellBiol ,2000 ,20 :413 524148.
[78]Kioyta Y,Miyamoto M,Nagaoka A ,et al. Cercbralembolization leads to memery impairment of several learning task in rats. Pharmacol Biochem Behav , 1986,24:687.
1.Benveniste M and Dingledine R.(2005)Limiting stroke-induced damage by targeting and acid channel.N.Engl.J.Med 352:85-86.
2.Altman J.(1962)Are neurons formed in the brains of adult mammals? Science 135:1127-1128.
3. Rakic P. (1985) Limits of neurogenesis in primates. Science 227,1054-1056.
4. Horner P.J and Gage F.H. (2000) Regenerating the damaged central nervous system. Nature 407: 963-970.
5. Temple S. (2001) The develompment of neural stem cells. Nature 414: 112-117.
6. Gage FH. (2002) Mammalian neural stem cells. Science 287: 1433-1438.
7. Song H, Stevens CF, Gage FH. (2002) Astroglia induce neurogenesis from adult neural stem cells. Nature 417: 39-44
8. Macklis JD. (2001) New memories from new neurons. Nature 314-317.
9. Nakatomi H, Kuriu T, Okabe S, et al. (2002) Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110: 429-441.
10. Van Praag H, Schinder AF, Christie BR et al. (2002) Functional neurogenesis in the adult hippocampus. Nature 2002: 415: 1030-1034.
11. Kornack DR and Rakic P. (2001) Cell proliferation without neurogenesis in adult primate neocortex. Science 294: 2127-2130.
12. Magavi SS, Leavitt BR, Macklis JD. (2000) Induction of neurogenesis in the neocortex of adult mice. Nature 405: 951-955.
13. Gould E, Reeves AJ, Graziano MS, Gross CG. (1999) Science 286: 548-552.
14. Horner PJ, Gage FH. (2000) Regenerating the damaged central nervous system. Nature 407: 963-970.
15. Shors TJ, Miesegaes G, Beylin A et al. (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410: 372-376.
16. Altaian J (1969) . Autoradiographic and histological studies of postnatal neurogenesis: IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 137:433-458
17. Lois and Alvarez-Buylla A. (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264: 1145-1148.
18. Lois C, Garcia-Verdugo JM, Alvarez-Buylla A. (1996) Chain migration of neuronal precursors. Science 271:978-981.
19. Peretto P, Merighi A, Fasolo A, et al. (1997) Glial tubes in the rostral migratory stream of the adult rat. Brain Res Bull 42:9-21.
20. Bonfanti L, Theodosis DT. (1994) Expression of polysialylated neural cell adhesion molecule by proliferating cells in the subependymal layer of the adult rat, in its rostral extension and in the olfactory bulb. Neuroscience 62: 291-305.
21. Doetsch F, Caille I, Lim DA, et al. (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703-716.
22. Gleeson JG, Lin PT, Flanagan LA, et al. ( 1999 ) Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23: 257-271.
23. Gheusi G, Cremer H, McLean H, et al. (2000) Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc Natl Acad Sci U S A 97: 1823-1828.
24. Kaplan MS, Hinds JW. (1977) Neurogenesis in adult rat: electron microscopic analysis of light radioautographs. Science 197: 1092-1094.
25. Cameron HA, Woolley CS, McEwen BS, Gould E. (1993) Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56: 337-344.
26. Kuhn HG, Dickinson-Anson H, Gage FH. (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027-2033.
27. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn A, Nordborg C, Peterson DA, and others. (1998) Neurogenesis in the adult human hippocampus. Nature Med 4: 1313-1317.
28. Stanfield BB, Trice JE. (1988) Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Exp Brain Res 72: 399-406.
29. Markakis EA, Gage FH. (1999) Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vesicles. J Comp Neurol 406: 449-460.
30. Raineteau O, Rietschin L, Gradwohl G, Guillemot F and Gahwiler BH. (2004) Neurogenesis in hippocampal slice cultures. Mol Cell Neurosci 26 (2) : 241-50.
31.Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E. (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410: 372-376.
32. Johe, K.K., Hazel, T.G., Muller, T., Dugich-Djordjevic, MM, McKay, R.D., 1996. Single factors direct the differentiation of stemcells fromthe fetal and adult central nervous system. Genes Dev. 10, 3129-3140.
33. Nguyen, L., Besson, A., Roberts, J.M., Guillemot, F., 2006. Coupling cell cycle exit, neuronal differentiation and migration in cortical neurogenesis. Cell Cycle 5, 2314-2318.
34. Herrera, D.G., Yague, A.G., Johnsen-Soriano, S., Bosch-Morell, F., Collado-Morente, L., Muriach, M, Romero, F.J., Garcia-Verdugo, J.M., 2003. Selective impairment of hippocampal neurogenesis by chronic alcoholism: protective effects of an antioxidant. Proc. Natl. Acad. Sci. U.S.A. 100, 7919-7924.
35. Gould, E., McEwen, B.S., Tanapat, P., Galea, L.A., Fuchs, E., 1997. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 2492-2498.
36. Malberg, J.E., Eisch, A.J., Nestler, E.J., Duman, R.S., 2000. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104-9110.
37. Dranovsky, A., Hen, R., 2006. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol. Psychiatry 59, 1136-1143.
38. Powrozek, T.A., Sari, Y, Singh, R.P., Zhou, F.C., 2004. Neurotransmitters and substances of abuse: effects on adult neurogenesis. Curr. Neurovasc. Res. 1, 251-260.
39. Mirescu, C, Peters, J.D., Gould, E., 2004. Early life experience alters response of adult neurogenesis to stress. Nat. Neurosci. 7, 841-846.
40. Hauser, K.F., Houdi, A.A., Turbek, C.S., Elde, R.P.,Maxson,W., 2000. Opioids intrinsically inhibit the genesis of mouse cerebellar granule neuron precursors in vitro: differential impact of mu and delta receptor activation on proliferation and neurite elongation. Eur. J. Neurosci. 12, 1281-1293.
41.Beauquis, J., Roig, P., Homo-Delarche, F., De Nicola, A., Saravia, F., 2006.Reduced hippocampal neurogenesis and number of hilar neurones in streptozotocin-induced diabetic mice: reversion by antidepressant treatment. Eur. J. Neurosci. 23,1539-1546.
