Department of Biological Chemistry, Institute of Chemistry and Biological Physicochemistry (IQUIFIB), School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Buenos Aires, Argentina.
Institute for Neurological Research Dr. Raúl Carrea, FLENI, Buenos Aires, Argentina.
Glia. 2019 Feb;67(2):291-308. doi: 10.1002/glia.23540. Epub 2018 Nov 19.
Multiple sclerosis (MS) is one of the most common causes of progressive disability affecting young people with very few therapeutic options available for its progressive forms. Its pathophysiology involves demyelination and neurodegeneration apparently driven by microglial activation, which is physiologically dependent on colony-stimulating factor-1 receptor (CSF-1R) signaling. In the present work, we used microglial modulation through oral administration of brain-penetrant CSF-1R inhibitor BLZ945 in acute and chronic cuprizone (CPZ)-induced demyelination to evaluate preventive and therapeutic effects on de/remyelination and neurodegeneration. Our results show that BLZ945 induced a significant reduction in the number of microglia. Preventive BLZ945 treatment attenuated demyelination in the acute CPZ model, mainly in cortex and external capsule. In contrast, BLZ945 treatment in the acute CPZ model failed to protect myelin or foster remyelination in myelin-rich areas, which may respond to a loss in microglial phagocytic capacity and the consequent impairment in oligodendroglial differentiation. Preventive and therapeutic BLZ945 treatment promoted remyelination and neuroprotection in the chronic model. These results could be potentially transferred to the treatment of progressive forms of MS.
多发性硬化症（MS）是影响年轻人的最常见的进行性残疾原因之一，其进行性形式的治疗选择非常有限。其病理生理学涉及脱髓鞘和神经退行性变，显然由小胶质细胞激活驱动，小胶质细胞激活在生理上依赖于集落刺激因子-1 受体（CSF-1R）信号。在本工作中，我们通过口服穿透性 CSF-1R 抑制剂 BLZ945 在急性和慢性铜锌诱导的脱髓鞘（CPZ）中调节小胶质细胞，以评估其对脱髓鞘/髓鞘再生和神经退行性变的预防和治疗作用。我们的结果表明，BLZ945 诱导小胶质细胞数量显著减少。预防性 BLZ945 治疗减轻了急性 CPZ 模型中的脱髓鞘，主要在皮质和外囊。相比之下，BLZ945 在急性 CPZ 模型中的治疗未能保护髓鞘或促进富含髓鞘的区域的髓鞘再生，这可能与小胶质细胞吞噬能力的丧失和少突胶质细胞分化的随后受损有关。预防性和治疗性 BLZ945 治疗促进了慢性模型中的髓鞘再生和神经保护。这些结果可能潜在地应用于进行性 MS 形式的治疗。
