蛙皮素对下丘脑和马神经元的作用研究
摘要
目的
蛙皮素(Bombesin),是一种脑肠肽,由14个氨基酸残基组成,对饮食和行为具有调节作用。在哺乳动物中,它的同类物有胃泌素释放激素(gastrin-releasing peptide, GRP)和神经介素B(neuromedin B, NMB)。作为一种脑肠肽,蛙皮素对神经系统肿瘤、缺血及学习记忆都具有良性作用。有研究表明在帕金森病人脑内蛙皮素浓度增加,具有内源性抗癫痫作用。此外还有很多实验表明蛙皮素具有神经保护作用。
下丘脑弓形核(arcuate nucleus, ARC),是成年哺乳动物体内能量平衡调节的重要区域。弓形核内的神经肽Y(neuropipte Y, NPY)神经元具有增加饮食的作用。
本论文使用NPY-GFP转基因小鼠,研究蛙皮素对于下丘脑弓形核内NPY神经元的作用及其可能机制。另外,还探索了蛙皮素对于脑缺血引起的大鼠学习记忆障碍的作用及其对于大鼠海马CA1区神经元离子通道的作用,从而进一步提供了蛙皮素神经保护作用的证据。
方法
第一部分：选取NPY-GFP转基因小鼠,NPY神经元中绿色荧光蛋白(green fluorescent protein, GFP)的表达由免疫组织化学和单细胞逆转录PCR(single-cell reverse transcription-PCR)确认。运用全细胞膜片钳技术,研究小鼠下丘脑脑片NPY神经元的电生理特性。首先观察蛙皮素对NPY神经元兴奋性的影响,然后观察蛙皮素对于NPY神经元串联电阻,反转电位的作用,最后在不同内外液条件下观察蛙皮素对NPY神经元的作用,来阐明蛙皮素对NPY神经元的作用机制。除此之外,我们还使用了蛙皮素家族的肽类(NMB和GRP)以及其他与饮食有关的肽类,比较了不同肽类对NPY神经元的作用。最后,还观察了蛙皮素对阿黑皮原(proopiomelanocortin, POMC)神经元的作用,与其对NPY神经元的作用进行比较。
第二部分：选取18只成年Wistar大鼠,随机分成正常组、缺血组和缺血后蛙皮素干预组。用双侧颈总动脉结扎的方法制作大鼠全脑缺血模型,使用Morris水迷宫和长时程增强(long-term potentiation, LTP)记录的方式来研究蛙皮素对缺血引起的学习记忆障碍的作用。然后使用幼年Wistar大鼠,制作海马脑片,用膜片钳中的电压钳技术研究蛙皮素对钠离子通道的作用。
所有实验数据经Student t检验或ANOVA等统计学处理,P<0.05表示存在显著性差异。
结果
1)从弓形核中收获单个GFP阳性神经元后,运用单细胞RT-PCR技术观察GFP阳性神经元中含有NPY编码的mRNA,从而证明NPY-GFP转基因小鼠系建立成功。
2)蛙皮素(250nM)使NPY神经元动作电位频率增加了61.5±14.2%(n=15,P<0.05),使神经元的膜电位去极化5.0±0.5 mV(n=15,P<0.05)。
3)NMB(250nM)使NPY神经元动作电位频率增加66.5±10.6%(n=16,P<0.05),使神经元的膜电位去极化5.6±0.4 mV(n=16,P<0.05).GRP (250nM)使NPY神经元动作电位频率增加9.2±10.5%(n=13,P>0.05),使神经元的膜电位去极化2.6±0.7 mV(n=13,P<0.05).
