老龄大鼠脑线粒体外周苯二氮卓受体（PBR）的变化及其对麻醉诱导剂阿托品的反应性研究
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摘要
术后精神障碍(postoperative mental disorder, POMD)是老龄患者术后常见的一种急性精神错乱状态,临床基本特征为意识、注意力、认知和知觉障碍。其发病原因机制较复杂,包括围术期多种因素。临床研究表明高龄和术前抗胆碱药的使用可能是其重要原因之一。
本研究旨在观察老龄大鼠基础认知水平的变化及抗胆碱药阿托品在临床剂量(0.06mg/kg)下对其记忆和精神状态的影响,并初步探讨其机制。我们采用水迷宫实验和Y迷宫实验测试老龄大鼠记忆能力的变化及给予阿托品后不同时间点(1天、4天、7天)其记忆能力的变化；采用开场和十字高架迷宫实验观察老龄大鼠精神状态的变化及给予阿托品后对其造成的影响。结果表明,自然衰老大鼠的记忆能力存在下降趋势,而临床常用剂量下的阿托品对衰老大鼠的学习记忆功能没有明显影响,但对其精神状态产生了影响,有一定的双向波动性及个体差异性。进一步研究其机制,我们采用放射性配基受体结合分析方法检测自然衰老大鼠脑皮层与学习记忆密切相关的线粒体外周苯二氮卓受体(PBRs)结合活性的变化及阿托品对其造成的影响。结果显示：老龄大鼠皮层线粒体PBRs代表受体数量的Bmax值及代表受体结合力的Kd值均显著增高(P<0.05),即受体数量增多但亲和力显著下降。而给予阿托品早期,老龄大鼠PBRs的表达数量明显增加而亲合力显著下降(P<0.05)。最后我们从基因转录水平和蛋白表达水平两个层次重点观察了老龄大鼠脑皮层神经甾体合成的关键蛋白(StAR、P450scc、3β-HSD)表达的变化及其对阿托品的反应性。结果发现,自然衰老大鼠皮层神经甾体合成相关蛋白的mRNA水平和蛋白表达水平均存在不同程度的降低。给予临床剂量阿托品后第4天老龄大鼠皮层P-450scc、3β-HSD的mRNA表达水平显著下降(P<0.05), StAR的mRNA表达水平也有所降低,而第7天这三种蛋白的mRNA表达水平均有所回升。而其蛋白表达水平对阿托品的反应相对滞后,呈现时程性的下降。
综上所述,本研究首先观察到自然衰老大鼠基础认知功能下降,这种变化与脑内PBRs受体亲和力降低及甾体合成相关蛋白表达水平下降呈现一定相关性,可能是高龄术后精神障碍的重要机制之一。术前麻醉诱导用药阿托品在临床剂量下对衰老大鼠的学习记忆功能没有明显影响,而对其精神状态会产生一定的影响,但程度比较轻微。抗胆碱药与麻醉药合用对老年患者术后精神障碍的影响有待进一步探讨。
The incidence of post-operative mental disorders (POMD) related to anaesthesia increases in elderly patients, which are characterized by post-operative delirium, cognitive impairment, anxiety and depression, and influence post-operative rehabilitation and threaten to life in some cases. The pathophysiology of POMD is poorly understood. Good evidence suggests neurotransmitter disturbances, especially acetylcholine deficiency. In the present study, the effect of anticholinergic agent—atropine which was used in the course of anesthesia induction on psychiatric symptoms and memory were evaluated in aging rats. Our data of morris water maze and Y maze showed the cognition of aging rats was impaired and atropine at clinical dose had no obvious effect on it.. However, atropine had a certain impact on psychiatric symptoms, which was showed in open field and elevated plus maze test. To confirm the precise mechanism of atropine, the quantitive changes of peripheral-type benzodiazepine recepors (PBRs) in brain mitochodria of aging rats and the effect of atropine on it were examined. Our findings showed that compared with 3-month rats, there was an increase in the maximal binding site density (Bmax), with an significant increase in the equilibrium dissociation constant (Kd) in cortex mitochondria of aging rats, which suggested the density of PBRs increased, whereas the binding affinity of PBRs decreased. On 1 st day after atropine treatment, the density of PBRs showed further enhancement but the binding affinity of PBRs further decreased. Meanwhile, we found that compared with 3-month rats, the transcriptional level and the protein level of the three proteins—P450scc、StAR and 3β-HSD which related to the neurosteroids'biosynthesis in the brain decreased. On 4th day after atropine treatment, the transcriptional levels of P450scc and 3β-HSD were significantly lower than those in the control aging rats. However, their levels were restored on 7th day. The changes of the protein level lagged behind the mRNA, and the protein expression decreased in a time-coursing pattern.
In conclusion, in this study, the decrease of the basal level of aged rats cognition, the binding activity of PBRs in brain mitochodria of aging rats and the expression of the proteins regard to neurosteroids de novo synthesis were observed, which maybe related to the susceptibility of old age to POMD. Anesthesia induction agents-atropine had no significant effect on memory function, but exerted some effect on psychiatric symptoms, implicating the influence of the combination of anticholinergic agents and anesthetics on POMD in old patients need to be further investigated.