42. Ekdahl, C.T., Claasen, J.H., Bonde, S., Kokaia, Z., Lindvall, O., 2003. Inflammation is detrimental for neurogenesis in adult brain. Proc. Natl. Acad. Sci. U.S.A. 100, 13632-13637.
43. Lindqvist, A., Mohapel, P., Bouter, B., Frielingsdorf, H., Pizzo, D., Brundin, P., Erlanson-Albertsson, C, 2006. High-fat diet impairs hippocampal neurogenesis in male rats. Eur. J. Neurol. 13, 1385-1388.
44. Raber, J., Fan, Y., Matsumori, Y., Liu, Z., Weinstein, P.R., Fike, J.R., Liu, J., 2004. Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. Ann. Neurol. 55,381-389.
45. Van Praag, H., Kempermann, G., Gage, F.H., 1999. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266-270.
46. Gould, E., Beylin, A., Tanapat, P., Reeves, A., Shors, T.J., 1999c. Learning enhances adult neurogenesis in the hippocampal formation. Nat. Neurosci. 2, 260-265.
47. Nakatomi, H., Kuriu, T., Okabe, S., Yamamoto, S., Hatano, O., Kawahara, N., Tamura, A., Kirino, T., Nakafuku, M., 2002. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110, 429-441.
48. Lichtenwalner, R.J., Parent, J.M., 2006. Adult neurogenesis and the ischemic forebrain. J. Cereb. Blood Flow Metab. 26,1-20.
49. Lee, J., Seroogy, K.B., Mattson, M.P., 2002. Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice. J. Neurochem. 80, 539-547.
50. Komitova, M., Perfilieva, E., Mattsson, B., Eriksson, P.S., Johansson, B.B., 2002. Effects of cortical ischemia and postischemic environmental enrichment on Hippocampal cell genesis and differentiation in the adult rat. J. Cereb. Blood Flow Metab. 22, 852-860.
51.Naylor, M., Bowen, K.K., Sailor, K.A., Dempsey, R.J., Vemuganti, R., 2005. Preconditioning-induced ischemic tolerance stimulates growth factor expression and neurogenesis in adult rat hippocampus. Neurochem. Int. 47, 565-572.
52. Imai, F., Suzuki, H., Oda, J., Ninomiya, T., Ono, K., Sano, H., Sawada, M., 2007. Neuroprotective effect of exogenous microglia in global brain ischemia. J. Cereb. Blood Flow Metab. 27,488-500.
53. Tonchev, A.B., Yamashima, T., Guo, J., Chaldakov, G.N., Takakura, N., 2007. Expression of angiogenic and neurotrophic factors in the progenitor cell niche of adult monkey subventricular zone. Neuroscience 144,1425-1435.
54. Jin, K., Wang, X., Xie, L., Mao, X.O., Zhu, W., Wang, Y., Shen, J., Mao, Y., Banwait, S., Greenberg, D.A., 2006. Evidence for stroke-induced neurogenesis in the human brain. Proc. Natl. Acad. Sci. U.S.A. 103,13198-13202.
55. Tonchev, A.B., Yamashima, T., Zhao, L., Okano, H.J., Okano, H., 2003. Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol. Cell Neurosci. 23,292-301.
56. Iwai,M., Sato, K., Omori, N., Nagano, I.,Manabe, Y., Shoji,M., Abe, K., 2002. Three steps of neural stem cells development in gerbil dentate gyrus after transient ischemia. J. Cereb. Blood Flow Metab. 22,411-419.
57. Liu, J., Bartels, M., Lu, A., Sharp, F.R., 2001. Microglia/macrophages proliferate in striatum and neocortex but not in hippocampus after brief global ischemia that produces ischemic tolerance in gerbil brain. J. Cereb. Blood Flow Metab. 21, 361-373.
58. Iwai,M., Sato, K., Kamada, H., Omori, N., Nagano, I., Shoji,M., Abe, K., 2003. Temporal profile of stem cell division, migration, and differentiation from subventricular zone to olfactory bulb after transient forebrain ischemia in gerbils. J. Cereb. Blood Flow Metab. 23, 331-341.
59. Dempsey, R.J., Sailor, K.A., Bowen, K.K., Tureyen, K., Vemuganti, R., 2003. Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-1 and GDNF. J. Neurochem. 87, 586-597.
60. Zhu, D.Y., Liu, S.H., Sun, H.S., Lu, Y.M., 2003. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J. Neurosci. 23, 223-229.
61. Gould, E., Reeves, A.J., Graziano, M.S., Gross, C.G., 1999. Neurogenesis in the neocortex of adult primates. Science 286, 548-552.
62. Rakic, P., 2002. Neurogenesis in adult primate neocortex: an evaluation of the evidence. Nat. Rev. Neurosci. 3, 65-71.
63. Arvidsson, A., Kokaia, Z., Lindvall, O., 2001. N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur. J. Neurosci. 14, 10-18.
64. Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z., Lindvall, O., 2002. Neuronal replacement fromendogenous precursors in the adult brain after stroke. Nat. Med. 8, 963-970.
65. Jin, K., Sun, Y., Xie, L., Peel, A.,Mao, X.O., Batteur, S., Greenberg, D.A., 2003. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol. Cell. Neurosci. 24, 171-189.
66. Parent, J.M., Vexler, Z.S., Gong, C., Derugin, N., Ferriero, D.M., 2002. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann. Neurol. 52, 802-813.
67. Lin, T.N., Te, J., Lee, M., Sun, G.Y., Hsu, C.Y., 1997. Induction of basic fibroblast growth factor bFGF. expression following focal cerebral ischemia. Brain Res. Mol. Brain Res. 49, 255-265.
68. Yoshimura, S., Takagi, Y., Harada, J., Teramoto, T., Thomas, S.S., Waeber, C., Bakowska, J.C., Breakefield, X.O., Moskowitz, M.A., 2001. FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc. Natl. Acad. Sci. U.S.A. 98, 5874-5879.
69. Leker, R.R., Soldner, F., Velasco, I., Gavin, D.K., Androutsellis-Theotokis, A., McKay, R.D., 2007. Long-lasting regeneration after ischemia in the cerebral cortex. Stroke 38, 153-161.