4)蛙皮素使NPY神经元的输入电阻减少22.4±5.7%(n=8,P<0.05)。内向电流显示其反转电位在-18.3±3.4 mV。
5)电极内液中加入BAPTA(10 mM)后,蛙皮素(250 nM)引起的NPY神经元膜电位去极化作用减少到2.0 mV±0.6 mV(n=5,P<0.05).使用无钙细胞外液时,蛙皮素(250 nM)引起的NPY神经元膜电位去极化作用增加到9.0±1.4mV(n=5,P<0.05)。在细胞外液中加入瞬时感受器电位(transient receptor potential,TRP)通道阻断剂SKF96365(30μM)后,蛙皮素(250 nM)引起的NPY神经元膜电位去极化作用减少到2.7 mV±0.6 mV(n=5,P<0.05).在细胞外液加入NiCl2(3mM)后,蛙皮素(250 nM)引起的NPY神经元膜电位去极化作用减少到2.4±0.7 mV(n=5,P<0.05).在细胞外液加入钠-钙交换泵阻断剂KB-R7943(60μM)后,蛙皮素(250 nM)引起的NPY神经元膜电位去极化作用减少到2.3±0.9 mV(n=6,P<0.05).
6)水迷宫实验中,缺血组大鼠在目标象限停留的时间(ischemia:24.7±3.8%；sham:37.8±6.1%；ischemia+bombesin:35.5±3.6%)显著缩短。而假手术组(P<0.05,ischemia vs sham)和蛙皮素组(P<0.05,ischemia vs ischemia +bombesin)停留时间较长。
7)在体LTP实验中,缺血组大鼠标准化的群峰电位的斜率明显减少(ischemia:114.0±3.1%;sham:129.8±4.5%,P<0.05),而在蛙皮素组,标准化的群峰电位的斜率与假手术组无显著差异(ischemia+bombesin:125.8±4.3%,P>0.05 vs sham;P<0.05 vs ischemia)。
8)电压钳实验中,给予蛙皮素(250nM)后,钠电流幅值变为原来的83.32±5.98%(n=6,P<0.05),而洗脱后电流幅值恢复到原来的97.55±2.19%(n=6,P>0.05)。
结论
1)蛙皮素能够可逆的兴奋NPY神经元和POMC神经元,并且具有浓度依赖性。
2)蛙皮素兴奋NPY神经元的机制可能来自激活非选择性阳离子通道和钠-钙交换泵。
3)蛙皮素能够改善双侧颈总动脉结扎脑缺血大鼠模型的学习和记忆障碍。
4)蛙皮素的神经保护作用可能与其抑制电压门控钠离子通道有关。
Objective
Bombesin is a 14 amino acid-containing peptide first isolated from the skin of the frog Bombina bombina. Since its isolation, two related mammalian neuropeptides, neuromedin B (NMB) and gastrin-releasing peptide (GRP), have been isolated and shown to have a widespread distribution. Bombesin, as a brain-gut peptide, plays an important role in food intake and behavior regulations. Hypothalamic arcuate nucleus (ARC) is an area in brain that regulates energy balance in adult mammalian animals. The arcuate nucleus NPY neurons are thought to play an important anabolic role in energy homeostasis.
As a brain-gut peptide, bombesin have profound effects on glioblastoma, ischemia and memory processing. Bombesin concentration increased in Parkinson's disease patients, and it can act as anti-epileptic peptide in the hippocampus. There are increasing evidences suggesting that bombesin have neuroprotective effects.
In this study, we look at the possible effects of bombesin on NPY neurons in hypothalamic arcuate nucleus, using NPY-GFP transgenetic mice. Further more, we investigate the effect of bombesin on ischemia-induced memory deficts rats and on rat hippocampal CA1 neruonal channel activity, trying to provide another insight for neuroprotective effect of bombesin.
Methods
Use NPY-GFP transgenetic mice to study the possible effect of bombesin on NPY neurons. The expression of green fluorescent protein (GFP) is confirmed by immunohistochemistry and single-cell reverse transcription-PCR. The effects of bombesin on NPY neurons were studied using patch-clamp techniques in the hypothalamic brain slice. The input-resistance and the reverse potential were measured. Various artificial cerebrospinal fluid (ACSF) and pipette solutions were used to access the mechanism of the effects of bombesin. Besides, for comparision purpose, we looked at the effects of bombesin-like peptide (GRP and NMB) and other food regulating peptides on NPY neurons. Finally, we examined the effect of bombesin on proopiomelanocortin (POMC) neurons.
