全身麻醉剂对发育期大脑神经元凋亡的影响及其机制

动物实验发现全身麻醉剂可引起发育期大脑神经元广泛凋亡和长期神经认知功能障碍。内源性及外源性凋亡途径均参与麻醉药物引起的细胞凋亡,而信号传导机制尚不明确,某些药物可能减轻麻醉引起的神经细胞凋亡。然而全麻药物神经毒性作用的临床研究证据尚不充分,尚需进一步多中心、大样本人类研究的支持。     

赤芍总苷退黄降酶的作用及机制研究

目的 探讨赤芍总苷退黄降酶的作用及机制。方法 ICR小鼠随机分成正常对照组,模型对照组,赤芍总苷低、中、高剂量组和苯巴比妥钠组;灌胃α-萘异硫氰酸酯(ANIT)诱导小鼠黄疸模型,分别在实验第6天和第12天观察各组药物对小鼠总胆红素(TBIL)、直接胆红素(DBIL)、胆汁酸(TBA)、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、碱性磷酸酶(ALP)等血清学指标及对小鼠胆汁分泌量和肝组织中尿苷二磷酸葡萄糖酸转移酶(UDPG-T)活性的影响,实验第6天观察各组药物对戊巴比妥钠睡眠时间的影响。结果 与模型对照组比较,除第6天赤芍总苷中剂量组ALT、第12天低剂量组AST无显著差异外,赤芍总苷3个剂量组血清学指标均明显下降(P<0.05或P<0.01);赤芍总苷中、高剂量组胆汁分泌量显著增加(P<0.01或P<0.05);3个剂量组和苯巴比妥钠组睡眠时间均明显缩短(P<0.01);赤芍总苷组肝组织UDPG-T活性明显提高(P<0.05)。结论 赤芍总苷具有退黄降酶作用,其作用机制可能与增加胆汁分泌量、提高肝药酶及UDPG-T活性有关。     

芦荟苷预处理对缺血再灌注大鼠心肌细胞凋亡、TNF-α含量和Ca2+-ATPase活性的影响

目的 研究芦荟苷(Barbaloin,Barb)对急性心肌缺血再灌注损伤大鼠心肌细胞凋亡的影响。方法 结扎大鼠左冠状动脉前降支复制心肌缺血再灌注损伤模型,实验分为假手术组、缺血再灌注组(IR)、Barb高、低剂量预处理组。采用原位缺口末端标记法(TUNEL)检测心肌细胞凋亡指数(AI),ELISA法测定血清TNF-α水平,化学法测定线粒体Ca²⁺-ATPase活性。结果 与IR组比较,Barb组AI和TNF-α水平显著降低 (P<0.05或P<0.01),Ca²⁺-ATPase活性明显增高(P<0.05)。结论 Barb能明显抑制IR引起的心肌细胞凋亡,其作用可能与降低TNF-α水平和提高Ca²⁺-ATPase活性有关。     

白藜芦醇对兔实验性骨关节炎血液流变学的影响

目的 探讨白藜芦醇对骨关节炎(osteoarthritis OA)模型兔血液流变学的影响。方法 42只健康新西兰兔分为正常对照组、假手术组、模型组、阳性药物组、白藜芦醇高、中、低剂量组,每组6只。除正常对照组和假手术组外,均用Hulth法建立实验性骨关节炎模型。造模8周后分别以10%羧甲基纤维素钠(2 mL·kg^-1)、阳性药物硫酸氨基葡萄糖(35 mg·kg^-1)、白藜芦醇高剂量(120 mg·kg^-1·d^-1)、中剂量(60 mg·kg^-1·d^-1)、低剂量(30 mg·kg^-1·d^-1)灌胃,连续给药6周后,抽血测定血液流变学全血黏度、血浆黏度、相对黏度和聚集指数指标并作统计学处理。结果 模型组的全血黏度、血浆黏度、相对黏度和聚集指数指标均高于正常对照组和假手术组(P<0.05)。而阳性药物组、白藜芦醇组全血黏度、血浆黏度、相对黏度和聚集指数指标均低于模型组 (P<0.05),白藜芦醇高、中剂量组与低剂量组之间比较有统计学意义(P<0.05),与正常对照组和假手术组比较无统计学意义(P>0.05)。结论 白藜芦醇能显著降低骨关节炎模型兔全血黏度、血浆黏度、相对黏度和聚集指数指标,有效改善骨关节炎血液流变学状态,从而起到防止并延缓关节软骨的退行性改变,有利于软骨的修复作用。     