本研究旨在观察老龄大鼠基础认知水平的变化及抗胆碱药阿托品在临床剂量(0.06mg/kg)下对其记忆和精神状态的影响,并初步探讨其机制。我们采用水迷宫实验和Y迷宫实验测试老龄大鼠记忆能力的变化及给予阿托品后不同时间点(1天、4天、7天)其记忆能力的变化；采用开场和十字高架迷宫实验观察老龄大鼠精神状态的变化及给予阿托品后对其造成的影响。结果表明,自然衰老大鼠的记忆能力存在下降趋势,而临床常用剂量下的阿托品对衰老大鼠的学习记忆功能没有明显影响,但对其精神状态产生了影响,有一定的双向波动性及个体差异性。进一步研究其机制,我们采用放射性配基受体结合分析方法检测自然衰老大鼠脑皮层与学习记忆密切相关的线粒体外周苯二氮卓受体(PBRs)结合活性的变化及阿托品对其造成的影响。结果显示：老龄大鼠皮层线粒体PBRs代表受体数量的Bmax值及代表受体结合力的Kd值均显著增高(P<0.05),即受体数量增多但亲和力显著下降。而给予阿托品早期,老龄大鼠PBRs的表达数量明显增加而亲合力显著下降(P<0.05)。最后我们从基因转录水平和蛋白表达水平两个层次重点观察了老龄大鼠脑皮层神经甾体合成的关键蛋白(StAR、P450scc、3β-HSD)表达的变化及其对阿托品的反应性。结果发现,自然衰老大鼠皮层神经甾体合成相关蛋白的mRNA水平和蛋白表达水平均存在不同程度的降低。给予临床剂量阿托品后第4天老龄大鼠皮层P-450scc、3β-HSD的mRNA表达水平显著下降(P<0.05), StAR的mRNA表达水平也有所降低,而第7天这三种蛋白的mRNA表达水平均有所回升。而其蛋白表达水平对阿托品的反应相对滞后,呈现时程性的下降。
综上所述,本研究首先观察到自然衰老大鼠基础认知功能下降,这种变化与脑内PBRs受体亲和力降低及甾体合成相关蛋白表达水平下降呈现一定相关性,可能是高龄术后精神障碍的重要机制之一。术前麻醉诱导用药阿托品在临床剂量下对衰老大鼠的学习记忆功能没有明显影响,而对其精神状态会产生一定的影响,但程度比较轻微。抗胆碱药与麻醉药合用对老年患者术后精神障碍的影响有待进一步探讨。
The incidence of post-operative mental disorders (POMD) related to anaesthesia increases in elderly patients, which are characterized by post-operative delirium, cognitive impairment, anxiety and depression, and influence post-operative rehabilitation and threaten to life in some cases. The pathophysiology of POMD is poorly understood. Good evidence suggests neurotransmitter disturbances, especially acetylcholine deficiency. In the present study, the effect of anticholinergic agent—atropine which was used in the course of anesthesia induction on psychiatric symptoms and memory were evaluated in aging rats. Our data of morris water maze and Y maze showed the cognition of aging rats was impaired and atropine at clinical dose had no obvious effect on it.. However, atropine had a certain impact on psychiatric symptoms, which was showed in open field and elevated plus maze test. To confirm the precise mechanism of atropine, the quantitive changes of peripheral-type benzodiazepine recepors (PBRs) in brain mitochodria of aging rats and the effect of atropine on it were examined. Our findings showed that compared with 3-month rats, there was an increase in the maximal binding site density (Bmax), with an significant increase in the equilibrium dissociation constant (Kd) in cortex mitochondria of aging rats, which suggested the density of PBRs increased, whereas the binding affinity of PBRs decreased. On 1 st day after atropine treatment, the density of PBRs showed further enhancement but the binding affinity of PBRs further decreased. Meanwhile, we found that compared with 3-month rats, the transcriptional level and the protein level of the three proteins—P450scc、StAR and 3β-HSD which related to the neurosteroids'biosynthesis in the brain decreased. On 4th day after atropine treatment, the transcriptional levels of P450scc and 3β-HSD were significantly lower than those in the control aging rats. However, their levels were restored on 7th day. The changes of the protein level lagged behind the mRNA, and the protein expression decreased in a time-coursing pattern.
In conclusion, in this study, the decrease of the basal level of aged rats cognition, the binding activity of PBRs in brain mitochodria of aging rats and the expression of the proteins regard to neurosteroids de novo synthesis were observed, which maybe related to the susceptibility of old age to POMD. Anesthesia induction agents-atropine had no significant effect on memory function, but exerted some effect on psychiatric symptoms, implicating the influence of the combination of anticholinergic agents and anesthetics on POMD in old patients need to be further investigated.
引文
[1]Meagher DJ, Moran M, Raju B, et al. Phenomenology of delirium—assessment of 100 adult cases using standardised measures [J]. Br J Psychiatry 2007; 190:135-41.
[2]David J. Meaghera, Alasdair M.J. MacLullichd, Jouko V. Laurilae. Defining delirium for the International Classification of Diseases,11th Revision [J]. Journal of Psychosomatic Research 2008; 65:207-214.
[3]Chishohn SE, Deniston OL, Igrisan R. Prevalence of confusion in postoperative patients[J]. J Geront Nursing,2003; 18(9):187-96.
[4]阮静,皋源,杭燕南.全麻后中枢神经系统并发症[J]中国医药导刊,2007;9(5):387-90.
[5]Michel Elie, Martin GC, Francois JP, et al. Delirium Risk Factors in Elderly Hospitalized Patients[J]. J Gen Intern Med.1998 March; 13(3):204-212.
[6]Inouye SK, Charpentier PA. Precipitating risk factors for delirium in hospitalised elderly persons: predictive model and inter-relationship with baseline vulnerability [J]. JAMA,1996; 275:852-7.
[7]Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 1998; 351:857-61.
[8]Peters A, Morrison JH, Rosene DL, et al. Feature article:are neurons lost from the primate cerebral cortex during normal aging? [J] Cereb. Cortex.1998,8:295-300.
[9]Peters A. Age-related changes in oligodendrocytes in monkey cerebral cortex[J]. J. Comp. Neurol. 1996,371(1):153-163.
[10]Kinirons MT, Crime P. Clinical pharmacokinetic considerations in the elderly [J]. An update. Clin Pharmacokinet 1997; 33:302-12
[11]Skoog I, Wallin A, Fredman P, et al. A population study on blood-brain barrier function in 85-year-olds:relation to Alzheimer's disease and vascular dementia [J]. Neurology 1998; 50:966-71.
[12]Muhlberg W, Platt D. Age-dependent changes in the kidney: pharmacological implications [J]. Gerontology 1999; 45:243-53.
[13]Dodds C, Allison J. Postoperative cognition deficit in the elderly surgical patient [J]. Br J Anaesth 1998; 81(3):383-393.
[14]Leavitt ML, Trzepacz PT, Ciongoli K. Rat model of delirium:atropine dose-response relationship[J]. J Neuropsychiatry Clin Neurosci 1994; 6(3):279-284.