Twenty-four male Wistar rats were randomly divided into three groups: sham-operation group, ischemia group and ischemia plus bombesin group. Sustained global cerebral ischemia was induced by bilateral occlusion of the carotid arteries. Morris water maze test and long-term potentiation (LTP) recording were performed to access the effect of bombesin on cognitive deficits with chronic cerebral ischemia.Besides, Young male Wistar rats on postnatal days 21-28 were decapitated and cut using an automatic oscillating tissue slicer. Using whole-cell patch clamp recording, the sodium currents (INa), were tested before and after applying bombesin in 350μm thick hippocampal slices.
Results
1) Single GFP-positive neurons harvested from ARC were proved to have NPY mRNS using single-cell reverse transcription-PCR.
2) Bombesin (250nM) increased the spike frequency by 61.5±14.2%(n=15, P <0.05) with a mean depolarization of 5.0±0.5 mV (n=15,P<0.05)
3) Neuromedin B, NMB (250nM) increased the spike frequency by 66.5±10.6%(n=16, P<0.05) with a mean depolarization of 5.6±0.4 mV (n=16,P< 0.05. Gastrin-releasing peptide,GRP (250nM) increased the spike frequency by 9.2±10.5%(n=13, P>0.05) with a mean depolarization of 2.6±0.7 mV(n=13, P< 0.05)
4) Bombesin (250nM) decreased whole-cell input resistance by 22.4±5.7%(n =8, P<0.05) and the induced inward-current reversed～-18.3±3.4 mV.
5) With BAPTA (10mM) in the pipette solution the bombesin (250 nM)-mediated depolarization of the NPY neuron was reduced to 2.0 mV±0.6 mV, (n=5, P<0.05). In contrast, when a Ca2+-free extracellular buffer was used, the bombesin-mediated depolarization was increased to 9.0±1.4 mV, (n=5, P<0.05). With SKF96365 (30μM) in the bath the bombesin-mediated depolarization of the NPY neuron was reduced to 2.7 mV±0.6 mV, (n=5, P<0.05). With NiCl2 in the bath, the depolarization by bombesin was 2.4±0.7 mV (n=5, P<0.05). With Na+/Ca2+ exchanger blocker KB-R7943 in the bath, the depolarization by bombesin was reduced to 2.3±0.9 mV (n=6, P<0.05)
6) In Morris water maze test, after five days of training, On day 6, animals in the ischemia group spent less time in the target quadrant (ischemia:24.7±3.8%; sham: 37.8±6.1%; ischemia+bombesin:35.5±3.6%,), whereas the sham-operated (P< 0.05, ischemia vs sham) and the ischemia+bombesin-treated (P<0.05, ischemia vs ischemia+bombesin) animals spent significantly longer times, respectively.
7) In LTP recording, bombesin protects against LTP changes in the hippocampus induced by chronic cerebral ischemia. In the ischemia group chronic ischemia significantly reduced the normalized slope of the fEPSP (ischemia:114.0±3.1%; sham:129.8±4.5%, P<0.05) but in the bombesin treated group there was no significant impairment of the fEPSP slope this being similar to sham levels (ischemia+bombesin:125.8±4.3%, P>0.05 vs sham; P<0.05 vs ischemia).
8) Bombesin decreased whole-cell sodium currents by 83.32±5.98%(n=6, P< 0.05) and after wash-out, the currents recovered to 97.55±2.19%(n=6,P>0.05) of its original amplitude.
Conclusion
1) Bombesin reversibly excites NPY and POMC neurons in a dose-dependent manner.
2) The excitatory effects of bombesin are most consistent with two mechanisms, activation of both a nonselective cation channel and of the sodium/calcium transporter.
3) Bombesin improved the performance of learning and memory of chronic cerebral ischemic rats, reversed the LTP deficit induced by ischemia
4) Bombesin decreased whole-cell sodium currents, which could be the underlying mechanism for its neuroprotective effects.
