Institute of Molecular Medicine and Pathobiochemistry, Voyno-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia.
Institute of Living Systems, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia.
Int J Mol Sci. 2021 Jul 22;22(15):7822. doi: 10.3390/ijms22157822.
Spinocerebellar ataxias are a family of fatal inherited diseases affecting the brain. Although specific mutated proteins are different, they may have a common pathogenetic mechanism, such as insufficient glutamate clearance. This function fails in reactive glia, leading to excitotoxicity and overactivation of NMDA receptors. Therefore, NMDA receptor blockers could be considered for the management of excitotoxicity. One such drug, memantine, currently used for the treatment of Alzheimer's disease, could potentially be used for the treatment of other forms of neurodegeneration, for example, spinocerebellar ataxias (SCA). We previously demonstrated close parallels between optogenetically induced cerebellar degeneration and SCA1. Here we induced reactive transformation of cerebellar Bergmann glia (BG) using this novel optogenetic approach and tested whether memantine could counteract changes in BG and Purkinje cell (PC) morphology and expression of the main glial glutamate transporter-excitatory amino acid transporter 1 (EAAT1). Reactive BG induced by chronic optogenetic stimulation presented increased GFAP immunoreactivity, increased thickness and decreased length of its processes. Oral memantine (~90 mg/kg/day for 4 days) prevented thickening of the processes (1.57 to 1.81 vs. 1.62 μm) and strongly antagonized light-induced reduction in their average length (186.0 to 150.8 vs. 171.9 μm). Memantine also prevented the loss of the key glial glutamate transporter EAAT1 on BG. Finally, memantine reduced the loss of PC (4.2 ± 0.2 to 3.2 ± 0.2 vs. 4.1 ± 0.3 cells per 100 μm of the PC layer). These results identify memantine as potential neuroprotective therapeutics for cerebellar ataxias.
脊髓小脑共济失调是一组致命的遗传性疾病，影响大脑。尽管特定的突变蛋白不同，但它们可能具有共同的发病机制，例如谷氨酸清除不足。这种功能在反应性神经胶质细胞中失败，导致兴奋性毒性和 NMDA 受体过度激活。因此，NMDA 受体阻滞剂可被认为用于治疗兴奋性毒性。一种这样的药物，美金刚，目前用于治疗阿尔茨海默病，可能可用于治疗其他形式的神经退行性疾病，例如脊髓小脑共济失调（SCA）。我们之前证明了光遗传学诱导的小脑变性与 SCA1 之间的紧密相似性。在这里，我们使用这种新型光遗传学方法诱导小脑伯格曼神经胶质（BG）的反应性转化，并测试美金刚是否可以对抗 BG 和浦肯野细胞（PC）形态的变化以及主要神经胶质谷氨酸转运体-兴奋性氨基酸转运体 1（EAAT1）的表达。慢性光遗传学刺激诱导的反应性 BG 表现出 GFAP 免疫反应性增加、其过程的厚度增加和长度减少。口服美金刚（~90mg/kg/天，持续 4 天）可防止过程变厚（1.57 至 1.81 与 1.62μm），并强烈拮抗光诱导的其平均长度的减少（186.0 至 150.8 与 171.9μm）。美金刚还防止 BG 上关键神经胶质谷氨酸转运体 EAAT1 的丢失。最后，美金刚减少了 PC 的丢失（4.2±0.2 至 3.2±0.2 与 4.1±0.3 个细胞/100μm 的 PC 层）。这些结果表明美金刚是治疗小脑共济失调的潜在神经保护治疗药物。
