Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71103 USA.
Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71103 USA.
Transl Res. 2024 Jun;268:40-50. doi: 10.1016/j.trsl.2024.01.008. Epub 2024 Jan 19.
Traumatic brain injury (TBI) has a significant impact on cognitive function, affecting millions of people worldwide. Myelin loss is a prominent pathological feature of TBI, while well-functioning myelin is crucial for memory and cognition. Utilizing drug repurposing to identify effective drug candidates for TBI treatment has gained attention. Notably, recent research has highlighted the potential of clemastine, an FDA-approved allergy medication, as a promising pro-myelinating drug. Therefore, in this study, we aim to investigate whether clemastine can enhance myelination and alleviate cognitive impairment following mild TBI using a clinically relevant rat model of TBI. Mild diffuse TBI was induced using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA). Animals were treated with either clemastine or an equivalent volume of the vehicle from day 1 to day 14 post-injury. Following treatment, memory-related behavioral tests were conducted, and myelin pathology in the cortex and hippocampus was assessed through immunofluorescence staining and ProteinSimple® capillary-based immunoassay. Our results showed that TBI leads to significant myelin loss, axonal damage, glial activation, and a decrease in mature oligodendrocytes in both the cortex and hippocampus. The TBI animals also exhibited notable deficits in memory-related tests. In contrast, animals treated with clemastine showed an increase in mature oligodendrocytes, enhanced myelination, and improved performance in the behavioral tests. These preliminary findings support the therapeutic value of clemastine in alleviating TBI-induced cognitive impairment, with substantial clinical translational potential. Our findings also underscore the potential of remyelinating therapies for TBI.
创伤性脑损伤 (TBI) 对认知功能有重大影响，影响着全球数百万人。髓鞘丢失是 TBI 的一个突出的病理特征，而功能良好的髓鞘对记忆和认知至关重要。利用药物再利用来鉴定 TBI 治疗的有效药物候选物已引起关注。值得注意的是，最近的研究强调了氯苯那敏（一种已获 FDA 批准的过敏药物）作为一种有前途的促髓鞘形成药物的潜力。因此，在这项研究中，我们旨在使用临床相关的 TBI 大鼠模型研究氯苯那敏是否可以增强髓鞘形成并减轻轻度 TBI 后的认知障碍。使用经工程化旋转加速度闭合性头部撞击模型 (CHIMERA) 诱导轻度弥漫性 TBI。动物从损伤后第 1 天至第 14 天接受氯苯那敏或等量载体治疗。治疗后，进行与记忆相关的行为测试，并通过免疫荧光染色和 ProteinSimple®毛细管基免疫分析评估皮质和海马中的髓鞘病理。我们的结果表明，TBI 导致皮质和海马中的髓鞘大量丢失、轴突损伤、胶质细胞激活和成熟少突胶质细胞减少。TBI 动物在与记忆相关的测试中也表现出明显的缺陷。相比之下，接受氯苯那敏治疗的动物表现出成熟少突胶质细胞增加、髓鞘增强以及行为测试表现改善。这些初步发现支持氯苯那敏在缓解 TBI 引起的认知障碍方面的治疗价值，具有很大的临床转化潜力。我们的研究结果还强调了用于 TBI 的髓鞘再形成疗法的潜力。