F2007对新型控暴剂辣椒素所致呼吸道中毒症状的治疗作用

目的 建立新型控暴剂辣椒素中毒模型,评价比较A, B两种单药单独及联合应用条件下对辣椒素中毒所致咳嗽、哮喘等呼吸道刺激症状的治疗效果,筛选并确定新型刺激性毒剂中毒治疗药物处方。方法 96只豚鼠随机分为12组,每组8只动物,包括：空白对照组,模型组,A单药组（低剂量、中剂量、高剂量）,B单药组（低剂量、中剂量、高剂量）,F2007复方组（低剂量、中剂量、高剂量）,并以我军装备的原有刺激性毒剂治疗药物K作为阳性药物对照组。模型建立方法：将豚鼠置入多功能诱咳引喘仪,以0.15 ml·min^-1喷雾0.2 mmol·L^-1的辣椒素溶液5 min,停止染毒后继续观察10 min。给药方式：染毒前雾化给药3 min,药物作用3 min。观察指标：记录从染毒起至观察结束15 min内的咳嗽次数、抓嘴抓鼻数、流涎、紫绀、抽搐、呼吸困难等症状;实验结束后处死动物,分离气管及肺组织,计算肺湿干比并进行病理学检查。试验数据采用SPSS16.0软件包one-way ANOVA分析,方差齐者采用LSD检验进行比较,方差不齐者采用Games-Howell检验比较。结果 ① A单药组药效评价结果：与模型组相比,A单药各剂量组均可显著减少辣椒素中毒所致抓嘴抓鼻次数（P＜0.01）,且高剂量组对抓嘴抓鼻抑制作用要明显优于阳性对照药K（P＜0.05）;但A单药各剂量组对辣椒素引起的咳嗽、呼吸困难、紫绀及肺水肿等症状均无明显改善作用。② B单药组药效评价结果：B单药各剂量组对辣椒素诱发的咳嗽均有显著抑制作用（P<0.01）,且各剂量组镇咳效果要明显优于对照药物K（P<0.01）;此外,B单药中、高剂量给药组对辣椒素中毒引起的哮喘、紫绀、流涎、抽搐、呼吸困难及肺组织损伤等症状均有明确治疗效果,但对辣椒素刺激引起的抓嘴抓鼻无明显抑制作用。③ F2007药效评价结果：由A单药及B单药以一定比例组成的F2007复方对辣椒素诱发的咳嗽均有显著抑制作用,每只动物用药后咳嗽数均为0,较对照药物K组有显著统计学差异（P<0.01）;对辣椒素刺激诱发的抓嘴抓鼻数有显著抑制作用（P<0.01）,其中中、高剂量组对较对抓嘴抓鼻的抑制作用要明显优于对照药物K（P<0.05）,动物几乎已无扎嘴抓鼻现象出现;此外,F2007复方各剂量给药组对辣椒素刺激引起的哮喘、紫绀、流涎、抽搐、呼吸困难、肺组织损伤等症状均有显著治疗作用,中毒动物症状表现与正常动物相当。结论 我军装备的原有刺激性毒剂防治药物K可显著抑制新型控暴剂辣椒素中毒所致的、以抓嘴抓鼻为主要表现的呼吸道刺激症状,但对辣椒素诱发的咳嗽、呼吸困难及紫绀等症状无任何改善作用;由A单药及B单药组成的F2007既可很好地控制辣椒素引起的抓嘴抓鼻刺激症状,又能显著改善咳嗽、呼吸困难、紫绀、肺组织损伤等症状,因而从药效学角度提示其具有良好的应用前景。     