70. Ninomiya, M., Yamashita, T., Araki, N., Okano, H., Sawamoto, K., 2006 Enhanced neurogenesis in the ischemic striatum following EGF-induced expansion of transit-amplifying cells in the subventricular zone. Neurosci Lett. 403, 63-67.
71. Jin, K.,Mao, X.O., Sun, Y., Xie, L., Jin, L., Nishi, E., Klagsbrun,M., Greenberg, D.A., 2002. Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo. J. Neurosci. 22, 5365-5373.
72. Jin, K., Mao, X.O., Sun, Y., Xie, L., Greenberg, D.A., 2002. Stem cell factor stimulates neurogenesis in vitro and in vivo. J. Clin. Invest. 110, 311-319.
73. Sugiura, S., Kitagawa, K., Tanaka, S., Todo, K., Omura-Matsuoka, E., Sasaki, T., Mabuchi, T., Matsushita, K., Yagita, Y., Hori, M., 2005. Adenovirus-mediated gene transfer of heparin-binding epidermal growth factor-like growth factor enhances neurogenesis and angiogenesis after focal cerebral ischemia in rats. Stroke 36, 859-864.
74. Nakatomi, H., Kuriu, T., Okabe, S., Yamamoto, S., Hatano, O., Kawahara, N., Tamura, A., Kirino, T., Nakafuku, M., 2002. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110, 429-441.
75. Wang, L., Zhang, Z.,Wang, Y., Zhang, R., Chopp,M., 2004. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35,1732-1737.
76. Jin, K., Zhu, Y., Sun, Y., Mao, X.O., Xie, L., Greenberg, D.A., 2002. Vascular endothelial growth factor VEGF stimulates neurogenesis in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 99,11946-11950.
77. Nygren, J., Kokaia, M., Wieloch, T., 2006. Decreased expression of brain-derived neurotrophic factor in BDNF+/~L .Mice is associated with enhanced recovery of motor performance and increased neuroblast number following experimental stroke. J. Neurosci. Res. 84, 626-631.
78. Chen, J., Zacharek, A., Zhang, C., Jiang, H., Li, Y., Roberts, C., Lu, M., Kapke, A., Chopp, M., 2005. Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J. Neurosci. 25, 2366-2375.
79. Tsai, P.T., Ohab, J.J., Kertesz, N., Groszer, M., Matter, C., Gao, J., Liu, X.,Wu, H., Carmichael, S.T., 2006. A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J. Neurosci. 26, 1269-1274.
80. Wang, Y., Jin, K., Mao, X.O., Xie, L., Banwait, S., Marti, H.H., Greenberg, D.A., 2007. VEGF-overexpressing transgenic mice show enhanced post-ischemic neurogenesis and neuromigration. J. Neurosci. Res. 85, 740-747.
81. Yan, Y.P., Sailor, K.A., Vemuganti, R., Dempsey, R.J., 2006. Insulin-like growth factor-1 is an endogenous mediator of focal ischemia-induced neural progenitor proliferation. Eur. J. Neurosci. 24,45-54.
82. Kalluri, H.S., Vemuganti, R., Dempsey, R.J., 2007. Mechanism of insulin-like growth factor I-mediated proliferation of adult neural progenitor cells, role of Akt. Eur. J. Neurosci. 25,1041-1048.
83. Zhang R, Zhang L, Zhang Z, Wang Y, Lu M, Lapointe M, Chopp M .2001. A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol 50:602-611
84. Sun, Y., Jin, K., Childs, J.T., Xie, L., Mao, X.O., Greenberg, D.A., 2005. Neuronal nitric oxide synthase and ischemia-induced neurogenesis. J. Cereb. Blood Flow Metab. 25, 485-492.
85. Cameron, H.A., Hazel, T.G.,Mckay, R.D., 1998. Regulation of neurogenesis by growth factors and neurotransmtters. J. Neuorobiol. 30,287-306.
86. Nacher, J., Alonso-Llosa, G., Rosell, D.R., McEwen, B.S., 2003. NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol. Aging 24,273-284.
87. Borta, A., Hoglinger, G.U., 2007. Dopamine and adult neurogenesis. J. Neurochem. 100,587-595.
88. Kotani, S., Yamauchi, T., Teramoto, T., Ogura, H., 2006. Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats. Neuroscience 142, 505-514.
89. Kluska, M.M., Witte, O.W., Bolz, J., Redecker, C., 2005. Neurogenesis in the adult dentate gyrus after cortical infarcts: effects of infarct location N-methyl-D-aspartate receptor blockade and anti-inflammatory treatment. Neuroscience 135, 723-735.
90. Suzuki, S., Gerhold, L.M., Bottner,M., Rau, S.W., Dela Cruz, C., Yang, E., Zhu, H., Yu, J., Cashion, A.B., Kindy, M.S., Merchenthaler, I., Gage, F.H.,Wise, P.M., 2007. Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta. J. Comp. Neurol. 500, 1064-1075.
91. Louissaint, A., Rao, S., Leventhal, C., Goldman SA, 2002. Coordinaed interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34, 945-960.
92. Brannvall, K., Bogdanovic, N., Korhonen, L., Lindholm, D., 2005. 19-Nortestosterone influences neural stem cell proliferation and neurogenesis in the rat brain. Eur. J. Neurosci. 21 (4) , 871-878.
93. Miyashita, K., Itoh, H., Arai, H., Suganami, T., Sawada, N., Fukunaga, Y., Sone, M., Yamahara, K., Yurugu-Kobayashi, T., Park, K., Oyamada, N., Sawada, N., Taura, D., Tsujimoto, H., Chao, T.H., Tamura, N., Mukoyama, M., Nakao, K., 2006. The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential. Endocrionology 147, 1642-1653.
94. Monje, M.L., Toda, H., Palmer, T.D., 2003. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760-1765.
95. Liu, Z., Fan, Y.,Won, S.J., Neumann,M., Hu, D., Zhou, L.,Weinstein, P.R., Liu, J., 2007. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 38, 146-152.
96. Rahpeymai, Y., Hietala, M.A., Wilhelmsson, U., Fotheringham, A., Davies, I., Nilsson, A.K., Zwirner, J., Wetsel, R.A., Gerard, C, Pekny, M., Pekna, M., 2006. Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 25,1364-1374.