[15]Christine Thomas, Ute Hestermann, Juergen Kopitz, et al. Serum anticholinergic activity and cerebral cholinergic dysfunction:An EEG study in frail elderly with and without delirium[J]. BMC Neurosci.2008; 9:86.
[16]Tune L. Serum anticholinergic activity levels and delirium in the elderly[J]. Semin Clin Neuropsychiatry 2000; 5:149-53.
[17]Neal Slatkin, Michelle Rhiner. Treatment of Opioid-Induced Delirium with Acetylcholinesterase Inhibitors:A Case Report [J]. Journal of Pain and Symptom Management
[18]Lacapere JJ, Papadopoulos V. Peripheral-type benzodiazepine receptor: structure and function of a cholesterol binding protein in steroid and bile acid biosynthesis[J]. Steroids,2003,68(7-8):569-85.
[19]Syapin, P. J.; Skolnick, P. Characterisation of benzodiazepine binding sites in cultured cells of neural origin[J]. J. Neurochem.1979; 32:1047-1051.
[20]Lee DH, Kang SK, Lee RH, Ryu JM, Park HY, Choi HS, et al. Effects of peripheral benzodiazepine receptor ligands on proliferation and differentiation of human mesenchymal stem cells[J]. J.Cell. Physiol.2004; 198:91-99.
[21]Wang JK, Morgan JI, Spector S. Benzodiazepines that bind at peripheral sites inhibit cell proliferation [J]. Proc.Natl.Acad.Sci. U.S.A.1984; 81:753-756.
[22]Kelly-Hershkovitz E, Weizman R, Spanier I, Leschiner S, Lahav M, Weisinger G, et al. Effects of peripheral-type benzodiazepine receptor antisense knockout on MA-10 Leydig cell proliferation and steroidogenesis[J]. J.Biol.Chem.1998; 273:5478-5483.
[23]Wilms H, Claasen J, Rohl C, et al. Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases:evidence from activated microglial cells in vitro[J]. Neurobiol Dis 2003,14(3):417-24.
[24]Papadopoulos V, Berkovich A, Krueger KE, Costa E, Guidotti A. Diazepam binding inhibitor and itsprocessing products stimulate mitochondrial steroid biosynthesis via an interaction with mitochondrial benzodiazepine receptors[J]. Endocrinology 1991; 129:1481-1488.
[25]Papadopoulos V, Mukhin AG, Costa E, Krueger KE. The peripheral-type benzodiazepine receptor is functionally linked to Leydig cell steroidogenesis[J]. J.Biol.Chem 1990; 265:3772-3779.
[26]Papadopoulos V. Structure and function of the peripheral-type benzodiazepine receptor in steroidogenic cells[J]. Proc.Soc.Exp.Biol.Med.1998; 217:130-142.
[27]Woods MJ, Williams DC. Multiple forms and locations for the peripheral-type benzodiazepine receptor[J]. Biochem.Pharmacol 1996; 52:1805-1814.
[28]Woods MJ, Zisterer DM, Williams DC. Two cellular and subcellular locations for the peripheral-type benzodiazepine receptor in rat liver[J]. Biochem.Pharmacol.1996; 51:1283-1292.
[29]Azarashvili T, Krestinina O, Yurkov I, Evtodienko Y, Reiser G. High-affinity peripheral benzodiazepine receptor ligand, PK11195, regulates protein phosphorylation in rat brain mitochondria under control of Ca(2+)[J]. J.Neurochem.2005; 94:1054-1062.
[30]Hong SH, Choi HB, Kim SU, McLarnon JG. Mitochondrial ligand inhibits store-operated calcium influx and COX-2 production in human microglia[J]. J.Neurosci.Res.2006; 83:1293-1298.
[31]Lenfant M, Haumont J, Zavala F. In vivo immunomodulating activity of PK-11195, a structurally unrelated ligand for "peripheral" benzodiazepine binding sites--I. Potentiation in mice of the humoral response to sheep red blood cells[J]. Int.J.Immunopharmacol.1986; 8:825-828.
[32]Ruff MR, Pert CB, Weber RJ, et al. Benzodiazepine receptor-mediated chemotaxis of human monocytes[J]. Science 1985; 229:1281-1283.
[33]Verma A, Snyder SH. Peripheral type benzodiazepine receptors[J]. Annu.Rev.Pharmacol. Toxicol. 1989; 29:307-322
[34]Hirsch JD, Beyer CF, Malkowitz L, et al. Mitochondrial benzodiazepine receptors mediate inhibition of mitochondrial respiratory control. Mol.Pharmacol[J].1989; 35:157-163.
[35]Hirsch T, Decaudin D, Susin SA, Marchetti P, Larochette N, Resche-Rigon M, et al. PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection[J]. Exp.Cell.Res.1998; 241:426-434.
[36]Chena CF, Lang SY, Zuo PP, et al. Effects of D-galactose on the expression of hippocampal peripheral-type benzodiazepine receptor and spatial memory performances in rats[J]. Psychoneuroendocrinology 2006; 31,805-811.
[37]Gavish, M. et al. Enigma of the peripheral benzodiazepine receptor[J]. Pharmacol.Rev.1999; 51: 629-650.
[38]Schumacher M, Akwa Y, Guennoun R, et al. Steroid synthesis and metabolism in the nervous system:trophic and protective effects[J]. J. Neurocytol.2000; 29(5-6):307-326.
[39]Thierry Hauet, Zhi-Xing Yao, Himangshu S. Bose, et al. Peripheral-Type Benzodiazepine Receptor-Mediated Action of Steroidogenic Acute Regulatory Protein on Cholesterol Entry into Leydig Cell Mitochondria. Molecular Endocrinology,2005; 19(2):540-554.
[40]Atsuko Kita, Tomoko Kinoshita, Hitoshi Kohayakawa, et al. Lack of tolerance to anxiolysis and withdrawal symptoms in mice repeatedly treated with AC-5216, a selective TSPO ligand. Progress in Neuro-Psychopharmacology & Biological Psychiatry [J].2009; 33:1040-1045.
