NMDA channel blockers: memantine and amino-aklylcyclohexanes –In vivo characterization

The previous overviews provided the basis for better therapeutic efficacy/tolerability of low to moderate affinity NMDA channel blockers. This prediction finds support in in vitro studies comparing protective and plasticity impairing effects (therapeutic vs. side-effect) of memantine and (+)MK-801. In fact it turned out that memantine had a far better therapeutic index. But can it be confirmed in the in vivo situation?     

Design,synthesis, and evaluation of polyamine-memantine hybrids as NMDA channel blockers

N-Methyl-d-aspartate (NMDA) receptors have been implicated in learning and memory, and may also play a central role in various conditions leading to neuronal degradation. NMDA receptor antagonists could therefore be of therapeutic benefit for a number of neurological disorders. We have designed hybrid compounds of polyamines and memantine, both of which function as NMDA channel blockers. The triamine derivative with a guanidine moiety showed more potent antagonistic activity than memantine.     

Triptolide derivatives as potential multifunctional anti-Alzheimer agents: Synthesis and structure–activity relationship studies

Owning to the promising neuroprotective profile and the ability to cross the blood–brain barrier, triptolide has attracted extensive attention. Although its limited solubility and toxicity have greatly hindered clinical translation, triptolide has nonetheless emerged as a promising candidate for structure–activity relationship studies for Alzheimer’s disease. In the present study, a series of triptolide analogs were designed and synthesized, and their neuroprotective and anti-neuroinflammatory effects were then tested using a cell culture model. Among the triptolide derivatives tested, a memantine conjugate, compound 8, showed a remarkable neuroprotective effect against Aβ_1–42 toxicity in primary cortical neuron cultures as well as an inhibitory effect against LPS-induced TNF-α production in BV2 cells at a subnanomolar concentration. Our findings provide insight into the different pharmacophores that are responsible for the multifunctional effects of triptolide in the central nervous system. Our study should help in the development of triptolide-based multifunctional anti-Alzheimer drugs.     

<Emphasis Type="Italic">N</Emphasis>-Methyl-<Emphasis Type="SmallCaps">d</Emphasis>-aspartate Receptor Antagonists Have Variable Affect in 3-Nitropropionic Acid Toxicity

There is accumulating evidence that excitotoxicity and oxidative stress resulting from excessive activation of glutamate (N-methyl-d-aspartate) NMDA receptors are major participants in striatal degeneration associated with 3-nitropropionic acid (3NP) administration. Although excitotoxic and oxidative mechanisms are implicated in 3NP toxicity, there are conflicting reports as to whether NMDA receptor antagonists attenuate or exacerbate the 3NP-induced neurodegeneration. In the present study, we investigated the involvement of NMDA receptors in striatal degeneration, protein oxidation and motor impairment following systemic 3NP administration. We examined whether NMDA receptor antagonists, memantine and ifenprodil, influence the neurotoxicity of 3NP. The development of striatal lesion and protein oxidation following 3NP administration is delayed by memantine but not affected by ifenprodil. However, in behavioral experiments, memantine failed to improve and ifenprodil exacerbated the motor deficits associated with 3NP toxicity. Together, these findings suggest caution in the application of NMDA receptor antagonists as a neuroprotective agent in neurodegenerative disorders associated with metabolic impairment.     

Inhibitory effect of memantine, an NMDA-receptor antagonist, on electoporation-induced inward currents in pituitary GH3 cells

The membrane electroporation-induced inward current (I_MEP) in pituitary tumor (GH₃) cells was characterized. This current emerges irregularly when membrane hyperpolarizations to −200 mV with a holding potential of −80 mV were elicited. Neither E-4031 (10 μM), glibenclamide (30 μM), nor ZD7288 (30 μM) caused any effects on I_MEP. The single-channel conductance and pore radius were estimated to be around 1.12 nS and 1.7 nm, respectively. LaCl₃- and memantidine (MEM)-induced block of this current was also examined. The IC₅₀ value for LaCl₃- and MEM-induced inhibition of I_MEP was 35 and 75 μM, respectively. However, unlike LaCl₃, MEM (300 μM) did not exert any effect on voltage-gated Ca²⁺ current. In inside-out configuration, MEM applied to either external or internal surface of the excised patch did not suppress the activity of ATP-sensitive K⁺ channels expressed in GH₃ cells, although glibenclamide significantly suppressed channel activity. This study provides the first evidence to show that MEM, a non-competitive antagonist of N-methyl D-aspartate receptors, directly inhibits the amplitude of I_MEP in pituitary GH₃ cells. MEM-mediated block of I_MEP in these cells is unlinked to its inhibition of glutamate-induced currents or ATP-sensitive K⁺ currents. The channel-suppressing properties of MEM might contribute to the underlying mechanisms by which it and its structurally related compounds affect neuronal or neuroendocrine function.     