[2] Tatemichi TK, Desmond DW, Mayeux R, et al. Dementia after stroke: baseline frequency, risks, and clinical features in a hosp italized cohort. Neurology, 1992, 42:1185293.
[3] Hagek VE. Brief assessment of cognitive impairment in patients with stroke. Arch physMed. Rehabic, 1989, 70: 114.
[4] Asplund K, Stegmayr B, Pelltonen M. 1998. From the twentieth to the twenty-first century: A public health perspective on stroke. In: Ginsberg MD, Bogousslavsky J (Eds). Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management. Blackwell Science, Maiden, MA, p901-908.
[5] Temple S. (2001) The develompment of neural stem cells. Nature 414: 112-117.
[6] Gage FH. (2002) Mammalian neural stem cells. Science 287:1433-1438.
[7] Song H, Stevens CF, Gage FH. (2002) Astroglia induce neurogenesis from adult neural stem cells. Nature 417: 39-44.
[8] Macklis JD. (2001) New memories from new neurons. Nature 314-317.
[9] Van Praag H, Schinder AF, Christie BR et al. (2002) Functional neurogenesis in the adult hippocampus. Nature 2002: 415: 1030-1034.
[10]Kornack DR and Rakic P. (2001) Cell proliferation without neurogenesis in adult primate neocortex. Science 294: 2127-2130.
[11]Magavi SS, Leavitt BR, Macklis JD. (2000) Induction of neurogenesis in the neocortex of adult mice. Nature 405: 951-955.
[12] Gould E, Reeves AJ, Graziano MS, Gross CG. (1999) Science 286: 548-552.
[13]Horner PJ, Gage FH. (2000) Regenerating the damaged central nervous system. Nature 407: 963-970.
[14]Shors TJ, Miesegaes G, Beylin A et al. (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410: 372-376.
[15] Altaian J (1969). Autoradiographic and histological studies of postnatal neurogenesis: IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 137: 433-458.
[16] Lois and Alvarez-Buylla A. (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264: 1145-1148.
[17] Lois C, Garcia-Verdugo JM, Alvarez-Buylla A.(1996) Chain migration of neuronal precursors. Science 271:978-981.
[18]Gheusi G, Cremer H, McLean H, et al. (2000) Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc Natl Acad Sci U S A 97: 1823-1828.
[19]Raineteau O, Rietschin L, Gradwohl G, Guillemot F and Gahwiler BH. (2004) Neurogenesis in hippocampal slice cultures. Mol Cell Neurosci 26 (2): 241-50.
[20] Dam M, Tonin P, De Boni A, Pizzolato G, Casson S, Ermani M, Freo U, Piron L, Battistin L. 1996. Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke 27: 1211-1214.
[21] Morris RG, Garrud P, Rawlins JN, O'keefe J. 1982. Place navigation impaired in rats with hippocampal lesions. Nature 297: 681-683.
[22] Squire LR. 1992. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99: 195-231.
[23]Tsien JZ, Huerta PT, Tonegawa S. 1996. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87: 1327-1338.
[24]Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN. 2003. Spatial memory performance of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci U S A 100: 14385-14390.
[25]Kempermann G, Kuhn HG, Gage FH. 1997. More hippocampal neurons in adult mice living in an enriched environment. Nature 386: 493-495.
[26] Kuhn HG, Dickinson-Anson H, Gage FH. (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027-2033.
[27] Perfilieva E, Risedal A, Nyberg J, et al. (2001) Gender and strain influence on neurogenesis in dentate gyros of young rats. J Cereb Blood Flow Metab 21: 211-217.
[28] Jin K, Minami M, Lan JQ, et al. (2001) Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci USA 98:4710-4715.
[29] Liu J, Solway K, Messing RO, et al. (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci, 18: 7768-7778.
[30]Tham TN, Lazarini F, Franceschini IA, et al. (2001) Developmental pattern of expression of the alpha chemokine stromal cell-derived factor 1 in the rat central nervous system. Eur J Neurosci 13: 845-856.
[31]Nacher J, Rosell D, Alonso2Llosa G, et al. (2001) NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci 13: 512-520.
[32]Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104-10.
[33]Brezun JM, Daszuta A (1999) Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89: 999-1002.
[34] Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805-9.
[35]Sairanen M, Lucas G, Ernfors P, Castren M, Castren E. 2005. Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25: 1089-1094.
[36]Horsfield SA, Rosse RB, Tomasino V, Schwartz BL, Mastropaolo J, Deutsch SI. 2002. Fluoxetine's effects on cognitive performance in patients with traumatic brain injury. Int J Psychiatry Med 32: 337-344.
[37]Tiraboschi E, Tardito D, Kasahara J, Moraschi S, Pruneri P, Gennarelli M, Racagni G, Popoli M. 2004. Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. Neuropsychopharmacology 29:1831-1840.
[38]Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW. 2000. Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 101: 305-312.
[39]Tamura A, Graham D I, McCulloch J, et al. Focal cerebral ischemia in the rat: 1. Descrip tion of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab, 1981,1: 53260.
[40] 程明,朱熊兆. 学习记忆的行为学研究方法. 中国行为医学科学, 2005,14: 65266.
[41]Z Longa EZ,Weinstein PR, Carlson S, et al. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke, 1989, 20: 84291.
[42]Kollmar R, SchabitzWR, Heiland S, et al. Neurop rotective effect of delayed moderate hypothermia after focal cerebral ischemia: anMR I study. Stroke, 2002, 33: 189921904.
[43]TamuraM, Aoki Y, Seto T, et al. Cerebrop rotective action of a Na + /Ca2 + channel blockerNS27. II. Effect on the cerebral infarction, behavioral and cognitive impairments at the chronic stage of permanent middle cerebral artery occlusion in rats. Brain Res, 2001, 890: 1702176.
[44] Aoki Y, TamuraM, Itoh Y, et al. Cerebrop rotective action of a Na+ /Ca2+ channel blockerNS27. I. Effect on the cerebral infarction and edema at the acute stage of permanentmiddle cerebral artery occlusion in rats. Brain Res, 2001, 890: 1622169.
