Treatment of Alzheimer’s disease across the spectrum of severity

Alzheimer’s disease (AD) is the most common cause of dementia affecting nearly 18 million people around the world and 4.5 million in the US. It is a progressive neurodegenerative condition that is estimated to dramatically increase in prevalence as the elderly population continues to grow. As the cognitive and neuropsychiatric signs and symptoms of AD progresses in severity over time, affected individuals become increasingly dependent on others for assistance in performing all activities of daily living. The burden of caring for someone affected by the disorder is great and has substantial impact on a family’s emotional, social and financial well-being. In the US, the currently approved medications for the treatment of mild to moderate stages of AD are the cholinesterase inhibitors (ChEIs). Cholinesterase inhibitors have shown modest efficacy in terms of symptomatic improvement and stabilization for periods generally ranging from 6 to 12 months. There are additional data that have emerged, which suggest longer-term benefits. For the moderate to severe stages of AD, memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist is in widespread use and has shown modest benefit as monotherapy and in combination with ChEIs. The cost effectiveness of the currently available therapeutic agents for AD has undergone great scrutiny and remains controversial, especially outside the US. Neuropsychiatric symptoms such as agitation and psychosis are common in AD. Unfortunately, in the US there are no Food and Drug Administration (FDA)-approved agents for the treatment of these symptoms, although atypical antipsychotics have shown some efficacy and have been widely used. However, the use of these agents has recently warranted special caution due to reports of associated adverse effects such as weight gain, hyperlipidemia, glucose intolerance, cerebrovascular events, and an increased risk for death. Alternative agents used to treat neuropsychiatric symptoms include serotonergic antidepressants, benzodiazepines, and anticonvulsant medications.     

Patch clamp studies on the kinetics and selectivity of N-methyl-d-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan)

Memantine (1-amino-3,5-dimethyladamantan) was tested as an antagonist of N-methyl-d-aspartate (NMDA) receptors on cultured superior collicular and hippocampal neurones using the patch clamp technique and its actions were compared to those of Mg²⁺ ions, ketamine, dextrorphan, dextromethorphan, phencyclidine and dizocilpine (MK-801). Memantine (2–33 μM) concentration-dependently antagonized responses to NMDA 100 μM with an IC₅₀ of 2.92 ± 0.05 μM. In contrast, current responses to (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (l-AMPA 50–100 μM) and γ-amino butyric acid (GABA 10 μM) were unaffected by Memantine 8 μM. Memantine 8 μM caused a non-parallel shift of the NMDA concentration-response curve to the right in a manner indicative of uncompetitive open channel block. The effects of memantine were similar to ketamine in that both antagonists were weakly use- and strongly voltage-dependent. In contrast, MK-801, phencyclidine and dextrorphan showed much slower kinetics that was reflected in their marked use- and weaker voltage-dependency. The antagonistic effects of memantine were not reversed by increasing concentrations of glycine (0.1–100 μM) ruling out the possibility of an interaction of memantine with the strychnine-insensitive glycine modulatory site associated with the NMDA receptor-channel complex. Memantine (1–100 μM) also selectively antagonized responses to NMDA (40 μM) in the cortical wedge preparation with IC₅₀ of 12.9 ± 1.5 μM.     

Memantine,amantadine, and L-deprenyl potentiate the action of L-DOPA in monoamine-depleted rats

Summary Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and -methyl-p-tyrosine. In the present study memantine (2.5, 5.0mg/kg), amantadine (10, 20mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0mg/kg) and L-DOPA (50, 100mg/kg, + benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10mg/kg) and L-DOPA (100, 200mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-DOPA produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-DOPA with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.     

美金胺、黄芪对新生大鼠脑缺氧缺血再灌注损伤的保护作用

目的 评价美金胺和黄芪对新生大鼠缺氧缺血再灌注损伤的脑保护作用。方法 通过夹闭新生大鼠双侧颈总动脉1h、缺氧2h，建立脑缺氧缺血再灌注损伤模型。将新生大鼠随机分成正常对照组、假手术组、缺氧缺血再灌注组(HIR组)、美金胺治疗组、黄芪治疗组、黄芪和美金胺联合治疗组，每组12只，于术后6h或48h处死。取耳间线前2mm水平做冠状位脑组织切片，通过脑组织病理检查及病理评分评估美金胺和黄芪的脑保护效果。结果 缺氧缺血可引起新生大鼠明显的脑病理改变，经单独或联合应用黄芪和美金胺后，新生大鼠的脑病理改变明显减轻，各治疗组病理评分均显著低于缺血再灌注组。结论美 金胺和黄芪对治疗新生儿脑缺氧缺血损伤可能具有一定的潜在意义，尤其两药联合治疗新生儿脑缺氧缺血损伤，有望获得更好效果。     

金刚烷类药物的研究进展

对具有饱和三环癸烷结构的金刚烷胺类药物的抗病毒、抗帕金森氏综合征、抗丙型肝炎等临床药理作用及部分药物的合成路线作一综述。     

Molecular mechanisms for the antidepressant-like effects of a low-dose ketamine treatment in a DFP-based rat model for Gulf War Illness