蛙皮素(Bombesin),是一种脑肠肽,由14个氨基酸残基组成,对饮食和行为具有调节作用。在哺乳动物中,它的同类物有胃泌素释放激素(gastrin-releasing peptide, GRP)和神经介素B(neuromedin B, NMB)。作为一种脑肠肽,蛙皮素对神经系统肿瘤、缺血及学习记忆都具有良性作用。有研究表明在帕金森病人脑内蛙皮素浓度增加,具有内源性抗癫痫作用。此外还有很多实验表明蛙皮素具有神经保护作用。
下丘脑弓形核(arcuate nucleus, ARC),是成年哺乳动物体内能量平衡调节的重要区域。弓形核内的神经肽Y(neuropipte Y, NPY)神经元具有增加饮食的作用。
本论文使用NPY-GFP转基因小鼠,研究蛙皮素对于下丘脑弓形核内NPY神经元的作用及其可能机制。另外,还探索了蛙皮素对于脑缺血引起的大鼠学习记忆障碍的作用及其对于大鼠海马CA1区神经元离子通道的作用,从而进一步提供了蛙皮素神经保护作用的证据。
方法
第一部分：选取NPY-GFP转基因小鼠,NPY神经元中绿色荧光蛋白(green fluorescent protein, GFP)的表达由免疫组织化学和单细胞逆转录PCR(single-cell reverse transcription-PCR)确认。运用全细胞膜片钳技术,研究小鼠下丘脑脑片NPY神经元的电生理特性。首先观察蛙皮素对NPY神经元兴奋性的影响,然后观察蛙皮素对于NPY神经元串联电阻,反转电位的作用,最后在不同内外液条件下观察蛙皮素对NPY神经元的作用,来阐明蛙皮素对NPY神经元的作用机制。除此之外,我们还使用了蛙皮素家族的肽类(NMB和GRP)以及其他与饮食有关的肽类,比较了不同肽类对NPY神经元的作用。最后,还观察了蛙皮素对阿黑皮原(proopiomelanocortin, POMC)神经元的作用,与其对NPY神经元的作用进行比较。
第二部分：选取18只成年Wistar大鼠,随机分成正常组、缺血组和缺血后蛙皮素干预组。用双侧颈总动脉结扎的方法制作大鼠全脑缺血模型,使用Morris水迷宫和长时程增强(long-term potentiation, LTP)记录的方式来研究蛙皮素对缺血引起的学习记忆障碍的作用。然后使用幼年Wistar大鼠,制作海马脑片,用膜片钳中的电压钳技术研究蛙皮素对钠离子通道的作用。
所有实验数据经Student t检验或ANOVA等统计学处理,P<0.05表示存在显著性差异。
结果
1)从弓形核中收获单个GFP阳性神经元后,运用单细胞RT-PCR技术观察GFP阳性神经元中含有NPY编码的mRNA,从而证明NPY-GFP转基因小鼠系建立成功。
2)蛙皮素(250nM)使NPY神经元动作电位频率增加了61.5±14.2%(n=15,P<0.05),使神经元的膜电位去极化5.0±0.5 mV(n=15,P<0.05)。
3)NMB(250nM)使NPY神经元动作电位频率增加66.5±10.6%(n=16,P<0.05),使神经元的膜电位去极化5.6±0.4 mV(n=16,P<0.05).GRP (250nM)使NPY神经元动作电位频率增加9.2±10.5%(n=13,P>0.05),使神经元的膜电位去极化2.6±0.7 mV(n=13,P<0.05).