[45] Sun YJ, Jin KL, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA. 2003. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 11:1843-1851.
[46]Takasawa K, Kitagawa K, Yagita Y, Sasaki T, Tanaka S, Matsushita K, Ohstuki T, Miyata T, Okano H, Hori M, Matsumoto M. 2002. Increased proliferation of neural progenitor cells but reduced survival of newborn cells in the contralateral hippocampus after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 22:299-307.
[47] Jolkkonen J, Puurunen K, Rantakomi S, Sirvio J, Haapalinna A, Sivenius J. 2000. Effects-of fluoxetine on sensorimotor and spatial learning deficits following focal cerebral ischemia in rats. Restor Neurol Neurosci 17: 211-216.
[48]Zhao CS, Puurunen K, Schallert T, Sivenius J, Jolkkonen J. 2005. Behavioral and histological effects of chronic antipsychotic and antidepressant drug treatment in aged rats with focal ischemic brain injury. Behav Brain Res 158: 211-220.
[49] Windle V, Corbett D. 2005. Fluoxetine and recovery of motor function after focal ischemia in rats. Brain Res 1044: 25-32.
[50] Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M. 2001. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32: 1005-1011.
[51]Gibson CL, Bath PM, Murphy SP. 2005. G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 25: 431-439.
[52] Morris R. 1984. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11: 47-60.
[53]Zhu DY, Liu SH, Sun HS, Lu YM. 2003. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J Neurosci 23: 223-229.
[54] Cipriani A, Brambilla P, Furukawa T, Geddes J, Gregis M, Hotopf M, Malvini L, Barbui C. 2005. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev 4: CD004185.
[55]Pariente J, Loubinoux I, Carel C, Albucher JF, Leger A, Manelfe C, Rascol O, Chollet F. 2001. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann Neurol 50: 718-729.
[56] Chang YC, Tzeng SF, Yu L, Huang AM, Lee HT, Huang CC, Ho CJ. 2006. Early-life fluoxetine exposure reduced functional deficits after hypoxic-ischemia brain injury in rat pups. Neurobiol Dis 24 : 101-113.
[57]Mowla A, Mosavinasab M, Pani A. 2007. Does fluoxetine have any effect on the cognition of patients with mild cognitive impairment? A double-blind, placebo-controlled, clinical trial. J Clin Psychopharmacol 27: 67-70.
[58]Raber J, Fan Y, Matsumori Y, Liu Z, Weinstein PR, Fike JR, Liu J. 2004. Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. Ann Neurol 55: 381-389.
[59] Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L, Weinstein PR, Liu J. 2007. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 38: 146-152.
[60]Luo CX, Jiang J, Zhou QG, Zhu XJ, Wang W, Zhang ZJ, Han X, Zhu DY. 2007. Voluntary exercise-induced neurogenesis in the postischemic dentate gyrus is associated with spatial memory recovery from stroke. J Neurosci Res 85: 1637-1646.
[61]Chiou SH, Chen SJ, Peng CH, Chang YL, Ku HH, Hsu WM, Ho LL, Lee CH. 2006. Fluoxetine up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-induced apoptosis in hippocampus-derived neural stem cell. Biochem Biophys Res Commun 343: 391-400.
[62] Chen H, Pandey G N and Dwivedi Y. 2006. Hippocampal cell proliferation regulation by repeated stress and antidepressants. Neuroreport 17: 863-867.
[63]Dranovsky A and Hen R. 2006. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol. Psychiatry 59: 1136-1143.
[64]Robinson RG. 1998. Treatment issues in poststroke depression. Depress Anxiety 8: 85-90.
[65] Endres M, Gertz K, Lindauer U, Katchanov J, Schultze J, Schrock H, Nickenig G, Kuschinsky W, Dirnagl U, Laufs U. 2003. Mechanisms of stroke protection by physical activity. Ann Neurol 54: 582-590.
[66] Malberg JE, Duman RS. 2003. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28: 1562-1571.
[67] van Praag H, Christie BR, Sejnowski TJ, Gage FH. 1999. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A. 96:13427-13431.
[68] Lee TH, Yang JT, Kato H, Wu JH, Chen ST. 2004. Expression of brain-derived neurotrophic factor immunoreactivity and mRNA in the hippocampal CA1 and cortical areas after chronic ischemia in rats.J Neurosci Res. 76:705-712.
[69] Choi YS, Cho KO, Kim SY. 2007.Fluoxetine does not affect the ischemia-induced increase of neurogenesis in the adult rat dentate gyrus. Arch PharmRes.30:641-645.
[70]Lonze and Ginty, 2002; Lonze BE, Ginty DD. 2002. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35: 605-623.
[71]Mizuno K, Giese KP. 2005. Hippocampus-dependent memory formation: do memory type-specific mechanisms exist? J Pharmacol Sci 98: 191-197.
[72]Nakagawa S, Kim J-E, Lee R, Malberg JE, Chen J, Steffen C, Zhang Y-J, Nestler EJ, Duman RS. 2002. Regulation of neurogenesis in adult mouse hippocampus by cAMP and cAMP response element-binding protein. J Neurosci 22: 3673-3682.
[73]Zhu DY, Lau L, Liu SH, Wei JS, Lu YM. 2004. Activation of cAMP-response element-binding protein (CREB) after focal cerebral ischemia stimulates neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 101: 9453-9457.
[74] Dowlatshahi D, MacQueen GM, Wang JF, Young LT. 1998. Increased temporal cortex CREB concentrations and antidepressant treatment in major depression. Lancet 352: 1754-1755.
[75] Kim do H, Li H, Yoo KY, Lee BH, Hwang IK, Won MH. 2007. Effects of fluoxetine on ischemic cells and expressions in BDNF and some antioxidants in the gerbil hippocampal CA1 region induced by transient ischemia. Exp Neurol 204: 748-758.
[76]Abdel-Salam OM, Baiuomy AR, Arbid MS. 2004. Studies on the anti-inflammatory effect of fluoxetine in the rat. Pharmacol Res 49: 119-131.
[77] Kwon YT ,Balogh SA ,Davydov IV ,et al . Altered activity ,social behavior ,and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the N-end rule pathway.Mol CellBiol ,2000 ,20 :413 524148.