抗帕金森病新药研究进展

帕金森病(Parkinson's disease,PD)是一种常见的神经退行性疾病,其特征为黑质纹状体通路的多巴胺能神经元的丢失。左旋多巴一直作为临床治疗的主导用药,然而,该药长期应用会引起症状波动和运动障碍。目前最有希望治疗帕金森病的药物包括能够阻碍或者降低神经退行性过程的神经保护性药物,能够恢复大脑功能的药物,多巴胺替代和保留的药物,作用于纹状体以外的非多巴胺的神经递质的抗运动障碍药物。此外,一些具有崭新作用机制的药物,如腺苷A_(2A)受体阻滞剂、抗细胞凋亡药物等,都可能以单用或合并用药治疗PD。现综述目前临床治疗和开发中的抗PD新药的研究进展。     

安宫牛黄丸通过诱导细胞凋亡和降低线粒体膜电位抑制肿瘤细胞增殖

目的 观察安宫牛黄丸的抗肿瘤作用,并探索其可能的作用机制。方法 安宫牛黄丸9,30,90,300和900 mg·L^-1分别与人胃癌MGC-803和人肝癌BEL-7402细胞孵育24,48和72 h。采用噻唑蓝(3-(4,5-二甲基噻唑-2-基)-5(3-羧基甲基苯基)-2-(4-磺酸苯基)-2H-四氮唑)细胞毒实验MTS法和克隆实验观察安宫牛黄丸对MGC-803和BEL-7402细胞增殖的影响;应用Hoechst 33258/PI染色和流式细胞仪检测细胞凋亡;荧光分光光度计检测线粒体膜电位。结果 安宫牛黄丸具有浓度依赖性地抑制肿瘤细胞增殖的作用。MTS法测定结果表明,安宫牛黄丸作用48和72 h对MGC-803细胞增殖具有抑制作用,浓度-效应相关系数分别为0.996(P=0.002)和0.756(P=0.024);与BEL-7402细胞作用48和72 h的浓度-效应相关系数分别为0.732(P=0.030)和0.702(P=0.037)。细胞克隆实验结果表明,安宫牛黄丸作用24 h可浓度依赖性地抑制MGC-803细胞(r=0.914,P=0.011)和BEL-7402细胞(r=0.871,P=0.024)克隆形成。Hoechst 33258/PI染色和流式细胞仪检测结果表明,安宫牛黄丸900 mg·L^-1作用24 h可诱导MGC-803和BEL-7402细胞凋亡,细胞凋亡百分率分别达27.2%和19.7%。安宫牛黄丸900 mg·L^-1作用后连续检测3 min,MGC-803和BEL-7402细胞的线粒体膜电位比对照组分别下降15.9%和15.0%。结论 安宫牛黄丸具有抑制肿瘤细胞增殖的作用,其作用机制与诱导细胞凋亡和降低肿瘤细胞线粒体膜电位有关。     

专家视点:精神科患者的10种神经保护治疗

<正>证据显示,精神病、躁狂或抑郁复发可导致神经退行性变,其神经毒性的机制包括神经炎症、活性氧、活性氮及细胞凋亡等。上述神经退行性变可导致神经组织丧失及脑功能的下降,不仅影响患者的功能恢复,甚至会影响日后治疗应答及转归。幸运的是,精神科药物治疗不仅可以稳定临床症状,同时还可通过其神经保护作用拮抗神经精神疾病对神经的损害。我们已有很多研究显示,抗抑郁药、心境稳定剂及非典型抗精神病药均具有神经     

L-精氨酸对溶血性磷脂酰胆碱损伤离体大鼠心肌的保护作用

在离体大鼠心脏观察了L-精氨酸对溶血性磷脂酰胆碱 (LPC) 损伤心肌作用的影响. LPC(5 μmol·L^-1) 引起心率减慢, 冠脉流量减少, 心脏功能降低 (LVP和LV dp/dt_ma下降) 及肌酸激酶 (CPK) 释放增加. 30 μmol·L^-1 L-精氨酸能促进心率恢?复, 增加冠脉流量和改善心脏功能, 但仅LV dP/dt_max恢复显?示统计学差异; 300 μmol·L^-1 L-精氨酸能显著改善心脏功能, 促进心率和冠脉流量的恢复, 减少CPK释放. 结果提示: L-精氨酸对LPC所致心肌损伤具有一定的保护作用.     