4)蛙皮素使NPY神经元的输入电阻减少22.4±5.7%(n=8,P<0.05)。内向电流显示其反转电位在-18.3±3.4 mV。
5)电极内液中加入BAPTA(10 mM)后,蛙皮素(250 nM)引起的NPY神经元膜电位去极化作用减少到2.0 mV±0.6 mV(n=5,P<0.05).使用无钙细胞外液时,蛙皮素(250 nM)引起的NPY神经元膜电位去极化作用增加到9.0±1.4mV(n=5,P<0.05)。在细胞外液中加入瞬时感受器电位(transient receptor potential,TRP)通道阻断剂SKF96365(30μM)后,蛙皮素(250 nM)引起的NPY神经元膜电位去极化作用减少到2.7 mV±0.6 mV(n=5,P<0.05).在细胞外液加入NiCl2(3mM)后,蛙皮素(250 nM)引起的NPY神经元膜电位去极化作用减少到2.4±0.7 mV(n=5,P<0.05).在细胞外液加入钠-钙交换泵阻断剂KB-R7943(60μM)后,蛙皮素(250 nM)引起的NPY神经元膜电位去极化作用减少到2.3±0.9 mV(n=6,P<0.05).
6)水迷宫实验中,缺血组大鼠在目标象限停留的时间(ischemia:24.7±3.8%；sham:37.8±6.1%；ischemia+bombesin:35.5±3.6%)显著缩短。而假手术组(P<0.05,ischemia vs sham)和蛙皮素组(P<0.05,ischemia vs ischemia +bombesin)停留时间较长。
7)在体LTP实验中,缺血组大鼠标准化的群峰电位的斜率明显减少(ischemia:114.0±3.1%;sham:129.8±4.5%,P<0.05),而在蛙皮素组,标准化的群峰电位的斜率与假手术组无显著差异(ischemia+bombesin:125.8±4.3%,P>0.05 vs sham;P<0.05 vs ischemia)。
8)电压钳实验中,给予蛙皮素(250nM)后,钠电流幅值变为原来的83.32±5.98%(n=6,P<0.05),而洗脱后电流幅值恢复到原来的97.55±2.19%(n=6,P>0.05)。
结论
1)蛙皮素能够可逆的兴奋NPY神经元和POMC神经元,并且具有浓度依赖性。
2)蛙皮素兴奋NPY神经元的机制可能来自激活非选择性阳离子通道和钠-钙交换泵。
3)蛙皮素能够改善双侧颈总动脉结扎脑缺血大鼠模型的学习和记忆障碍。
4)蛙皮素的神经保护作用可能与其抑制电压门控钠离子通道有关。
Objective
Bombesin is a 14 amino acid-containing peptide first isolated from the skin of the frog Bombina bombina. Since its isolation, two related mammalian neuropeptides, neuromedin B (NMB) and gastrin-releasing peptide (GRP), have been isolated and shown to have a widespread distribution. Bombesin, as a brain-gut peptide, plays an important role in food intake and behavior regulations. Hypothalamic arcuate nucleus (ARC) is an area in brain that regulates energy balance in adult mammalian animals. The arcuate nucleus NPY neurons are thought to play an important anabolic role in energy homeostasis.
As a brain-gut peptide, bombesin have profound effects on glioblastoma, ischemia and memory processing. Bombesin concentration increased in Parkinson's disease patients, and it can act as anti-epileptic peptide in the hippocampus. There are increasing evidences suggesting that bombesin have neuroprotective effects.
In this study, we look at the possible effects of bombesin on NPY neurons in hypothalamic arcuate nucleus, using NPY-GFP transgenetic mice. Further more, we investigate the effect of bombesin on ischemia-induced memory deficts rats and on rat hippocampal CA1 neruonal channel activity, trying to provide another insight for neuroprotective effect of bombesin.
Methods
Use NPY-GFP transgenetic mice to study the possible effect of bombesin on NPY neurons. The expression of green fluorescent protein (GFP) is confirmed by immunohistochemistry and single-cell reverse transcription-PCR. The effects of bombesin on NPY neurons were studied using patch-clamp techniques in the hypothalamic brain slice. The input-resistance and the reverse potential were measured. Various artificial cerebrospinal fluid (ACSF) and pipette solutions were used to access the mechanism of the effects of bombesin. Besides, for comparision purpose, we looked at the effects of bombesin-like peptide (GRP and NMB) and other food regulating peptides on NPY neurons. Finally, we examined the effect of bombesin on proopiomelanocortin (POMC) neurons.