[41]Alasdair MJ MacLullich, Anna Beaglehole, Roanna J. Hall, et al. Delirium and long-term cognitive impairment [J]. International Review of Psychiatry 2009; 21(1):30-42.
[42]Bitsch M, Foss N, Kristensen B, et al. Pathogenesis of and management strategies for postoperative delirium after hip fracture:a review[J]. Acta Orthop Scand 2004; 75:378-389.
[43]Young J, Inouye SK. Delirium in older people. Br Med J 2007;334:842D-6D.
[44]Abildstrom H, Rasmussen LS, Rentowl P, et al. Cognitive dysfunctionl-2 years after non-cardiac surgery in the elderly. ISPOCD group. International Study of Post-Operative Cognitive Dysfunction. Acta Anaesthesiol Scand 2000; 44:1246-51.
[45]Morris JC, McMarnus DQ. The neurology of aging; normal versus pathologic change[J]. Geriatrics 1991; 46:47-51.
[46]Piet Eikelenboom, Witte J.G. Hoogendijk. Do Delirium and Alzheimer's Dementia Share Specific Pathogenetic Mechanisms?[J]. Dement Geriatr Cogn Disord 1999; 10:319-324.
[47]Franceschi C, Capri M, Monti D, et al. Inflammaging and anti-inflammaging: a systemic perspective on ageing and longevity emerged from studies in humans[J]. Mech Ageing Dev 2007; 128:92-105.
[48]Van Munster BC, Korevaar JC, Zwinderman AH, et al. Time-Course of Cytokines During Delirium in Elderly Patients with Hip Fractures[J]. J Am Geriatr Soc 2008; 56:1704-1709.
[49]James LR, Basel R, George AK, et al. Chemokines are Associated with Delirium after Cardiac Surgery[J]. J Gerontol A Biol Sci Med Sci.2008 February; 63 (2):184-189.
[50]Larry E., Tune SE. Acetylcholine and Delirium [J]. Dement Geriatr Cogn Disord 1999; 10: 342-344
[51]Gibson GE, Blass JP, Huang FM, et al. The cellular basis of delirium and its relevance to age-related disorders including Alzheimer's disease[J]. Int Psychogeriatr 1991; 3:373-395.
[52]Itil T, Fink M. Anticholinergic drug-induced delirium; experimental modification, quantitative EEG and behavioral correlations[J]. J Nerv Ment Dis 1966; 143:492-507.
[53]Hshieh TT, Fong TG, Marcantonio ER, et al. Cholinergic deficiency hypothesis in delirium:a synthesis of current evidence[J]. Gerontol A Biol Sci Med Sci.2008; 63(7):764-72.
[54]Mach JR, Dysken MW, Kuskowski M, et al. Serum anticholinergic activity in hospitalized older persons with delirium:a preliminary study[J]. J Am Geriatr Soc.1995;43:491-5.
[55]Serena D, Charles R. H, Claude MW, et al. Methylthioninium chloride reverses cognitive deficits induced by scopolamine:comparison with rivastigmine[J]. Psychopharmacology 2009; 202:53-65.
[56]Posner JB, Plum F:The toxic effects of carbon dioxide and acetazolamide in hepatic encephalopathy[J]. J Clin Invest 1960; 39:1246-1258.
[57]Godbout JP, Chen J, Abraham J, et al. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system [J]. Faseb J 2005; 19: 1329-1331.
[58]Flacker JM, Cummings V, Mach JR, et al. An association between serum anticholinergic activity and delirium in elderly medical patients has been documented [J].. Am J Geriatr Psychiatry 1998;6:31-41.
[59]Feinberg M. The problems of anticholinergic adverse effects in older patients [J]. Drugs & Aging 1993; 3:335-48.
[60]Roy L. Soiza, Vijay Sharma, Karen Ferguson, et al. Neuroimaging studies of delirium:A systematic review [J]. Journal of Psychosomatic Research 2008; 65:239-248.
[61]Rupprecht R, Holsboer F. Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives[J]. Trends Neurosci 1999; 22:410-416.
[62]Baulieu, E.E.,1981. Steroid hormones in the brain:several mechanisms? In:Fuxe, K., Gustafsson, J.A., Wetterberg, L.(Eds.), Steroid Hormone Regulation of the Brain. Pergamon Press, Oxford, pp.3-14.
[63]Barnett JH, Salmond CH, Jones PB, et al:Cognitive reserve in neuropsychiatry. Psychol Med 2006; 36:1053-1064.
[64]Papadopoulos V, Lecanu L, Brown RC, et al. Peripheral-type benzodiazepine receptors in neurosteroid biosynthesis,neurosteroid biosynthesis,neuropathology and neurological disorders. Neuroscience 138 (2006) 749-756
[65]Atsuko Kita, Kiyoshi Furukawa. Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice [J]. Pharmacology, Biochemistry and Behavior 2008; 89:171-178.
[66]Christine E Marx, Robert D Stevens, Lawrence J Shampine, et al. Neuroactive Steroids are Altered in Schizophrenia and Bipolar Disorder: Relevance to Pathophysiology and Therapeutics [J]. Neuropsychopharmacology 2006; 31,1249-1263.
[67]Maninger N, Wolkowitz OM, Reus VI, et al. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)[J]. Front Neuroendocrinol 2009; 30(1):65-91.
[68]Strous RD, Maayan R, Lapidus R, et al. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatr 200360:133-141.
[69]De Simone R, Ajmone-Cat MA, Carnevale D, et al.Activation of a7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures [J]. J Neuroinfl ammation 2005; 2:4.
[70]Nizri E, Irony-Tur-Sinai M, Faranesh N, et al. Suppression of neuroinflammation and immunomodulation by the acetylcholinesterase inhibitor rivastigmine [J]. J Neuroimmunol 2008; 203:12-22.
[1]Gavish M, Bachman I, Shoukrun R, et al. Enigma of the peripheral benzodiazepine receptor[J]. Pharmacol Rev,1999,51(4):629-50.