[78]Kioyta Y,Miyamoto M,Nagaoka A ,et al. Cercbralembolization leads to memery impairment of several learning task in rats. Pharmacol Biochem Behav , 1986,24:687.
1.Benveniste M and Dingledine R.(2005)Limiting stroke-induced damage by targeting and acid channel.N.Engl.J.Med 352:85-86.
2.Altman J.(1962)Are neurons formed in the brains of adult mammals? Science 135:1127-1128.
3. Rakic P. (1985) Limits of neurogenesis in primates. Science 227,1054-1056.
4. Horner P.J and Gage F.H. (2000) Regenerating the damaged central nervous system. Nature 407: 963-970.
5. Temple S. (2001) The develompment of neural stem cells. Nature 414: 112-117.
6. Gage FH. (2002) Mammalian neural stem cells. Science 287: 1433-1438.
7. Song H, Stevens CF, Gage FH. (2002) Astroglia induce neurogenesis from adult neural stem cells. Nature 417: 39-44
8. Macklis JD. (2001) New memories from new neurons. Nature 314-317.
9. Nakatomi H, Kuriu T, Okabe S, et al. (2002) Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110: 429-441.
10. Van Praag H, Schinder AF, Christie BR et al. (2002) Functional neurogenesis in the adult hippocampus. Nature 2002: 415: 1030-1034.
11. Kornack DR and Rakic P. (2001) Cell proliferation without neurogenesis in adult primate neocortex. Science 294: 2127-2130.
12. Magavi SS, Leavitt BR, Macklis JD. (2000) Induction of neurogenesis in the neocortex of adult mice. Nature 405: 951-955.
13. Gould E, Reeves AJ, Graziano MS, Gross CG. (1999) Science 286: 548-552.
14. Horner PJ, Gage FH. (2000) Regenerating the damaged central nervous system. Nature 407: 963-970.
15. Shors TJ, Miesegaes G, Beylin A et al. (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410: 372-376.
16. Altaian J (1969) . Autoradiographic and histological studies of postnatal neurogenesis: IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 137:433-458
17. Lois and Alvarez-Buylla A. (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264: 1145-1148.
18. Lois C, Garcia-Verdugo JM, Alvarez-Buylla A. (1996) Chain migration of neuronal precursors. Science 271:978-981.
19. Peretto P, Merighi A, Fasolo A, et al. (1997) Glial tubes in the rostral migratory stream of the adult rat. Brain Res Bull 42:9-21.
20. Bonfanti L, Theodosis DT. (1994) Expression of polysialylated neural cell adhesion molecule by proliferating cells in the subependymal layer of the adult rat, in its rostral extension and in the olfactory bulb. Neuroscience 62: 291-305.
21. Doetsch F, Caille I, Lim DA, et al. (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703-716.
22. Gleeson JG, Lin PT, Flanagan LA, et al. ( 1999 ) Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23: 257-271.
23. Gheusi G, Cremer H, McLean H, et al. (2000) Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc Natl Acad Sci U S A 97: 1823-1828.
24. Kaplan MS, Hinds JW. (1977) Neurogenesis in adult rat: electron microscopic analysis of light radioautographs. Science 197: 1092-1094.
25. Cameron HA, Woolley CS, McEwen BS, Gould E. (1993) Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56: 337-344.
26. Kuhn HG, Dickinson-Anson H, Gage FH. (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027-2033.
27. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn A, Nordborg C, Peterson DA, and others. (1998) Neurogenesis in the adult human hippocampus. Nature Med 4: 1313-1317.
28. Stanfield BB, Trice JE. (1988) Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Exp Brain Res 72: 399-406.
29. Markakis EA, Gage FH. (1999) Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vesicles. J Comp Neurol 406: 449-460.
30. Raineteau O, Rietschin L, Gradwohl G, Guillemot F and Gahwiler BH. (2004) Neurogenesis in hippocampal slice cultures. Mol Cell Neurosci 26 (2) : 241-50.
31.Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E. (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410: 372-376.
32. Johe, K.K., Hazel, T.G., Muller, T., Dugich-Djordjevic, MM, McKay, R.D., 1996. Single factors direct the differentiation of stemcells fromthe fetal and adult central nervous system. Genes Dev. 10, 3129-3140.
33. Nguyen, L., Besson, A., Roberts, J.M., Guillemot, F., 2006. Coupling cell cycle exit, neuronal differentiation and migration in cortical neurogenesis. Cell Cycle 5, 2314-2318.
34. Herrera, D.G., Yague, A.G., Johnsen-Soriano, S., Bosch-Morell, F., Collado-Morente, L., Muriach, M, Romero, F.J., Garcia-Verdugo, J.M., 2003. Selective impairment of hippocampal neurogenesis by chronic alcoholism: protective effects of an antioxidant. Proc. Natl. Acad. Sci. U.S.A. 100, 7919-7924.
35. Gould, E., McEwen, B.S., Tanapat, P., Galea, L.A., Fuchs, E., 1997. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 2492-2498.
36. Malberg, J.E., Eisch, A.J., Nestler, E.J., Duman, R.S., 2000. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104-9110.
37. Dranovsky, A., Hen, R., 2006. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol. Psychiatry 59, 1136-1143.
38. Powrozek, T.A., Sari, Y, Singh, R.P., Zhou, F.C., 2004. Neurotransmitters and substances of abuse: effects on adult neurogenesis. Curr. Neurovasc. Res. 1, 251-260.
39. Mirescu, C, Peters, J.D., Gould, E., 2004. Early life experience alters response of adult neurogenesis to stress. Nat. Neurosci. 7, 841-846.
40. Hauser, K.F., Houdi, A.A., Turbek, C.S., Elde, R.P.,Maxson,W., 2000. Opioids intrinsically inhibit the genesis of mouse cerebellar granule neuron precursors in vitro: differential impact of mu and delta receptor activation on proliferation and neurite elongation. Eur. J. Neurosci. 12, 1281-1293.
41.Beauquis, J., Roig, P., Homo-Delarche, F., De Nicola, A., Saravia, F., 2006.Reduced hippocampal neurogenesis and number of hilar neurones in streptozotocin-induced diabetic mice: reversion by antidepressant treatment. Eur. J. Neurosci. 23,1539-1546.
