石杉碱甲治疗老年性记忆功能减退

石杉碱甲是我国首先从石杉属植物Haperzia serrata(Thunb.)Trev.中分到的一种新生物碱,具有明显抗胆碱酯酶作用。用双盲法,10词提醒测验并与海特琴比较,共观察100例老年性记忆减退患者,其中男54,女46例,年龄46-82岁,石杉碱甲30μg肌注后1-4h记忆功能明显改善,作用持续约6h,无明显副作用,优于海特琴600μg肌注。     

石杉碱甲片剂对记忆的作用

老年性痴呆及良性老年性记忆功能减退患者24例,男女各12例,年龄50-68yr,平均58±SD4yr,病程2-10yr,平均5.0±0.4yr。分为治疗组和对照组各12例,应用石杉碱甲片剂100-500μg9组不同剂量tid口服,以双盲法、韦氏记忆量表、十词提醒法对照比较,发现150-300μg的4组的记忆功能有明显提高。     

The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys

IDRA 21, a positive allosteric modulator of the glutamate AMPA receptor, produced a concentration-dependent inhibition of glutamate-induced inactivation of membrane currents in recombinant HEK 293 (human embryonic kidney) cells stably transfected with human GluR1/2 flip receptors. IDRA 21 doubled the charge transfer at a concentration of 70 microM, suggesting that this compound can facilitate excitatory neurotransmission via GluR 1/2 receptors. We next sought to exploit this mechanism of action by examining the drug as a potential cognition-enhancing agent in non-human primates. Oral administration of IDRA 21 produced a highly significant improvement in the performance of a delayed matching-to-sample (DMTS) task by young adult rhesus monkeys. The pattern of task improvement over the dose range 0.15-10 mg/kg was maintained to 48 hr after the single dose administration. For sessions run after administration of the individualized Best Dose of IDRA 21, task accuracy for Long delay (most difficult) trials was increased by 34% of vehicle. Animals were randomly assigned fixed doses of IDRA 21 to determine whether the positive mnemonic response could be maintained. The repeated doses were separated by 3 days, thus allowing for potential cumulative effects. IDRA 21 produced a gradual increase in task accuracy that was maintained on average above vehicle performance levels over an intermittent dosing schedule during a total period of 3 weeks. A separate group of aged monkeys (>20 y) were, as a group, impaired (during vehicle testing) in DMTS performance efficiency relative to the young cohort. IDRA 21 also improved task accuracy by aged rhesus monkeys over the same dose range, but the responses were not as robust as those exhibited by young animals. Aged subjects also appeared to be more individually sensitive to drug dose, and they exhibited shorter task latencies than did the young group. Despite these differences, when the individualized Best Doses were considered, IDRA 21 produced a robust increase in DMTS accuracy of up to 18% of vehicle for trials associated with Medium delay intervals. For both study groups, no obvious untoward effects of IDRA 21 were noted. These findings support the use of AMPA modulators like IDRA 21 in the treatment of cognitive/memory disorders, including those associated with aging. They also indicate that the drug is associated with long-term effects that could limit dosing regimens to one dose every two or three days. The nature of the protracted mnemonic effects produced by the compound remains to be elucidated.     

Effects of chronic administration of huperzine A on memory in guinea pigs

Effects of subchronic administration of huperzine A, a cholinesterase inhibitor, on spatial memory were studied in guinea pig. Spatial memory was appreciated by the Morris water maze test. At a dose of 0.25 microgram/h, inhibiting 36% of blood AChE and 14-20% of central AChE, no effect on spatial learning was found. At a dose of 1 microgram/h, inhibiting 20% of blood AChE and 14-20% of central AChE, no memory impairment was found, on the other hand, a memory enhancing effect, limited to the first day was shown. It thus appears that subchronic administration of huperzine A did not induce deleterious effects on spatial memory.     

Serial-probe recognition in rhesus macaques: effects of midazolam

A serial-probe recognition task was used to assess the effects of midazolam on visual attention and short-term memory in three rhesus monkeys. On each trial, six unique alphanumeric sample stimuli (list items) were presented sequentially followed by a choice period. Choosing the 'probe' stimulus was correct if the probe matched one of the list items; otherwise, choosing the 'default' stimulus (a white square) was correct. Behavior was examined under a range of doses of midazolam (0.065, 0.13, 0.26, and 0.52 mg/kg IM). Midazolam did not significantly reduce choice accuracy or change the shape of the serial position function and did not significantly reduce choice responding. However, choice reaction time was significantly increased by the two highest doses of midazolam. Responding directed at the sample stimuli was reduced at the two highest doses of midazolam. Furthermore, 0.52 mg/kg midazolam significantly increased sample-stimulus reaction time at all six serial positions. Overall, these data suggest that the two highest doses of midazolam tested increase reaction time, but do not directly impair short-term visual recognition memory. This is noteworthy because such doses appear capable of protecting against nerve agent-induced seizures.     