[2]Lacapere JJ, Papadopoulos V. Peripheral-type benzodiazepine receptor: structure and function of a cholesterolbinding protein in steroid and bile acid biosynthesis[J]. Steroids,2003,68(7-8): 569-85.
[3]James M, Selleri S, Kassiou M. Development of ligands for the peripheral benzodiazepine receptor[J]. Curr Med Chem,2006,13(17):1991-2001.
[4]Wendler GM, Lindemann P, Lacape're JJ, et al. Protoporphyrin IX binding and transport by recombinant mouse PBR[J]. Biochem Biophys Res Commun,2003,311(4):847-52.
[5]Casellas P, Galiegue S, Basile AS. Peripheral benzodiazepine receptors and mitochondrial function[J]. Neurochem Int,2002,40(6):475-86.
[6]Wilms H, Claasen J, Rohl C, et al. Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro[J]. Neurobiol Dis,2003,14(3):417-24.
[7]Lang, S. The role of peripheral benzodiazepine receptors (PBRs) in CNS pathophysiology[J]. Curr Med Chem,2002,9(15):1411-5.
[8]Lee DH, Kang SK, Lee RH, et al. Effects of peripheral benzodiazepine receptor ligands on proliferation and differentiation of human mesenchymal stem cells[J]. J Cell Physiol,2004,198(1): 91-9.
[9]Azarashvili T, Krestinina O, Yurkov I, et al. High-affinity peripheral benzodiazepine receptor ligand, PK11195, regulates protein phosphorylation in rat brain mitochondria under control of Ca2+[J]. J Neurochem,2005,94(4):1054-62.
[10]Hong SH, Choi HB, Kim SU, et al. Mitochondrial ligand inhibits store-operated calcium influx and COX-2 production in human microglia[J]. JNeurosci.Res,2006,83(7):1293-8.
[11]Jamin N, Neumann JM, Ostuni MA, et al. Characterization of the cholesterol recognition amino acid consensus sequence of the peripheral-type benzodiazepine receptor[J]. Mol Endocrinol, 2005,19(3):588-94.
[12]Everett H, Barry M, Sun X, et al. The myxoma poxvirus protein,M11L, prevents apoptosis by direct interaction with the mitochondrial permeability transition pore[J]. J Exp Med,2002,196(9): 1127-39.
[13]Veenman L, Papadopoulos V, Gavish M. Channel-like functions of the 18-kDa translocator protein(TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response[J]. Curr Pharm Des,2007,13(23): 2385-405.
[14]Versijpt JJ, Dumont F, Van Laere, KJ, et al. Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography[J]. Eur Neurol,2003,50(1):39-47.
[15]Choi HB, Khoo C, Ryu JK, et al. Inhibition of lipopolysaccharide-induced cyclooxygenase-2, tumor necrosis factor-alpha, and [Ca2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195[J]. J Neurochem,2002,83(3):546-55.
[16]Papadopoulos V, Lecanu L, Brown RC, et al. Peripheral-type benzodiazepine receptor inneurosteroid biosynthesis, neuropathology and neurological disorders[J]. Neuroscience,2006, 138(3):749-56.
[17]Soreni N, Apter A, Weizman A, et al. Decreased platelet peripheral-type benzodiazepine receptors in adolescent inpatients with repeated suicide attempts[J]. Biol Psychiatry,1999,46(4): 484-8.
[18]Varga B, Marko K, Hadinger N, et al. Translocator protein (TSPO 18kDa) is expressed by neural stem and neuronal precursor cells[J]. Neurosci Lett,2009,462(3):257-62.
[19]Tsujimoto Y, Shimizu S. Role of the mitochondrial membrane permeability transition in cell death[J]. Apoptosis,2007,12(5):835-40.
[20]Murail S, Robert JC, Coi¨c YM, et al. Secondary and tertiary structures of the transmembrane domains of the translocator protein TSPO determined by NMR. Stabilization of the TSPO tertiary fold upon ligand binding[J]. Biochim Biophys Acta,2008,1778(6):1375-81.
[21]Atsuko Kita, Kiyoshi Furukawa. Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice[J]. Pharmacol Biochem Behav,2008,89(2):171-78.
[22]Brown RC, Han Z, Cascio C, et al. Oxidative stress-mediated DHEA formation in Alzheimer's disease pathology[J]. Neurobiol Aging,2003,24(1):567-72.
[23]Hauet T, Yao ZX, Bose HS, et al. Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into Leydig cell mitochondria[J]. Mol Endocrinol,2008,19(2):540-54.
[24]Mills C, Makwana M, Wallace A, et al. Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats[J]. Eur JNeurosci,2008,27(4):937-46.
[25]Chen CF, Lang SY, Zuo PP, et al. Effects of D-galactose on the expression of hippocampal peripheral-type benzodiazepine receptor and spatial memory performances in rats[J]. Psychoneuroendocrinology,2006,31(4):805-11.
[26]Leo Veenman, Moshe Gavish. The peripheral-type benzodiazepine receptor and the cardiovascular system. Implications for drug development[J]. Pharmacology & Therapeutics, 2006,110(3):503-24.
[2]David J. Meaghera, Alasdair M.J. MacLullichd, Jouko V. Laurilae. Defining delirium for the International Classification of Diseases,11th Revision [J]. Journal of Psychosomatic Research 2008; 65:207-214.
[3]Chishohn SE, Deniston OL, Igrisan R. Prevalence of confusion in postoperative patients[J]. J Geront Nursing,2003; 18(9):187-96.
[4]阮静,皋源,杭燕南.全麻后中枢神经系统并发症[J]中国医药导刊,2007;9(5):387-90.
[5]Michel Elie, Martin GC, Francois JP, et al. Delirium Risk Factors in Elderly Hospitalized Patients[J]. J Gen Intern Med.1998 March; 13(3):204-212.
[6]Inouye SK, Charpentier PA. Precipitating risk factors for delirium in hospitalised elderly persons: predictive model and inter-relationship with baseline vulnerability [J]. JAMA,1996; 275:852-7.
[7]Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 1998; 351:857-61.