42. Ekdahl, C.T., Claasen, J.H., Bonde, S., Kokaia, Z., Lindvall, O., 2003. Inflammation is detrimental for neurogenesis in adult brain. Proc. Natl. Acad. Sci. U.S.A. 100, 13632-13637.
43. Lindqvist, A., Mohapel, P., Bouter, B., Frielingsdorf, H., Pizzo, D., Brundin, P., Erlanson-Albertsson, C, 2006. High-fat diet impairs hippocampal neurogenesis in male rats. Eur. J. Neurol. 13, 1385-1388.
44. Raber, J., Fan, Y., Matsumori, Y., Liu, Z., Weinstein, P.R., Fike, J.R., Liu, J., 2004. Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. Ann. Neurol. 55,381-389.
45. Van Praag, H., Kempermann, G., Gage, F.H., 1999. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266-270.
46. Gould, E., Beylin, A., Tanapat, P., Reeves, A., Shors, T.J., 1999c. Learning enhances adult neurogenesis in the hippocampal formation. Nat. Neurosci. 2, 260-265.
47. Nakatomi, H., Kuriu, T., Okabe, S., Yamamoto, S., Hatano, O., Kawahara, N., Tamura, A., Kirino, T., Nakafuku, M., 2002. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110, 429-441.
48. Lichtenwalner, R.J., Parent, J.M., 2006. Adult neurogenesis and the ischemic forebrain. J. Cereb. Blood Flow Metab. 26,1-20.
49. Lee, J., Seroogy, K.B., Mattson, M.P., 2002. Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice. J. Neurochem. 80, 539-547.
50. Komitova, M., Perfilieva, E., Mattsson, B., Eriksson, P.S., Johansson, B.B., 2002. Effects of cortical ischemia and postischemic environmental enrichment on Hippocampal cell genesis and differentiation in the adult rat. J. Cereb. Blood Flow Metab. 22, 852-860.
51.Naylor, M., Bowen, K.K., Sailor, K.A., Dempsey, R.J., Vemuganti, R., 2005. Preconditioning-induced ischemic tolerance stimulates growth factor expression and neurogenesis in adult rat hippocampus. Neurochem. Int. 47, 565-572.
52. Imai, F., Suzuki, H., Oda, J., Ninomiya, T., Ono, K., Sano, H., Sawada, M., 2007. Neuroprotective effect of exogenous microglia in global brain ischemia. J. Cereb. Blood Flow Metab. 27,488-500.
53. Tonchev, A.B., Yamashima, T., Guo, J., Chaldakov, G.N., Takakura, N., 2007. Expression of angiogenic and neurotrophic factors in the progenitor cell niche of adult monkey subventricular zone. Neuroscience 144,1425-1435.
54. Jin, K., Wang, X., Xie, L., Mao, X.O., Zhu, W., Wang, Y., Shen, J., Mao, Y., Banwait, S., Greenberg, D.A., 2006. Evidence for stroke-induced neurogenesis in the human brain. Proc. Natl. Acad. Sci. U.S.A. 103,13198-13202.
55. Tonchev, A.B., Yamashima, T., Zhao, L., Okano, H.J., Okano, H., 2003. Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol. Cell Neurosci. 23,292-301.
56. Iwai,M., Sato, K., Omori, N., Nagano, I.,Manabe, Y., Shoji,M., Abe, K., 2002. Three steps of neural stem cells development in gerbil dentate gyrus after transient ischemia. J. Cereb. Blood Flow Metab. 22,411-419.
57. Liu, J., Bartels, M., Lu, A., Sharp, F.R., 2001. Microglia/macrophages proliferate in striatum and neocortex but not in hippocampus after brief global ischemia that produces ischemic tolerance in gerbil brain. J. Cereb. Blood Flow Metab. 21, 361-373.
58. Iwai,M., Sato, K., Kamada, H., Omori, N., Nagano, I., Shoji,M., Abe, K., 2003. Temporal profile of stem cell division, migration, and differentiation from subventricular zone to olfactory bulb after transient forebrain ischemia in gerbils. J. Cereb. Blood Flow Metab. 23, 331-341.
59. Dempsey, R.J., Sailor, K.A., Bowen, K.K., Tureyen, K., Vemuganti, R., 2003. Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-1 and GDNF. J. Neurochem. 87, 586-597.
60. Zhu, D.Y., Liu, S.H., Sun, H.S., Lu, Y.M., 2003. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J. Neurosci. 23, 223-229.
61. Gould, E., Reeves, A.J., Graziano, M.S., Gross, C.G., 1999. Neurogenesis in the neocortex of adult primates. Science 286, 548-552.
62. Rakic, P., 2002. Neurogenesis in adult primate neocortex: an evaluation of the evidence. Nat. Rev. Neurosci. 3, 65-71.
63. Arvidsson, A., Kokaia, Z., Lindvall, O., 2001. N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur. J. Neurosci. 14, 10-18.
64. Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z., Lindvall, O., 2002. Neuronal replacement fromendogenous precursors in the adult brain after stroke. Nat. Med. 8, 963-970.
65. Jin, K., Sun, Y., Xie, L., Peel, A.,Mao, X.O., Batteur, S., Greenberg, D.A., 2003. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol. Cell. Neurosci. 24, 171-189.
66. Parent, J.M., Vexler, Z.S., Gong, C., Derugin, N., Ferriero, D.M., 2002. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann. Neurol. 52, 802-813.
67. Lin, T.N., Te, J., Lee, M., Sun, G.Y., Hsu, C.Y., 1997. Induction of basic fibroblast growth factor bFGF. expression following focal cerebral ischemia. Brain Res. Mol. Brain Res. 49, 255-265.
68. Yoshimura, S., Takagi, Y., Harada, J., Teramoto, T., Thomas, S.S., Waeber, C., Bakowska, J.C., Breakefield, X.O., Moskowitz, M.A., 2001. FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc. Natl. Acad. Sci. U.S.A. 98, 5874-5879.
69. Leker, R.R., Soldner, F., Velasco, I., Gavin, D.K., Androutsellis-Theotokis, A., McKay, R.D., 2007. Long-lasting regeneration after ischemia in the cerebral cortex. Stroke 38, 153-161.