The effects of scopolamine on working memory in healthy young volunteers

Twenty healthy young adults completed a series of nonverbal and problem solving tasks in a repeated measures design involving placebo and 0.6 mg scopolamine, administered by subcutaneous injection. Subjects completed the test battery under standard presentation conditions and with concurrent articulation, which precludes verbal recoding of test material. Under standard presentation conditions, scopolamine significantly impaired performance on the problem solving task and on tasks of visuo-spatial and spatial memory; memory for abstract shapes was not impaired. Concurrent articulation impaired performance on the shape recognition and interacted with drug treatment on the problem solving task. The results suggest that scopolamine impairs working memory, and that the decrement is at the level of the central executive mechanism rather than the subsystems which it controls.     

石杉碱甲和他克林对大鼠肝脏的急性效应

目的：观察石杉碱甲（HupA）和他克林（TAH）对大鼠肝脏的急性效应。方法：单次给药后检测肝脏系数和血液生化指标,观察组织病理学变化。肝细胞体外培养检测细胞内外乳酸脱氢酶。结果：HupA和TAH均可引起大鼠肝脏系数增加,天冬酸氨基转移酶和丙氨酸氨基转移酶增高。TAH可导致肝脏组织病理学变化。阿托品可纠正HupA对肝脏的急性效应,而不能纠正TAH对肝脏的急性效应,肝细胞体外培养显示TAH可引起剂量相关的细胞毒性,而未见HupA有肝细胞毒性。结论：HupA对大鼠肝脏的急性效应与肝毒性无关,TAH对大鼠肝脏的急性效应与肝毒性有关。     

Prolonged effects of poly(lactic-co-glycolic acid) microsphere-containing huperzine A on mouse memory dysfunction induced by scopolamine

Huperzine A is an anticholinesterase and cognitive enhancer, which is able to alleviate the symptoms of memory dysfunction in the mouse. The fast metabolization rate and narrow therapeutic spectrum makes it unfit for clinical use. Poly(lactic-co-glycolic acid) microsphere as delivery system effectively maintains the blood concentration of huperzine A by a slow-release effect over a long time. In the present article, we investigated the prolonged protective effect of microsphere-containing huperzine A on memory dysfunction induced by scopolamine. Spectrophotometric assay was used to determine the activity of acetylcholinesterase (AChE) and passive avoidance tests to evaluate memory performance. The results show that a bolus dose of microsphere-containing huperzine A (at a dose of 300 microg/kg or 600 microg/kg) administered intramuscularly can effectively maintain drug activity and significantly decrease the activity of AChE from day 3 to 14, the strongest effect seen on day 3 and 7. Accompanying the reduction of the activity of AChE, microsphere-containing huperzine A (300 microg/kg or 600 microg/kg) remarkably increased transfer latency time and no transfer response on the second trial through mitigating the memory impairments induced by scopolamine as compared to the scopolamine model group. Microsphere-containing huperzine A showed cognitive enhancing properties and anticholinesterase activity and may thus be a candidate for treatment of memory impairment.     

石杉碱甲对基底核大细胞部损毁所致工作记忆障碍的影响

目的：研究石杉碱甲对基底核大细胞部（ＮＢＭ）损毁诱导的工作记忆障碍的影响。方法：采用八臂迷宫延迟板程序研究空间记忆。胆碱乙酰转移酶（ＣｈＡＴ）活力测定采用［＾３Ｈ］乙酰辅酶Ａ转变成［＾３Ｈ］乙酰胆碱的方法。结果：单侧损毁ＮＢＭ（卡因酸０．０２μｍｏｌ）导致空间记忆障碍。在不同的延迟间隔，大鼠完成程序产生的正确数减少和错误数增多。损毁侧大脑皮层ＣｈＡＴ酶的含量下降了大约４０％。石杉碱甲（０．２ｍｇ·     

Effects of huperzine A on nucleus basalis magnocellular is lesion-induced spatial working memory deficit

目的：研究石杉碱甲对基底核大细胞部（ＮＢＭ）损毁诱导的工作记忆障碍的影响．方法：采用八臂迷宫延迟插板的程序研究空间记忆．胆碱乙酰转移酶（ＣｈＡＴ）活力测定采用［３Ｈ］乙酰辅酶Ａ转变成［３Ｈ］乙酰胆碱的方法．结果：单侧损毁ＮＢＭ（卡因酸００２μｍｏｌ）导致空间记忆障碍．在不同的延迟间隔，大鼠完成程序产生的正确数减少和错误数增多．损毁侧大脑皮层ＣｈＡＴ酶的含量下降了大约４０％．石杉碱甲（０２ｍｇ·ｋｇ－１实验前３０ｍｉｎｉｐ）改善这种空间记忆障碍．毒扁豆碱（０２－０３ｍｇ·ｋｇ－１实验前２０ｍｉｎｉｐ）也有改善作用．结论：完整的ＮＢＭ是空间记忆形成的关键．石杉碱甲有效的改善ＮＢＭ损毁导致的空间记忆障碍．     

Galanin regulates spatial memory but not visual recognition memory or synaptic plasticity in perirhinal cortex

It has previously been shown that the neuropeptide galanin plays a role in the age-dependent regulation of hippocampal synaptic plasticity and spatial memory. Here, we further extend these studies by demonstrating that galanin knockout mice also have deficits in an object-in-place spatial memory task. In contrast however, there is no deficit in single item object recognition memory, a memory that depends on perirhinal cortex. Furthermore, in perirhinal cortex slices there are no differences in activity-dependent long-term potentiation or depotentiation, nor in muscarinic receptor-dependent long-term depression between galanin knockout mice and wild-type litter-mates. Therefore, these results suggest that galanin has a differential role in hippocampal-dependent and perirhinal cortex-dependent memory.     