[8]Peters A, Morrison JH, Rosene DL, et al. Feature article:are neurons lost from the primate cerebral cortex during normal aging? [J] Cereb. Cortex.1998,8:295-300.
[9]Peters A. Age-related changes in oligodendrocytes in monkey cerebral cortex[J]. J. Comp. Neurol. 1996,371(1):153-163.
[10]Kinirons MT, Crime P. Clinical pharmacokinetic considerations in the elderly [J]. An update. Clin Pharmacokinet 1997; 33:302-12
[11]Skoog I, Wallin A, Fredman P, et al. A population study on blood-brain barrier function in 85-year-olds:relation to Alzheimer's disease and vascular dementia [J]. Neurology 1998; 50:966-71.
[12]Muhlberg W, Platt D. Age-dependent changes in the kidney: pharmacological implications [J]. Gerontology 1999; 45:243-53.
[13]Dodds C, Allison J. Postoperative cognition deficit in the elderly surgical patient [J]. Br J Anaesth 1998; 81(3):383-393.
[14]Leavitt ML, Trzepacz PT, Ciongoli K. Rat model of delirium:atropine dose-response relationship[J]. J Neuropsychiatry Clin Neurosci 1994; 6(3):279-284.
[15]Christine Thomas, Ute Hestermann, Juergen Kopitz, et al. Serum anticholinergic activity and cerebral cholinergic dysfunction:An EEG study in frail elderly with and without delirium[J]. BMC Neurosci.2008; 9:86.
[16]Tune L. Serum anticholinergic activity levels and delirium in the elderly[J]. Semin Clin Neuropsychiatry 2000; 5:149-53.
[17]Neal Slatkin, Michelle Rhiner. Treatment of Opioid-Induced Delirium with Acetylcholinesterase Inhibitors:A Case Report [J]. Journal of Pain and Symptom Management
[18]Lacapere JJ, Papadopoulos V. Peripheral-type benzodiazepine receptor: structure and function of a cholesterol binding protein in steroid and bile acid biosynthesis[J]. Steroids,2003,68(7-8):569-85.
[19]Syapin, P. J.; Skolnick, P. Characterisation of benzodiazepine binding sites in cultured cells of neural origin[J]. J. Neurochem.1979; 32:1047-1051.
[20]Lee DH, Kang SK, Lee RH, Ryu JM, Park HY, Choi HS, et al. Effects of peripheral benzodiazepine receptor ligands on proliferation and differentiation of human mesenchymal stem cells[J]. J.Cell. Physiol.2004; 198:91-99.
[21]Wang JK, Morgan JI, Spector S. Benzodiazepines that bind at peripheral sites inhibit cell proliferation [J]. Proc.Natl.Acad.Sci. U.S.A.1984; 81:753-756.
[22]Kelly-Hershkovitz E, Weizman R, Spanier I, Leschiner S, Lahav M, Weisinger G, et al. Effects of peripheral-type benzodiazepine receptor antisense knockout on MA-10 Leydig cell proliferation and steroidogenesis[J]. J.Biol.Chem.1998; 273:5478-5483.
[23]Wilms H, Claasen J, Rohl C, et al. Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases:evidence from activated microglial cells in vitro[J]. Neurobiol Dis 2003,14(3):417-24.
[24]Papadopoulos V, Berkovich A, Krueger KE, Costa E, Guidotti A. Diazepam binding inhibitor and itsprocessing products stimulate mitochondrial steroid biosynthesis via an interaction with mitochondrial benzodiazepine receptors[J]. Endocrinology 1991; 129:1481-1488.
[25]Papadopoulos V, Mukhin AG, Costa E, Krueger KE. The peripheral-type benzodiazepine receptor is functionally linked to Leydig cell steroidogenesis[J]. J.Biol.Chem 1990; 265:3772-3779.
[26]Papadopoulos V. Structure and function of the peripheral-type benzodiazepine receptor in steroidogenic cells[J]. Proc.Soc.Exp.Biol.Med.1998; 217:130-142.
[27]Woods MJ, Williams DC. Multiple forms and locations for the peripheral-type benzodiazepine receptor[J]. Biochem.Pharmacol 1996; 52:1805-1814.
[28]Woods MJ, Zisterer DM, Williams DC. Two cellular and subcellular locations for the peripheral-type benzodiazepine receptor in rat liver[J]. Biochem.Pharmacol.1996; 51:1283-1292.
[29]Azarashvili T, Krestinina O, Yurkov I, Evtodienko Y, Reiser G. High-affinity peripheral benzodiazepine receptor ligand, PK11195, regulates protein phosphorylation in rat brain mitochondria under control of Ca(2+)[J]. J.Neurochem.2005; 94:1054-1062.
[30]Hong SH, Choi HB, Kim SU, McLarnon JG. Mitochondrial ligand inhibits store-operated calcium influx and COX-2 production in human microglia[J]. J.Neurosci.Res.2006; 83:1293-1298.
[31]Lenfant M, Haumont J, Zavala F. In vivo immunomodulating activity of PK-11195, a structurally unrelated ligand for "peripheral" benzodiazepine binding sites--I. Potentiation in mice of the humoral response to sheep red blood cells[J]. Int.J.Immunopharmacol.1986; 8:825-828.
[32]Ruff MR, Pert CB, Weber RJ, et al. Benzodiazepine receptor-mediated chemotaxis of human monocytes[J]. Science 1985; 229:1281-1283.
[33]Verma A, Snyder SH. Peripheral type benzodiazepine receptors[J]. Annu.Rev.Pharmacol. Toxicol. 1989; 29:307-322
[34]Hirsch JD, Beyer CF, Malkowitz L, et al. Mitochondrial benzodiazepine receptors mediate inhibition of mitochondrial respiratory control. Mol.Pharmacol[J].1989; 35:157-163.
[35]Hirsch T, Decaudin D, Susin SA, Marchetti P, Larochette N, Resche-Rigon M, et al. PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection[J]. Exp.Cell.Res.1998; 241:426-434.
[36]Chena CF, Lang SY, Zuo PP, et al. Effects of D-galactose on the expression of hippocampal peripheral-type benzodiazepine receptor and spatial memory performances in rats[J]. Psychoneuroendocrinology 2006; 31,805-811.
