Laboratório de Biologia da Neurotransmissão, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Brazil, Belo Horizonte, MG.
Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Exp Physiol. 2022 Aug;107(8):933-945. doi: 10.1113/EP090327. Epub 2022 May 25.
What is the central question of this study? We investigated the effects of intrathecal administration of a novel toxin, CTK 01512-2, in a mouse model of Huntington's disease. We asked whether spinal cord neurons can represent a therapeutic target, given that the spinal cord seems to be involved in motor symptoms of Huntington's disease. Pharmacological approaches focusing on the spinal cord and skeletal muscles might represent a more feasible strategy than a high-risk brain intervention. What is the main finding and its importance? We provided evidence of a novel, local, neuroprotective effect of CTK 01512-2, paving a path for the development of approaches to treat motor symptoms of Huntington's disease beyond the brain.
Phα1β is a neurotoxin from the venom of the Phoneutria nigriventer spider, available as CTK 01512-2, a recombinant peptide. Owing to its antinociceptive and analgesic properties, CTK 01512-2 has been described to alleviate neuroinflammatory responses. Despite the diverse actions of CTK 01512-2 on the nervous system, little is known regarding its neuroprotective effect, especially in neurodegenerative conditions such as Huntington's disease (HD), a genetic movement disorder without cure. Here, we investigated whether CTK 01512-2 has a neuroprotective effect in a mouse model of HD. We hypothesized that spinal cord neurons might represent a therapeutic target, because the spinal cord seems to be involved in the motor symptoms of HD (BACHD) mice. We treated BACHD mice with CTK 01512-2 by intrathecal injection and performed in vivo motor behavioural and morphological analyses in the CNS (brain and spinal cord) and muscles. Our data showed that intrathecal injection of CTK 01512-2 significantly improved motor performance in the open field task. CTK 01512-2 protected neurons in the spinal cord (but not in the brain) from death, suggesting a local effect. CTK 01512-2 exerted its neuroprotective effect by inhibiting BACHD neuronal apoptosis, as revealed by a reduction in caspase-3 in the spinal cord. CTK 01512-2 was also able to revert BACHD muscle atrophy. In conclusion, our data suggest a novel role for CTK 01512-2 acting directly in the spinal cord to ameliorate morphofunctional aspects of spinal cord neurons and muscles and improve the performance of BACHD mice in motor behavioural tests. Given that HD shares similar symptoms with many neurodegenerative conditions, the findings presented herein might also be applicable to other disorders.
本研究的核心问题是什么？我们研究了新型毒素 CTK 01512-2 在亨廷顿病小鼠模型中的鞘内给药的效果。我们询问脊髓神经元是否可以成为治疗靶点，因为脊髓似乎参与了亨廷顿病的运动症状。专注于脊髓和骨骼肌的药物治疗方法可能比高风险的脑部干预更可行。主要发现及其重要性是什么？我们提供了 CTK 01512-2 具有新型局部神经保护作用的证据，为开发治疗亨廷顿病运动症状的方法铺平了道路，超越了大脑。
Phα1β 是 Phoneutria nigriventer 蜘蛛毒液中的一种神经毒素，可作为 CTK 01512-2，一种重组肽。由于其镇痛和止痛特性，CTK 01512-2 已被描述为减轻神经炎症反应。尽管 CTK 01512-2 对神经系统有多种作用，但对其神经保护作用知之甚少，特别是在亨廷顿病（HD）等神经退行性疾病中，HD 是一种无法治愈的遗传性运动障碍。在这里，我们研究了 CTK 01512-2 是否对 HD 小鼠模型具有神经保护作用。我们假设脊髓神经元可能是一个治疗靶点，因为脊髓似乎参与了 HD（BACHD）小鼠的运动症状。我们通过鞘内注射 CTK 01512-2 治疗 BACHD 小鼠，并在中枢神经系统（大脑和脊髓）和肌肉中进行体内运动行为和形态学分析。我们的数据表明，鞘内注射 CTK 01512-2 可显著改善旷场任务中的运动表现。CTK 01512-2 可保护脊髓神经元免于死亡（但不保护大脑神经元），表明其具有局部作用。CTK 01512-2 通过抑制 BACHD 神经元凋亡发挥其神经保护作用，这一点从脊髓中 caspase-3 的减少可以看出。CTK 01512-2 还能够逆转 BACHD 肌肉萎缩。总之，我们的数据表明 CTK 01512-2 在脊髓中直接发挥作用以改善脊髓神经元和肌肉的形态功能方面具有新的作用，并改善 BACHD 小鼠在运动行为测试中的表现。鉴于 HD 与许多神经退行性疾病具有相似的症状，本文的发现可能也适用于其他疾病。