4-［4″-(2″, 2″, 6″, 6″-四甲基-1″-哌啶氮氧自由基)氨基］-4′-去甲表鬼臼毒素对K562/ADM细胞的抑制作用

目的 比较4-［4″-(2″, 2″, 6″, 6″-四甲基-1″-哌啶氮氧自由基)氨基］-4′-去甲表鬼臼毒素（GP-7）对多药耐药人慢性粒细胞白血病K562的多柔比星耐药株细胞（K562/ADM细胞）的抑制作用是否优于依托泊苷。方法 以依托泊苷和K562细胞为对照，用不同浓度GP-7处理K562/ADM细胞不同时间，MTT比色法测定细胞增殖，流式细胞仪测定细胞周期和细胞凋亡率，普通光学显微镜观察细胞凋亡形态，琼脂糖凝胶电泳观察细胞DNA凋亡性降解。结果 8～128 mol·L^-1 GP-7处理48 h或64 μmol·L^-1 GP-7处理24～72 h，GP-7对K562/ADM细胞的增殖抑制呈剂量依赖性（r=0.947，P＜0.05)和时间依赖性(r=0.999，P＜0.01)。GP-7及依托泊苷对K562/ADM的IC₅₀分别为(45.9±1.8)及(68.7±4.6)μmol·L^-1；64 μmol·L^-1 GP-7作用48 h可使G₂/M期细胞明显增多，相同情况下依托泊苷则使S期细胞明显增多；GP-7可引起K562/ADM和K562细胞凋亡，但其引起的K562/ADM和K562细胞凋亡率与依托泊苷无明显差异；GP-7可引起K562/ADM和K562细胞典型的凋亡形态学变化和DNA凋亡性降解，但GP-7引起的K562/ADM细胞DNA凋亡性降解弱于K562细胞；128及256 μmol·L^-1 GP-7或依托泊苷处理K562/ADM和K562细胞48 h，GP-7诱导DNA凋亡性降解的作用强于依托泊苷，但32和64 μmol·L^-1时作用则相反。结论 GP-7可抑制多药耐药白血病细胞株K562/ADM的增殖,诱导细胞凋亡。GP-7抑制多药耐药白血病细胞株K562/ADM的作用优于依托泊苷。     

General anesthetics in pediatric anesthesia: influences on the developing brain

Millions of newborn and infants receive anesthetic, sedative and analgesic drugs for surgery and painful procedures on a daily basis. However, recent laboratory reports clearly demonstrate that anesthetic and sedative drugs induced both neuroapoptosis and neurocognitive deficits in laboratory models. This issue is of paramount interest to pediatric anesthesiologists and intensivists because it questions the safety of anesthetics used for fetal and neonatal anesthesia. Most clinically utilized anesthetic drugs have been found to induce neuronal cell death in the developing brain and to potentially cause long-term neurological impairment. Conversely, painful stimuli without analgesia and anesthesia have been implicated in triggering neuro-apoptosis in juvenile mammalian models. Published retrospective reviews demonstrate temporary neurological sequelae after prolonged anesthetic exposure in young children and larger studies identify long-term neurodevelopmental impairment after neonatal surgery and anesthesia. This paper examines the evidence for the effects of commonly used anesthetics on neuronal structure and neurocognitive function in laboratory models and reviews the relevant clinical human epidemiologic data.     