[37]Gavish, M. et al. Enigma of the peripheral benzodiazepine receptor[J]. Pharmacol.Rev.1999; 51: 629-650.
[38]Schumacher M, Akwa Y, Guennoun R, et al. Steroid synthesis and metabolism in the nervous system:trophic and protective effects[J]. J. Neurocytol.2000; 29(5-6):307-326.
[39]Thierry Hauet, Zhi-Xing Yao, Himangshu S. Bose, et al. Peripheral-Type Benzodiazepine Receptor-Mediated Action of Steroidogenic Acute Regulatory Protein on Cholesterol Entry into Leydig Cell Mitochondria. Molecular Endocrinology,2005; 19(2):540-554.
[40]Atsuko Kita, Tomoko Kinoshita, Hitoshi Kohayakawa, et al. Lack of tolerance to anxiolysis and withdrawal symptoms in mice repeatedly treated with AC-5216, a selective TSPO ligand. Progress in Neuro-Psychopharmacology & Biological Psychiatry [J].2009; 33:1040-1045.
[41]Alasdair MJ MacLullich, Anna Beaglehole, Roanna J. Hall, et al. Delirium and long-term cognitive impairment [J]. International Review of Psychiatry 2009; 21(1):30-42.
[42]Bitsch M, Foss N, Kristensen B, et al. Pathogenesis of and management strategies for postoperative delirium after hip fracture:a review[J]. Acta Orthop Scand 2004; 75:378-389.
[43]Young J, Inouye SK. Delirium in older people. Br Med J 2007;334:842D-6D.
[44]Abildstrom H, Rasmussen LS, Rentowl P, et al. Cognitive dysfunctionl-2 years after non-cardiac surgery in the elderly. ISPOCD group. International Study of Post-Operative Cognitive Dysfunction. Acta Anaesthesiol Scand 2000; 44:1246-51.
[45]Morris JC, McMarnus DQ. The neurology of aging; normal versus pathologic change[J]. Geriatrics 1991; 46:47-51.
[46]Piet Eikelenboom, Witte J.G. Hoogendijk. Do Delirium and Alzheimer's Dementia Share Specific Pathogenetic Mechanisms?[J]. Dement Geriatr Cogn Disord 1999; 10:319-324.
[47]Franceschi C, Capri M, Monti D, et al. Inflammaging and anti-inflammaging: a systemic perspective on ageing and longevity emerged from studies in humans[J]. Mech Ageing Dev 2007; 128:92-105.
[48]Van Munster BC, Korevaar JC, Zwinderman AH, et al. Time-Course of Cytokines During Delirium in Elderly Patients with Hip Fractures[J]. J Am Geriatr Soc 2008; 56:1704-1709.
[49]James LR, Basel R, George AK, et al. Chemokines are Associated with Delirium after Cardiac Surgery[J]. J Gerontol A Biol Sci Med Sci.2008 February; 63 (2):184-189.
[50]Larry E., Tune SE. Acetylcholine and Delirium [J]. Dement Geriatr Cogn Disord 1999; 10: 342-344
[51]Gibson GE, Blass JP, Huang FM, et al. The cellular basis of delirium and its relevance to age-related disorders including Alzheimer's disease[J]. Int Psychogeriatr 1991; 3:373-395.
[52]Itil T, Fink M. Anticholinergic drug-induced delirium; experimental modification, quantitative EEG and behavioral correlations[J]. J Nerv Ment Dis 1966; 143:492-507.
[53]Hshieh TT, Fong TG, Marcantonio ER, et al. Cholinergic deficiency hypothesis in delirium:a synthesis of current evidence[J]. Gerontol A Biol Sci Med Sci.2008; 63(7):764-72.
[54]Mach JR, Dysken MW, Kuskowski M, et al. Serum anticholinergic activity in hospitalized older persons with delirium:a preliminary study[J]. J Am Geriatr Soc.1995;43:491-5.
[55]Serena D, Charles R. H, Claude MW, et al. Methylthioninium chloride reverses cognitive deficits induced by scopolamine:comparison with rivastigmine[J]. Psychopharmacology 2009; 202:53-65.
[56]Posner JB, Plum F:The toxic effects of carbon dioxide and acetazolamide in hepatic encephalopathy[J]. J Clin Invest 1960; 39:1246-1258.
[57]Godbout JP, Chen J, Abraham J, et al. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system [J]. Faseb J 2005; 19: 1329-1331.
[58]Flacker JM, Cummings V, Mach JR, et al. An association between serum anticholinergic activity and delirium in elderly medical patients has been documented [J].. Am J Geriatr Psychiatry 1998;6:31-41.
[59]Feinberg M. The problems of anticholinergic adverse effects in older patients [J]. Drugs & Aging 1993; 3:335-48.
[60]Roy L. Soiza, Vijay Sharma, Karen Ferguson, et al. Neuroimaging studies of delirium:A systematic review [J]. Journal of Psychosomatic Research 2008; 65:239-248.
[61]Rupprecht R, Holsboer F. Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives[J]. Trends Neurosci 1999; 22:410-416.
[62]Baulieu, E.E.,1981. Steroid hormones in the brain:several mechanisms? In:Fuxe, K., Gustafsson, J.A., Wetterberg, L.(Eds.), Steroid Hormone Regulation of the Brain. Pergamon Press, Oxford, pp.3-14.
[63]Barnett JH, Salmond CH, Jones PB, et al:Cognitive reserve in neuropsychiatry. Psychol Med 2006; 36:1053-1064.
[64]Papadopoulos V, Lecanu L, Brown RC, et al. Peripheral-type benzodiazepine receptors in neurosteroid biosynthesis,neurosteroid biosynthesis,neuropathology and neurological disorders. Neuroscience 138 (2006) 749-756
[65]Atsuko Kita, Kiyoshi Furukawa. Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice [J]. Pharmacology, Biochemistry and Behavior 2008; 89:171-178.