Dissociative effects of scopolamine on working memory in healthy young volunteers

Performance on tasks of digit span, mental rotation and immediate free recall of supraspan word lists was measured before and after oral administration of 1.2 mg scopolamine or placebo to healthy young volunteers. Digit span and mental rotation were sensitive to task-specific interference from articulatory suppression and spatial tapping tasks, respectively. Neither task was affected by scopolamine when completed alone or in combination with a secondary task. A concurrent secondary task reduced immediate free recall in a nonspecific fashion (i.e., spatial tapping or articulatory suppression impaired performance equally). Scopolamine significantly reduced the number of words recalled under all conditions. The results are interpreted as evidence for selective impairment of the central executive mechanism by scopolamine without disruption of function in the articulatory loop or visuospatial scratch pad.     

石杉碱甲的研究进展

综述石杉碱甲的研究进展,分别从作用机制、药理作用、合成以及结构修饰等方面对石杉碱甲的研究进行总结,并简述其发展方向：ZT-1作为石杉碱甲的替代物,已经在欧洲完成II期临床,有望成为我国具有自主知识产权,又有希望打入国际市场的创新药物。     

Arousal and stress effects on consolidation and reconsolidation of recognition memory.

This study examined the effects of the arousal level of the rat and exposure to a behavioral stressor on consolidation and reconsolidation of a nonaversive learning paradigm, the object recognition task. Learning was tested under two arousal conditions: no previous habituation to the experimental context (high novelty stress/arousal level) or extensive prior habituation (reduced novelty stress/arousal level). Results indicated that in the habituated rats, exposure to an out-of-context stressor (ie, elevated platform stress) impaired long-term consolidation and reconsolidation of object recognition. RU-486, a glucocorticoid receptor (GR) antagonist, infused into the basolateral amygdala (BLA), reversed the impairing effects of the stressor. In contrast, the nonhabituated aroused rats were impaired when consolidation was examined, but their memory was intact following reactivation of the memory trace. Exposure of nonhabituated rats to an out-of-context stressor enhanced the long-term consolidation of recognition memory, but impaired reconsolidation, and the effects were reversed by a GR antagonist infused into the BLA. Additionally, nonhabituated control rats showed intact retrieval following microinfusion of propranolol to the BLA immediately after the training, suggesting an involvement of beta-adrenoceptors in the BLA in the arousal-induced impairment of consolidation. These findings demonstrate opposite effects, detrimental and facilitative, of arousal and stress on memory consolidation and reconsolidation. In addition, the data suggests that although some general features underlie consolidation and reconsolidation, there is a possible dissimilarity between the two processes, which is dependent on the arousal level of the animal during training.     

Inhibitory effects of huperzine B on cholinesterase activity in mice

目的：测试石杉碱乙的抗胆碱酯酶作用并与他克林进行比较．方法：比色法用于测定胆碱酯酶活性．结果：石杉碱乙和他克林对ＢｕＣｈＥ和ＡＣｈＥ抑制的ＩＣ５０值的比率分别为６５８和０５４．石杉碱乙对乙酰胆碱酯酶有更强的选择性抑制作用．石杉碱乙灌胃对脑内ＡＣｈＥ的抑制作用明显强于他克林．而他克林对ＢｕＣｈＥ的抑制作用强于石杉碱乙,并有严重副反应．单次灌胃石杉碱乙在４小时内对脑内ＡＣｈＥ产生较为稳定的抑制作用．结论：与他克林比较石杉碱乙是乙酰胆碱酯酶的高选择性抑制剂,灌胃时药效高,毒性低．     

石杉碱甲对老年大鼠异常的脂质过氧化和超氧化物歧化酶的改善作用(英文)

目的:研究石杉碱甲对老年大鼠海马、皮层和血清的脂质过氧化和超氧化物歧化酶的作用。方法:硫代巴比妥酸法测定组织中MDA水平;黄嘌呤氧化酶法测定组织中超氧化物歧化酶的活性。结果:雄性老年大鼠海马、皮层和血清中MDA水平和Mn-SOD活性明显高于成年大鼠。石杉碱甲明显降低雄性老年大鼠海马、皮层和血清中MDA水平和SOD活性,而对成年大鼠的这两项指标无明显影响。结论:石杉碱甲能明显改善衰老导致的自由基系统的异常变化,这种神经保护作用可能有益于AD的治疗。