Laboratório de Biologia da Neurotransmissão, Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Laboratório de Biologia da Neurotransmissão, Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Departamento de Medicina, Faculdade Ciências Médicas de Minas Gerais, FCMMG, Belo Horizonte, MG, Brazil.
Neuropeptides. 2021 Feb;85:102111. doi: 10.1016/j.npep.2020.102111. Epub 2020 Dec 6.
Abnormal calcium influx and glutamatergic excitotoxicity have been extensively associated with neuronal death in Huntington's disease (HD), a genetic movement disorder. Currently, there is no effective treatment for this fatal condition. The neurotoxin Phα1β has demonstrated therapeutic effects as a calcium channel blocker, for example during pain control. However, little is known about its neuroprotective effect in HD. Herein, we investigated if Phα1β is effective in inhibiting neuronal cell death in the BACHD mouse model for HD. We performed intrastriatal injection of Phα1β in WT and BACHD mice. No side effects or unusual behaviors were observed upon Phα1β administration. Using three different motor behavior tests, we observed that injection of the toxin in BACHD mice greatly improved the animals' motor-force as seen in the Wire-hang test, and also the locomotor performance, according to the Open field test. NeuN labeling for mature neuron detection revealed that Phα1β toxin promoted neuronal preservation in the striatum and cortex, when injected locally. Intrastriatal injection of Phα1β was not able to preserve neurons from the spinal cord and also not revert muscle atrophy in BACHD mice. Finally, we observed that Phα1β might, at least in part, exert its protective effect by decreasing L-glutamate, measured in cerebrospinal fluid. Our data provide evidence of a novel neuroprotector effect of Phα1β, paving a path for the development of new approaches to treat HD motor symptoms.
异常的钙内流和谷氨酸能兴奋性毒性与亨廷顿病（HD）中的神经元死亡密切相关，HD 是一种遗传性运动障碍。目前，这种致命疾病还没有有效的治疗方法。神经毒素 Phα1β 已被证明具有钙通道阻滞剂的治疗效果，例如在控制疼痛方面。然而，人们对其在 HD 中的神经保护作用知之甚少。在此，我们研究了 Phα1β 是否能有效抑制 BACHD 小鼠 HD 模型中的神经元死亡。我们在 WT 和 BACHD 小鼠中进行了纹状体注射 Phα1β。在 Phα1β 给药后没有观察到副作用或异常行为。通过三种不同的运动行为测试，我们观察到在 BACHD 小鼠中注射毒素极大地改善了动物在悬线测试中的运动力，并且根据开放场测试，运动性能也得到了改善。用于检测成熟神经元的 NeuN 标记显示，Phα1β 毒素在局部注射时促进了纹状体和皮层中的神经元保存。纹状体注射 Phα1β 不能保护 BACHD 小鼠脊髓中的神经元，也不能逆转肌肉萎缩。最后，我们观察到 Phα1β 可能至少部分通过降低脑脊液中的 L-谷氨酸来发挥其保护作用。我们的数据提供了 Phα1β 具有新型神经保护作用的证据，为开发治疗 HD 运动症状的新方法铺平了道路。