Exposure to organophosphates (OP) during the First Gulf War is among one of the factors for Gulf War Illness (GWI) development in veterans and it has been challenging to treat GWI symptoms with existing therapies. Ketamine produces a rapid-onset and sustained antidepressant response, but there is no evidence whether ketamine treatment is effective for GWI depression. Repeated, low-dose exposure to diisopropyl fluorophosphate (DFP) mimic Gulf War related OP exposures and produces a chronic depressive state in rats. In this study, DFP-exposed rats treated with ketamine (10 mg/kg, i.p.) exhibited antidepressant-like effect on the Forced Swim Test at 1-h. This effect persisted at 24-h post ketamine, a time-point by which it is eliminated from the brain suggesting involvement of mechanisms that affect long-term synaptic plasticity. Western blot analysis showed significantly lower Brain-Derived Neurotrophic Factor (BDNF) levels in DFP rat brains. Ketamine produced a nonsignificant increase in BDNF expression at 1-h but produced a larger, significant (2.2-fold) increase at 24-h in DFP rats. We previously reported chronic hippocampal calcium elevations ([Ca²⁺]_i) in DFP rats. Ketamine-treated DFP rats exhibited significantly lower [Ca²⁺]_i at 1-h but not at 24-h. Interestingly, treatment with ANA-12, a TrkB-BDNF receptor antagonist, in DFP rats blunted ketamine’s antidepressant-like effect at 24-h but not at 1-h. These experiments suggest that in a rat model of DFP-induced depression, inhibition of the NMDAR-Ca²⁺ contributes to the rapid-onset antidepressant effects of ketamine while the antidepressant actions that persisted at 24-h post ketamine administration involve upregulation of BDNF signaling.     

五种治疗阿尔茨海默病药物分子结构与性质的密度泛函计算分析

目的：在模拟大脑油性环境下对五种抗阿尔茨海默病药物进行整体和局部性质计算比较分析。方法：采用密度泛函B3LYP/TZVP计算方法,对五种抗阿尔茨海默病药物的几何结构、电子结构、紫外光谱和概念密度泛函分析,利用环己烷模拟大脑油性环境。结果：共轭效应使得极性键键长缩短;静电势差异决定了分子间作用位点的不同,在酶反应中,与蛋白质构象的改变密切相关;溶剂效应对紫外光谱产生影响,其中溶剂的极性越大红移越大。由福井函数结合相对亲电指数与相对亲核指数,表明多奈哌齐和卡巴拉汀亲电、亲核能力都很强,加兰他敏亲核能力强,美金刚和石杉碱甲亲电、亲核能力均比较弱。结论：五种药物分子的结构差异、电性差异影响药物的理化性质并决定了药物不同的作用机制。四种抗胆碱酯酶抑制剂活性略有差异但明显高于N-甲基-D-天冬氨酸受体拮抗剂,其中多奈哌齐药理作用最强。     

Differentiation renders susceptibility to excitotoxicity in HT22 neurons

HT22 is an immortalized mouse hippocampal neuronal cell line that does not express cholinergic and glutamate receptors like mature hippocampal neurons in vivo.This in part prevents its use as a model for mature hippocampal neurons in memory-related studies.We now report that HT22 cells were appropriately induced to differentiate and possess properties similar to those of mature hippocampal neurons in vivo,such as becoming more glutamate-receptive and excitatory.Results showed that sensitivity of HT22 cells to glutamate-induced toxicity changed dramatically when comparing undifferentiated with differentiated cells,with the half-effective concentration for differentiated cells reducing approximately two orders of magnitude.Moreover,glutamate-induced toxicity in differentiated cells,but not undifferentiated cells,was inhibited by the N-methyl-Daspartate receptor antagonists MK-801 and memantine.Evidently,differentiated HT22 cells expressed N-methyl-D-aspartate receptors,while undifferentiated cells did not.Our experimental findings indicated that differentiation is important for immortalized cell lines to render post-mitotic neuronal properties,and that differentiated HT22 neurons represent a better model of hippocampal neurons than undifferentiated cells.     

硫化氢供体型美金刚衍生物的合成及其活性

H₂S具有保护缺血再灌注损伤的神经元、显著降低脑梗死面积的作用,但高浓度H₂S产生神经毒性。N-甲基-D-天冬氨酸(NMDA)受体拮抗剂美金刚可以降低高浓度H₂S引起的神经毒性。将硫化氢缓释供体5-对羟基苯基-1,2-二硫杂环戊烯-3-硫酮(ADT-OH)与美金刚通过烷烃连接臂拼合,设计了9个结构全新的化合物I₁~I₉,以ADT-OH为原料,经过4步反应得到目标化合物,其化学结构经¹H NMR、¹³C NMR和HRMS确证。利用MTT法评价不同浓度目标化合物对谷氨酸损伤的HT-22细胞的影响,结果发现,该类化合物在1 μmol/L时能明显提高受损HT-22细胞的生存率(P<0.01),对于谷氨酸诱导损伤的神经元细胞具有较好的保护作用。