Chvojkova Marketa, Kubova Hana, Vales Karel
Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic.
Brain Sci. 2021 Mar 22;11(3):400. doi: 10.3390/brainsci11030400.
Research of treatment options addressing the cognitive deficit associated with neurodegenerative disorders is of particular importance. Application of trimethyltin (TMT) to rats represents a promising model replicating multiple relevant features of such disorders. N-methyl-D-aspartate (NMDA) receptor antagonists and gamma-aminobutyric acid type A (GABA) receptor potentiators have been reported to alleviate the TMT-induced cognitive deficit. These compounds may provide synergistic interactions in other models. The aim of this study was to investigate, whether co-application of NMDA receptor antagonist dizocilpine (MK-801) and GABA receptor potentiator midazolam would be associated with an improved effect on the TMT-induced model of cognitive deficit. Wistar rats injected with TMT were repeatedly (12 days) treated with MK-801, midazolam, or both. Subsequently, cognitive performance was assessed. Finally, after a 17-day drug-free period, hippocampal neurodegeneration (neuronal density in CA2/3 subfield in the dorsal hippocampus, dentate gyrus morphometry) were analyzed. All three protective treatments induced similar degree of therapeutic effect in Morris water maze. The results of histological analyses were suggestive of minor protective effect of the combined treatment (MK-801 and midazolam), while these compounds alone were largely ineffective at this time point. Therefore, in terms of mitigation of cognitive deficit, the combined treatment was not associated with improved effect.
针对与神经退行性疾病相关的认知缺陷的治疗方案研究尤为重要。给大鼠应用三甲基锡（TMT）是一种很有前景的模型，可复制此类疾病的多个相关特征。据报道，N-甲基-D-天冬氨酸（NMDA）受体拮抗剂和γ-氨基丁酸A型（GABA）受体增强剂可减轻TMT诱导的认知缺陷。这些化合物在其他模型中可能会产生协同作用。本研究的目的是调查NMDA受体拮抗剂地佐环平（MK-801）和GABA受体增强剂咪达唑仑联合应用是否会对TMT诱导的认知缺陷模型产生更好的效果。给注射了TMT的Wistar大鼠反复（12天）给予MK-801、咪达唑仑或两者。随后，评估认知表现。最后，在17天的无药期后，分析海马神经变性（背侧海马CA2/3亚区的神经元密度、齿状回形态学）。所有三种保护性治疗在莫里斯水迷宫中诱导出相似程度的治疗效果。组织学分析结果提示联合治疗（MK-801和咪达唑仑）有轻微的保护作用，而在这个时间点单独使用这些化合物基本无效。因此，就减轻认知缺陷而言，联合治疗并未产生更好的效果。