[66]Christine E Marx, Robert D Stevens, Lawrence J Shampine, et al. Neuroactive Steroids are Altered in Schizophrenia and Bipolar Disorder: Relevance to Pathophysiology and Therapeutics [J]. Neuropsychopharmacology 2006; 31,1249-1263.
[67]Maninger N, Wolkowitz OM, Reus VI, et al. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)[J]. Front Neuroendocrinol 2009; 30(1):65-91.
[68]Strous RD, Maayan R, Lapidus R, et al. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatr 200360:133-141.
[69]De Simone R, Ajmone-Cat MA, Carnevale D, et al.Activation of a7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures [J]. J Neuroinfl ammation 2005; 2:4.
[70]Nizri E, Irony-Tur-Sinai M, Faranesh N, et al. Suppression of neuroinflammation and immunomodulation by the acetylcholinesterase inhibitor rivastigmine [J]. J Neuroimmunol 2008; 203:12-22.
[1]Gavish M, Bachman I, Shoukrun R, et al. Enigma of the peripheral benzodiazepine receptor[J]. Pharmacol Rev,1999,51(4):629-50.
[2]Lacapere JJ, Papadopoulos V. Peripheral-type benzodiazepine receptor: structure and function of a cholesterolbinding protein in steroid and bile acid biosynthesis[J]. Steroids,2003,68(7-8): 569-85.
[3]James M, Selleri S, Kassiou M. Development of ligands for the peripheral benzodiazepine receptor[J]. Curr Med Chem,2006,13(17):1991-2001.
[4]Wendler GM, Lindemann P, Lacape're JJ, et al. Protoporphyrin IX binding and transport by recombinant mouse PBR[J]. Biochem Biophys Res Commun,2003,311(4):847-52.
[5]Casellas P, Galiegue S, Basile AS. Peripheral benzodiazepine receptors and mitochondrial function[J]. Neurochem Int,2002,40(6):475-86.
[6]Wilms H, Claasen J, Rohl C, et al. Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro[J]. Neurobiol Dis,2003,14(3):417-24.
[7]Lang, S. The role of peripheral benzodiazepine receptors (PBRs) in CNS pathophysiology[J]. Curr Med Chem,2002,9(15):1411-5.
[8]Lee DH, Kang SK, Lee RH, et al. Effects of peripheral benzodiazepine receptor ligands on proliferation and differentiation of human mesenchymal stem cells[J]. J Cell Physiol,2004,198(1): 91-9.
[9]Azarashvili T, Krestinina O, Yurkov I, et al. High-affinity peripheral benzodiazepine receptor ligand, PK11195, regulates protein phosphorylation in rat brain mitochondria under control of Ca2+[J]. J Neurochem,2005,94(4):1054-62.
[10]Hong SH, Choi HB, Kim SU, et al. Mitochondrial ligand inhibits store-operated calcium influx and COX-2 production in human microglia[J]. JNeurosci.Res,2006,83(7):1293-8.
[11]Jamin N, Neumann JM, Ostuni MA, et al. Characterization of the cholesterol recognition amino acid consensus sequence of the peripheral-type benzodiazepine receptor[J]. Mol Endocrinol, 2005,19(3):588-94.
[12]Everett H, Barry M, Sun X, et al. The myxoma poxvirus protein,M11L, prevents apoptosis by direct interaction with the mitochondrial permeability transition pore[J]. J Exp Med,2002,196(9): 1127-39.
[13]Veenman L, Papadopoulos V, Gavish M. Channel-like functions of the 18-kDa translocator protein(TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response[J]. Curr Pharm Des,2007,13(23): 2385-405.
[14]Versijpt JJ, Dumont F, Van Laere, KJ, et al. Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography[J]. Eur Neurol,2003,50(1):39-47.
[15]Choi HB, Khoo C, Ryu JK, et al. Inhibition of lipopolysaccharide-induced cyclooxygenase-2, tumor necrosis factor-alpha, and [Ca2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195[J]. J Neurochem,2002,83(3):546-55.
[16]Papadopoulos V, Lecanu L, Brown RC, et al. Peripheral-type benzodiazepine receptor inneurosteroid biosynthesis, neuropathology and neurological disorders[J]. Neuroscience,2006, 138(3):749-56.
[17]Soreni N, Apter A, Weizman A, et al. Decreased platelet peripheral-type benzodiazepine receptors in adolescent inpatients with repeated suicide attempts[J]. Biol Psychiatry,1999,46(4): 484-8.
[18]Varga B, Marko K, Hadinger N, et al. Translocator protein (TSPO 18kDa) is expressed by neural stem and neuronal precursor cells[J]. Neurosci Lett,2009,462(3):257-62.
[19]Tsujimoto Y, Shimizu S. Role of the mitochondrial membrane permeability transition in cell death[J]. Apoptosis,2007,12(5):835-40.
[20]Murail S, Robert JC, Coi¨c YM, et al. Secondary and tertiary structures of the transmembrane domains of the translocator protein TSPO determined by NMR. Stabilization of the TSPO tertiary fold upon ligand binding[J]. Biochim Biophys Acta,2008,1778(6):1375-81.
[21]Atsuko Kita, Kiyoshi Furukawa. Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice[J]. Pharmacol Biochem Behav,2008,89(2):171-78.
[22]Brown RC, Han Z, Cascio C, et al. Oxidative stress-mediated DHEA formation in Alzheimer's disease pathology[J]. Neurobiol Aging,2003,24(1):567-72.
[23]Hauet T, Yao ZX, Bose HS, et al. Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into Leydig cell mitochondria[J]. Mol Endocrinol,2008,19(2):540-54.
[24]Mills C, Makwana M, Wallace A, et al. Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats[J]. Eur JNeurosci,2008,27(4):937-46.
[25]Chen CF, Lang SY, Zuo PP, et al. Effects of D-galactose on the expression of hippocampal peripheral-type benzodiazepine receptor and spatial memory performances in rats[J]. Psychoneuroendocrinology,2006,31(4):805-11.
[26]Leo Veenman, Moshe Gavish. The peripheral-type benzodiazepine receptor and the cardiovascular system. Implications for drug development[J]. Pharmacology & Therapeutics, 2006,110(3):503-24.