General anesthetics and cytotoxicity: possible implications for brain health

Background: The search for agents that bring about faster induction and quicker recovery in the operating room have yielded numerous anesthetics whose mechanisms of action and potential toxic side effects remain unknown, especially in the young and aging brain. Objective: Taking advantage of our clinical and basic science expertise, here we subject the reader to an interesting perspective vis-à-vis the current applications of general anesthetics, and present evidence for their neurotoxic effects on the developing and elderly brains. Results: Recent studies have called into question the safety of general anesthetics, especially with regards to potentially significant detrimental impacts on the developing brains of young children, and cognitive decline in the elderly – often following multiple episodes of anesthesia. Despite accumulating evidence from animal studies demonstrating that general anesthesia leads to neurodegeneration and cognitive impairment, to date a clear consensus on the impact of anesthetics in humans remains elusive. Because a direct impact of anesthetics on human neuronal networks is often difficult to deduce experimentally, most laboratories have resorted to animal models – albeit with limited success in translating these findings back to the clinic. Moreover, the precise mechanisms that lead to potential cognitive, learning, and memory decline in young and elderly patients also remain to be fully defined. Conclusions: This review will focus primarily on the cytotoxic effects of anesthetics, and offer some practical resolutions that may attenuate their long-term harm. An urgent need for studies on animal models and an increased focus on highly controlled prospective epidemiological studies is also reinforced.     

Neurocognitive impairment associated with alcohol use disorders: implications for treatment

Between 50% and 80% of individuals with alcohol use disorders experience mild to severe neurocognitive impairment. There is a strong clinical rationale that neurocognitive impairment is an important source of individual difference affecting many aspects of addiction treatment, but empirical tests of the direct influence of impairment on treatment outcome have yielded weak and inconsistent results. The authors address the schism between applied-theoretical perspectives and research evidence by suggesting alternative conceptual models of the relationship between neurocognitive impairment and addiction treatment outcome. Methods to promote neurocognitive recovery and ways in which addiction treatments may be modified to improve psychosocial adaptation are suggested. Specific suggestions for future research that may help clarify the complex relations between neurocognitive impairment and addiction treatment are outlined.     

Cognitive dysfunction in bipolar disorder: future place of pharmacotherapy

Bipolar disorder is an episodic affective illness, once believed to involve complete inter-episode remission. More recent data have highlighted the presence of persistent symptoms during purported periods of wellness, including subsyndromal affective symptoms and neurocognitive impairment. These unremitting symptoms are of extreme clinical importance, as they are directly related to a worsening of clinical course, functional impairments and psychosocial difficulties in patients with bipolar disorder. Although there is now substantial evidence demonstrating the prevalence of neurocognitive impairment during euthymia, there have been few studies, to date, targeting this disabling aspect of the illness using pharmacological strategies. While treatment approaches have previously focused on primary affective and psychotic symptoms of the disease, it is important to consider the debilitating impact that impaired cognition has on patients with bipolar disorder. A recent focus has been placed on the significant need for large-scale clinical trials designed to specifically target cognitive impairment in patients with schizophrenia, with a parallel need existing in the field of bipolar research. There is now early evidence for the presence of neurocognitive deficits in patients with bipolar disorder and a relationship between these impairments and functional disability, making this a symptom domain that requires immediate clinical attention. Convergent data indicate a compelling need for formal assessment of cognition in patients with bipolar disorder, and for researchers and clinicans alike to consider the necessity for treatment specific to cognition in this population. Although limited data exist from cognitive enhancement trials in this population, there are a number of potential pharmacotherapy targets based on evidence from neuroimaging, molecular genetic, pharmacological and animal studies related to the pathophysiology of bipolar disorder. Future directions for potential cognitive enhancement strategies in bipolar disorder may include medications that influence dopaminergic or glutamatergic neurotransmission; however, further work is needed to adequately assess the safety and effectiveness of these agents in bipolar patients. Finally, psychosocial intervention and/or cognitive remediation should be considered as alternatives to medications, although these techniques will also require additional systematic study.     

Anesthetic-related neurotoxicity and the developing brain: shall we change practice?