针灸联合多奈哌齐和美金刚对重度老年痴呆患者行为能力和认知功能的影响

目的:研究针灸联合多奈哌齐和美金刚对重度老年痴呆患者行为能力和认知功能的影响。方法:选择2015年1月～2018年12月在我院精神科进行诊治的50例重度老年痴呆患者,采用随机数字表法将其平均分为两组,每组25例。对照组患者口服多奈哌齐以及美金刚治疗,初始给药剂量均为每天口服5 mg,逐渐将给药剂量升高至每天口服20 mg,每次1片,每天2次。观察组患者采取针灸联合多奈哌齐和美金刚治疗,每天针灸治疗1次,每治疗6 d后休息1 d。两组患者均连续治疗4周。记录和比较两组患者治疗前后的日常生活能力与认知功能的变化情况。结果:观察组患者治疗4w后的治疗有效率为92.00%(23/25),明显高于对照组[68.00%(17/25)](P0.05);两组治疗4w后的MMSE和BI评分均显著高于治疗前(P0.05),且观察组以上指标均显著高于对照组(P0.05)。结论:针灸联合多奈哌齐和美金刚对重度老年痴呆患者的治疗效果明显优于单纯使用多奈哌齐和美金刚治疗,其可更有效改善患者的行为能力和认知功能。     

血塞通滴丸联合盐酸美金刚治疗阿尔茨海默病的临床研究

目的：分析血塞通滴丸联合盐酸美金刚治疗阿尔茨海默病（Alzheimer＇s disease,AD）患者的临床疗效及安全性。方法：本院就诊的AD患者60例。对照组给予盐酸美金刚,观察组在对照组的基础上给予血塞通滴丸。结果：治疗后观察组MMSE、ADL及GDS评分明显优于对照组,差异显著（P〈0．05）。治疗后观察组TC、LDL-C明显少于对照组,差异显著（P〈0.05）。两组均未出现明显不良反应患者。结论：应用血塞通滴丸联合盐酸美金刚治疗AD患者近期疗效好,毒副作用少,临床价值高。     

The role of LINC00094/miR‐224‐5p (miR‐497‐5p)/Endophilin‐1 axis in Memantine mediated protective effects on blood‐brain barrier in AD microenvironment

The dysfunction of the blood‐brain barrier (BBB) is one of the main pathological features of Alzheimer's disease (AD). Memantine (MEM), an N‐methyl‐d ‐aspartate (NMDA) receptor antagonist, has been reported that been used widely for AD therapy. This study was performed to demonstrate the role of the MEM in regulating BBB permeability in AD microenvironment as well as its possible mechanisms. The present study showed that LINC00094 was dramatically increased in Abeta_1‐42‐incubated microvascular endothelial cells (ECs) of BBB model in vitro. Besides, it was decreased in MEM‐incubated ECs. Silencing LINC00094 significantly decreased BBB permeability, meanwhile up‐regulating the expression of ZO‐1, occludin and claudin‐5. Furthermore, silencing LINC00094 enhance the effect of MEM on decreasing BBB permeability in AD microenvironment. The analysis of the mechanism demonstrated that reduction of LINC00094 inhibited Endophilin‐1 expression by up‐regulating miR‐224‐4p/miR‐497‐5p, promoted the expression of ZO‐1, occludin and claudin‐5, and ultimately alleviated BBB permeability in AD microenvironment. Taken together, the present study suggests that the MEM/LINC00094/miR‐224‐5p (miR‐497‐5p)/Endophilin‐1 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment. Silencing LINC00094 combined with MEM provides a novel target for the therapy of AD.     

Separation methods for tricyclic antiviral drugs

A review of the published analytical methodology for the tricyclic antiviral (TAV) drugs is presented. While amantadine and rimantadine are the only two approved drugs for the prophylaxis and treatment of the influenza A virus, amantadine has also been approved for the treatment of Parkinson’s disease. In addition, a few structurally related compounds are finding important clinical applications in other central nervous system-related disorders. To effectively evaluate the pharmacokinetics, biotransformations, stability, and other critical parameters that are necessary for pre-clinical and clinical studies, analytical methodology that conforms to the rigors of regulatory requirements must be developed and made available. This review discusses the analytical methods used in the determination of amantadine, rimantadine, tromantadine and memantine and the pre-clinical and clinical application of these techniques.     

NGP1-01 is a Brain-permeable Dual Blocker of Neuronal Voltage- and Ligand-operated Calcium Channels

Calcium overload of neurons leads to cell death and is a key feature in neurodegenerative diseases. The polycyclic amine NGP1-01 blocks L-type voltage operated calcium channels in cardiomyocytes. Here, we tested whether NGP1-01 blocks neuronal calcium channels. NGP1-01 (1 μM) inhibited depolarization-induced calcium influx by 78% in cortical neurons preloaded with fura-2 AM, with a potency similar to nimodipine. NGP1-01 (1 μM) also inhibited N-methyl-d-aspartate (NMDA)-induced (1 mM) calcium influx by 52%, only slightly less potent than memantine. Using in vivo-microdialysis, we monitored choline release during NMDA infusion as a measure of excitotoxic membrane breakdown. Intraperitoneal injection of NGP1-01 (40 mg/kg) reduced NMDA-induced membrane breakdown by 31% (P<0.01) while memantine (10 mg/kg) reduced choline release by 40%. Our results demonstrate that NGP1-01 simultaneously blocks both major neuronal calcium channels and is sufficiently brain-permeable. We conclude that NGP1-01 is a promising lead structure for a new class of dual-mechanism neuroprotective agents.