70. Ninomiya, M., Yamashita, T., Araki, N., Okano, H., Sawamoto, K., 2006 Enhanced neurogenesis in the ischemic striatum following EGF-induced expansion of transit-amplifying cells in the subventricular zone. Neurosci Lett. 403, 63-67.
71. Jin, K.,Mao, X.O., Sun, Y., Xie, L., Jin, L., Nishi, E., Klagsbrun,M., Greenberg, D.A., 2002. Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo. J. Neurosci. 22, 5365-5373.
72. Jin, K., Mao, X.O., Sun, Y., Xie, L., Greenberg, D.A., 2002. Stem cell factor stimulates neurogenesis in vitro and in vivo. J. Clin. Invest. 110, 311-319.
73. Sugiura, S., Kitagawa, K., Tanaka, S., Todo, K., Omura-Matsuoka, E., Sasaki, T., Mabuchi, T., Matsushita, K., Yagita, Y., Hori, M., 2005. Adenovirus-mediated gene transfer of heparin-binding epidermal growth factor-like growth factor enhances neurogenesis and angiogenesis after focal cerebral ischemia in rats. Stroke 36, 859-864.
74. Nakatomi, H., Kuriu, T., Okabe, S., Yamamoto, S., Hatano, O., Kawahara, N., Tamura, A., Kirino, T., Nakafuku, M., 2002. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110, 429-441.
75. Wang, L., Zhang, Z.,Wang, Y., Zhang, R., Chopp,M., 2004. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35,1732-1737.
76. Jin, K., Zhu, Y., Sun, Y., Mao, X.O., Xie, L., Greenberg, D.A., 2002. Vascular endothelial growth factor VEGF stimulates neurogenesis in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 99,11946-11950.
77. Nygren, J., Kokaia, M., Wieloch, T., 2006. Decreased expression of brain-derived neurotrophic factor in BDNF+/~L .Mice is associated with enhanced recovery of motor performance and increased neuroblast number following experimental stroke. J. Neurosci. Res. 84, 626-631.
78. Chen, J., Zacharek, A., Zhang, C., Jiang, H., Li, Y., Roberts, C., Lu, M., Kapke, A., Chopp, M., 2005. Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J. Neurosci. 25, 2366-2375.
79. Tsai, P.T., Ohab, J.J., Kertesz, N., Groszer, M., Matter, C., Gao, J., Liu, X.,Wu, H., Carmichael, S.T., 2006. A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J. Neurosci. 26, 1269-1274.
80. Wang, Y., Jin, K., Mao, X.O., Xie, L., Banwait, S., Marti, H.H., Greenberg, D.A., 2007. VEGF-overexpressing transgenic mice show enhanced post-ischemic neurogenesis and neuromigration. J. Neurosci. Res. 85, 740-747.
81. Yan, Y.P., Sailor, K.A., Vemuganti, R., Dempsey, R.J., 2006. Insulin-like growth factor-1 is an endogenous mediator of focal ischemia-induced neural progenitor proliferation. Eur. J. Neurosci. 24,45-54.
82. Kalluri, H.S., Vemuganti, R., Dempsey, R.J., 2007. Mechanism of insulin-like growth factor I-mediated proliferation of adult neural progenitor cells, role of Akt. Eur. J. Neurosci. 25,1041-1048.
83. Zhang R, Zhang L, Zhang Z, Wang Y, Lu M, Lapointe M, Chopp M .2001. A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol 50:602-611
84. Sun, Y., Jin, K., Childs, J.T., Xie, L., Mao, X.O., Greenberg, D.A., 2005. Neuronal nitric oxide synthase and ischemia-induced neurogenesis. J. Cereb. Blood Flow Metab. 25, 485-492.
85. Cameron, H.A., Hazel, T.G.,Mckay, R.D., 1998. Regulation of neurogenesis by growth factors and neurotransmtters. J. Neuorobiol. 30,287-306.
86. Nacher, J., Alonso-Llosa, G., Rosell, D.R., McEwen, B.S., 2003. NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol. Aging 24,273-284.
87. Borta, A., Hoglinger, G.U., 2007. Dopamine and adult neurogenesis. J. Neurochem. 100,587-595.
88. Kotani, S., Yamauchi, T., Teramoto, T., Ogura, H., 2006. Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats. Neuroscience 142, 505-514.
89. Kluska, M.M., Witte, O.W., Bolz, J., Redecker, C., 2005. Neurogenesis in the adult dentate gyrus after cortical infarcts: effects of infarct location N-methyl-D-aspartate receptor blockade and anti-inflammatory treatment. Neuroscience 135, 723-735.
90. Suzuki, S., Gerhold, L.M., Bottner,M., Rau, S.W., Dela Cruz, C., Yang, E., Zhu, H., Yu, J., Cashion, A.B., Kindy, M.S., Merchenthaler, I., Gage, F.H.,Wise, P.M., 2007. Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta. J. Comp. Neurol. 500, 1064-1075.
91. Louissaint, A., Rao, S., Leventhal, C., Goldman SA, 2002. Coordinaed interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34, 945-960.
92. Brannvall, K., Bogdanovic, N., Korhonen, L., Lindholm, D., 2005. 19-Nortestosterone influences neural stem cell proliferation and neurogenesis in the rat brain. Eur. J. Neurosci. 21 (4) , 871-878.
93. Miyashita, K., Itoh, H., Arai, H., Suganami, T., Sawada, N., Fukunaga, Y., Sone, M., Yamahara, K., Yurugu-Kobayashi, T., Park, K., Oyamada, N., Sawada, N., Taura, D., Tsujimoto, H., Chao, T.H., Tamura, N., Mukoyama, M., Nakao, K., 2006. The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential. Endocrionology 147, 1642-1653.
94. Monje, M.L., Toda, H., Palmer, T.D., 2003. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760-1765.
95. Liu, Z., Fan, Y.,Won, S.J., Neumann,M., Hu, D., Zhou, L.,Weinstein, P.R., Liu, J., 2007. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 38, 146-152.
96. Rahpeymai, Y., Hietala, M.A., Wilhelmsson, U., Fotheringham, A., Davies, I., Nilsson, A.K., Zwirner, J., Wetsel, R.A., Gerard, C, Pekny, M., Pekna, M., 2006. Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 25,1364-1374.
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