利用拉米夫定在大鼠中建立小脑肢体运动失调和空间记忆损伤模型：初步研究。
Modeling cerebellar limb dysmetria and impaired spatial memory in rats using lamivudine: A preliminary study.
机构信息
Department of Anatomy, College of Medicine, University of Lagos, P.M.B. 12003, Idi-Araba, Lagos, Nigeria.
Department of Haematology and Blood Transfusion, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria.
出版信息
J Chem Neuroanat. 2020 Nov;109:101838. doi: 10.1016/j.jchemneu.2020.101838. Epub 2020 Jun 20.
BACKGROUND AND AIM
Neurodegeneration has been associated with the use of combination antiretroviral therapy (cART). This study is aimed at determining if any constituent of cART can induce cerebellar limb dysmetria and spatial memory impairments.
MATERIALS AND METHODS
Forty adult male Wistar rats were randomly grouped into four (n = 10): control (distilled water 0.5 mL); Tenofovir (6 mg/kg); Lamivudine (6 mg/kg) and Efavirenz (12 mg/kg). The following neurobehavioral studies were conducted: open field, beam walk, and Morris water maze. Immunohistochemistry of CD 68 and GFAP were used to test for neuroinflammation and neurodegeneration.
RESULTS
There was marked increase in pyknotic pyramidal cells of the hippocampus and ghost Purkinje cells in the cerebellum of treatment groups. There was also a significant increase in oxidative stress in lamivudine and efavirenz groups. In addition, Lamivudine caused a significant increase of microglial and astrocytic activity (p < 0.001, 0.05 respectively) compared to control. The open field test showed a significant decrease (p < 0.0001) of the line crossing performance in the efavirenz, lamivudine and tenofovir (with means: 26.4, 4.6, 17.4 respectively) compared to control (50.6). There was also a significant decrease in the grooming (p < 0.05) and rearing (p < 0.01) in lamivudine group. Whereas, walk latency increased in efavirenz (p < 0.01), and lamivudine (p < 0.0001) compared to control. While hind limb slips significantly increased in efavirenz (p < 0.05) and lamivudine (p < 0.0001) compared with control group. Likewise, Lamivudine and Tenofovir exposed groups experienced a significant delay in the time to identify the hidden platform in compared to control (p < 0.05).
CONCLUSION
Lamivudine altered efferent stimuli along the cerebellospinal tracts thereby causing motor impairments. The degenerating Purkinje fibers may have induced marked neurodegeneration in the hippocampus resulting in impaired spatial memory.
背景与目的
神经退行性变与联合抗逆转录病毒疗法（cART）的使用有关。本研究旨在确定 cART 的任何成分是否会引起小脑肢体运动障碍和空间记忆损伤。
材料和方法
将 40 只成年雄性 Wistar 大鼠随机分为四组（n=10）：对照组（蒸馏水 0.5 mL）；替诺福韦（6mg/kg）；拉米夫定（6mg/kg）和依非韦伦（12mg/kg）。进行了以下神经行为研究：旷场试验、平衡木行走试验和 Morris 水迷宫试验。用 CD68 和 GFAP 免疫组化检测神经炎症和神经退行性变。
结果
治疗组海马的锥体神经元出现明显的固缩，小脑浦肯野细胞呈鬼影样。拉米夫定和依非韦伦组的氧化应激也显著增加。此外，与对照组相比，拉米夫定组的小胶质细胞和星形胶质细胞活性显著增加（p<0.001，0.05）。旷场试验显示，依非韦伦、拉米夫定和替诺福韦组的线穿越性能显著降低（p<0.0001），分别为 26.4、4.6 和 17.4，与对照组（50.6）相比。拉米夫定组的梳理（p<0.05）和后肢滑倒（p<0.01）也显著减少。而依非韦伦（p<0.01）和拉米夫定（p<0.0001）组的行走潜伏期增加。而依非韦伦（p<0.05）和拉米夫定（p<0.0001）组的后肢滑倒是显著增加的。同样，与对照组相比，拉米夫定和替诺福韦暴露组在识别隐藏平台的时间上明显延迟（p<0.05）。
结论
拉米夫定改变了沿小脑脊髓束的传出刺激，从而导致运动障碍。退化的浦肯野纤维可能在海马中引起明显的神经退行性变，导致空间记忆受损。
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