Twenty-four male Wistar rats were randomly divided into three groups: sham-operation group, ischemia group and ischemia plus bombesin group. Sustained global cerebral ischemia was induced by bilateral occlusion of the carotid arteries. Morris water maze test and long-term potentiation (LTP) recording were performed to access the effect of bombesin on cognitive deficits with chronic cerebral ischemia.Besides, Young male Wistar rats on postnatal days 21-28 were decapitated and cut using an automatic oscillating tissue slicer. Using whole-cell patch clamp recording, the sodium currents (INa), were tested before and after applying bombesin in 350μm thick hippocampal slices.
Results
1) Single GFP-positive neurons harvested from ARC were proved to have NPY mRNS using single-cell reverse transcription-PCR.
2) Bombesin (250nM) increased the spike frequency by 61.5±14.2%(n=15, P <0.05) with a mean depolarization of 5.0±0.5 mV (n=15,P<0.05)
3) Neuromedin B, NMB (250nM) increased the spike frequency by 66.5±10.6%(n=16, P<0.05) with a mean depolarization of 5.6±0.4 mV (n=16,P< 0.05. Gastrin-releasing peptide,GRP (250nM) increased the spike frequency by 9.2±10.5%(n=13, P>0.05) with a mean depolarization of 2.6±0.7 mV(n=13, P< 0.05)
4) Bombesin (250nM) decreased whole-cell input resistance by 22.4±5.7%(n =8, P<0.05) and the induced inward-current reversed～-18.3±3.4 mV.
5) With BAPTA (10mM) in the pipette solution the bombesin (250 nM)-mediated depolarization of the NPY neuron was reduced to 2.0 mV±0.6 mV, (n=5, P<0.05). In contrast, when a Ca2+-free extracellular buffer was used, the bombesin-mediated depolarization was increased to 9.0±1.4 mV, (n=5, P<0.05). With SKF96365 (30μM) in the bath the bombesin-mediated depolarization of the NPY neuron was reduced to 2.7 mV±0.6 mV, (n=5, P<0.05). With NiCl2 in the bath, the depolarization by bombesin was 2.4±0.7 mV (n=5, P<0.05). With Na+/Ca2+ exchanger blocker KB-R7943 in the bath, the depolarization by bombesin was reduced to 2.3±0.9 mV (n=6, P<0.05)
6) In Morris water maze test, after five days of training, On day 6, animals in the ischemia group spent less time in the target quadrant (ischemia:24.7±3.8%; sham: 37.8±6.1%; ischemia+bombesin:35.5±3.6%,), whereas the sham-operated (P< 0.05, ischemia vs sham) and the ischemia+bombesin-treated (P<0.05, ischemia vs ischemia+bombesin) animals spent significantly longer times, respectively.
7) In LTP recording, bombesin protects against LTP changes in the hippocampus induced by chronic cerebral ischemia. In the ischemia group chronic ischemia significantly reduced the normalized slope of the fEPSP (ischemia:114.0±3.1%; sham:129.8±4.5%, P<0.05) but in the bombesin treated group there was no significant impairment of the fEPSP slope this being similar to sham levels (ischemia+bombesin:125.8±4.3%, P>0.05 vs sham; P<0.05 vs ischemia).
8) Bombesin decreased whole-cell sodium currents by 83.32±5.98%(n=6, P< 0.05) and after wash-out, the currents recovered to 97.55±2.19%(n=6,P>0.05) of its original amplitude.
Conclusion
1) Bombesin reversibly excites NPY and POMC neurons in a dose-dependent manner.
2) The excitatory effects of bombesin are most consistent with two mechanisms, activation of both a nonselective cation channel and of the sodium/calcium transporter.
3) Bombesin improved the performance of learning and memory of chronic cerebral ischemic rats, reversed the LTP deficit induced by ischemia
4) Bombesin decreased whole-cell sodium currents, which could be the underlying mechanism for its neuroprotective effects.
引文
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