Millions of human infants receive general anesthetics for surgery or diagnostic procedures every year worldwide, and there is a growing inquietude regarding the safety of these drugs for the developing brain. In fact, accumulating experimental evidence together with recent epidemiologic observations suggest that general anesthetics might exert undesirable effects on the immature nervous system. The goal of this review is to highlight basic science issues as well as to critically present experimental data and clinical observations relevant to this possibility. By acting on a plethora of ligand-gated ion channels, general anesthetics are powerful modulators of neural activity. Since even brief interference with physiologic activity patterns during critical periods of development are known to induce permanent alterations in brain circuitry, anesthetic-induced interference with brain development is highly plausible. In line with this hypothesis, compelling experimental evidence, from rodents to primates, suggests increased neuroapoptosis and associated long-term neurocognitive deficits following administration of these drugs at defined stages of development. Recent epidemiologic studies also indicate a potential association between anesthesia/surgery and subsequently impaired neurocognitive function in humans. It is, however, important to note that extrapolation of experimental studies to human practice requires extreme caution, and that currently available human data are hindered by a large number of potentially confounding factors. Thus, despite significant advances in the field, there is still insufficient evidence to determine whether anesthetics are harmful to the developing human brain. Consequently, no change in clinical practice can be recommended.     

阿尔茨海默病和轻度认知障碍常用实验动物模型的初步评价

阿尔茨海默病(AD)是一种典型的以进行性认知障碍和行为损害为特征的中枢神经退行性疾病,病理表现主要有细胞外淀粉样蛋白沉积、细胞内神经纤维缠结以及神经元丢失等。轻度认知障碍(MCI)是介于正常认知和AD之间的一种认知缺损状态,MCI具有转化为AD的高度危险性。以往大多通过建立具有临床AD特征的动物模型进行机制研究、药物筛选以及新药研发等,近年来,有研究者尝试建立具有临床MCI特征的动物模型,试图从MCI阶段进行早期干预,从而有效预防AD的发生。AD实验动物模型有多种类型,MCI研究模型应区别于AD模型。该文在对AD和MCI的特点进行较系统介绍的基础上,从模型建立的角度对常用AD和MCI实验动物模型进行了总结和初步评价,尝试为开展AD和MCI的研究提供建议。     

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

Obstructive sleep apnea (OSA) is well known for its metabolic as well as neurobehavioral consequences. Chronic intermittent hypoxia (IH) is a major component of OSA. In recent years, substantial advances have been made in elucidating the cellular and molecular mechanisms underlying the effect of chronic IH on neurocognitive functions, many of which are based on studies in animal models. A number of hypotheses have been put forward to explain chronic IH-induced neurological dysfunctions. Among these, the roles of oxidative stress and apoptosis-related neural injury are widely accepted. Here, focusing on results derived from animal studies, we highlight a possible role of reduced expression of brain-derived neurotrophic factor (BDNF) in causing impairment in long-term synaptic plasticity and neurocognitive functions during chronic IH. The possible relationship between BDNF and previous findings on this subject will be elucidated.     

Neuronal toxicity of efavirenz: a systematic review

Introduction: Efavirenz commonly causes early neuropsychiatric side effects, but tolerance develops in most patients. There is emerging evidence that efavirenz use may damage neurons, which could result in impaired neurocognitive performance.

Areas covered: The authors conducted a systematic review using the PubMed database, references cited by other articles and conference web sites to determine if there is evidence that efavirenz may contribute to cognitive impairment by damaging nerve cells.

Expert opinion: There is weak clinical evidence suggesting that efavirenz use may worsen neurocognitive impairment or be associated with less improvement in neurocognitive impairment than other antiretrovirals. Efavirenz, especially its major metabolite 8-hydroxy-efavirenz, is toxic in neuron cultures at concentrations found in the cerebrospinal fluid. Extensive metabolizers of efavirenz may therefore be more likely to develop efavirenz toxicity by forming more 8-hydroxy-efavirenz. Several potential mechanisms exist to explain the observed efavirenz neurotoxicity, including altered calcium hemostasis, decreases in brain creatine kinase, mitochondrial damage, increases in brain proinflammatory cytokines and involvement of the cannabinoid system. There is a need for large randomized controlled trials to determine if the neuronal toxicity induced by efavirenz results in clinically significant neurological impairment.