University of Ottawa Brain and Mind Research Institute (S.H.L., T.-L.L.C., K.S.A.-E., S.S.G.F.) and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada (S.H.L., T.-L.L.C., K.S.A.-E., S.S.G.F.); and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (K.S.A.-E.).
University of Ottawa Brain and Mind Research Institute (S.H.L., T.-L.L.C., K.S.A.-E., S.S.G.F.) and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada (S.H.L., T.-L.L.C., K.S.A.-E., S.S.G.F.); and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (K.S.A.-E.)
J Pharmacol Exp Ther. 2021 Oct;379(1):74-84. doi: 10.1124/jpet.121.000735. Epub 2021 Jul 30.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that leads to progressive motor impairments with no available disease-modifying treatment. Current evidence indicates that exacerbated postsynaptic glutamate signaling in the striatum plays a key role in the pathophysiology of HD. However, it remains unclear whether reducing glutamate release can be an effective approach to slow the progression of HD. Here, we show that the activation of metabotropic glutamate receptors 2 and 3 (mGluR2/3), which inhibit presynaptic glutamate release, improves HD symptoms and pathology in heterozygous zQ175 knockin mice. Treatment of both male and female zQ175 mice with the potent and selective mGluR2/3 agonist LY379268 for either 4 or 8 weeks improves both limb coordination and locomotor function in all mice. LY379268 also reduces mutant huntingtin aggregate formation, neuronal cell death, and microglial activation in the striatum of both male and female zQ175 mice. The reduction in mutant huntingtin aggregates correlates with the activation of a glycogen synthase kinase 3-dependent autophagy pathway in male, but not female, zQ175 mice. Furthermore, LY379268 reduces both Akt and ERK1/2 phosphorylation in male zQ175 mice but increases both Akt and ERK1/2 phosphorylation in female zQ175 mice. Taken together, our results indicate that mGluR2/3 activation mitigates HD neuropathology in both male and female mice but is associated with the differential activation and inactivation of cell signaling pathways in heterozygous male and female zQ175 mice. This further highlights the need to take sex into consideration when developing future HD therapeutics. SIGNIFICANCE STATEMENT: The mGluR2/3 agonist LY379268 improves motor impairments and reduces pathology in male and female zQ175 Huntington's disease mice. The beneficial outcomes of LY379268 treatment in Huntington's disease mice were mediated by divergent cell signaling pathways in both sexes. We provide evidence that mGluR2/3 agonists can be repurposed for the treatment of Huntington's disease, and we emphasize the importance of investigating sex as a biological variable in preclinical disease-modifying studies.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，导致进行性运动障碍，目前尚无可行的疾病修饰治疗方法。目前的证据表明，纹状体中突触后谷氨酸信号的加剧在 HD 的病理生理学中起着关键作用。然而，减少谷氨酸释放是否可以成为减缓 HD 进展的有效方法仍不清楚。在这里，我们表明，代谢型谷氨酸受体 2 和 3（mGluR2/3）的激活，抑制突触前谷氨酸释放，改善杂合子 zQ175 敲入小鼠的 HD 症状和病理学。用有效的和选择性的 mGluR2/3 激动剂 LY379268 治疗雄性和雌性 zQ175 小鼠 4 或 8 周，均可改善所有小鼠的肢体协调和运动功能。LY379268 还减少了雄性和雌性 zQ175 小鼠纹状体中突变亨廷顿蛋白聚集体的形成、神经元细胞死亡和小胶质细胞激活。突变亨廷顿蛋白聚集体的减少与雄性 zQ175 小鼠中糖原合酶激酶 3 依赖性自噬途径的激活相关，但在雌性 zQ175 小鼠中不相关。此外，LY379268 降低了雄性 zQ175 小鼠中的 Akt 和 ERK1/2 磷酸化，但增加了雌性 zQ175 小鼠中的 Akt 和 ERK1/2 磷酸化。总之，我们的结果表明，mGluR2/3 的激活减轻了雄性和雌性 zQ175 小鼠的 HD 神经病理学，但与杂合雄性和雌性 zQ175 小鼠中细胞信号通路的差异激活和失活有关。这进一步强调了在开发未来的 HD 治疗方法时需要考虑性别因素。意义声明：mGluR2/3 激动剂 LY379268 改善了雄性和雌性 zQ175 亨廷顿病小鼠的运动障碍，并降低了其病理学。LY379268 在亨廷顿病小鼠中的有益作用是通过两性中不同的细胞信号通路介导的。我们提供的证据表明，mGluR2/3 激动剂可被重新用于治疗亨廷顿病，并且我们强调在疾病修饰的临床前研究中研究性别作为生物学变量的重要性。
