Wies Mancini Victoria S B, Di Pietro Anabella A, de Olmos Soledad, Silva Pinto Pablo, Vence Marianela, Marder Mariel, Igaz Lionel M, Marcora María S, Pasquini Juana M, Correale Jorge D, Pasquini Laura A
Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Cátedra de Química Biológica Patológica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Universidad de Buenos Aires, Buenos Aires, Argentina.
J Neurochem. 2022 Mar;160(6):643-661. doi: 10.1111/jnc.15566. Epub 2022 Jan 9.
Multiple sclerosis (MS), especially in its progressive phase, involves early axonal and neuronal damage resulting from a combination of inflammatory mediators, demyelination, and loss of trophic support. During progressive disease stages, a microenvironment is created within the central nervous system (CNS) favoring the arrival and retention of inflammatory cells. Active demyelination and neurodegeneration have also been linked to microglia (MG) and astrocyte (AST)-activation in early lesions. While reactive MG can damage tissue, exacerbate deleterious effects, and contribute to neurodegeneration, it should be noted that activated MG possess neuroprotective functions as well, including debris phagocytosis and growth factor secretion. The progressive form of MS can be modeled by the prolonged administration to cuprizone (CPZ) in adult mice, as CPZ induces highly reproducible demyelination of different brain regions through oligodendrocyte (OLG) apoptosis, accompanied by MG and AST activation and axonal damage. Therefore, our goal was to evaluate the effects of a reduction in microglial activation through orally administered brain-penetrant colony-stimulating factor-1 receptor (CSF-1R) inhibitor BLZ945 (BLZ) on neurodegeneration and its correlation with demyelination, astroglial activation, and behavior in a chronic CPZ-induced demyelination model. Our results show that BLZ treatment successfully reduced the microglial population and myelin loss. However, no correlation was found between myelin preservation and neurodegeneration, as axonal degeneration was more prominent upon BLZ treatment. Concomitantly, BLZ failed to significantly offset CPZ-induced astroglial activation and behavioral alterations. These results should be taken into account when proposing the modulation of microglial activation in the design of therapies relevant for demyelinating diseases. Cover Image for this issue: https://doi.org/10.1111/jnc.15394.
多发性硬化症（MS），尤其是在其进展期，涉及由炎症介质、脱髓鞘和营养支持丧失共同导致的早期轴突和神经元损伤。在疾病进展阶段，中枢神经系统（CNS）内会形成一种有利于炎症细胞到达和留存的微环境。早期病变中的活跃脱髓鞘和神经变性也与小胶质细胞（MG）和星形胶质细胞（AST）激活有关。虽然反应性MG会损害组织、加剧有害影响并导致神经变性，但应注意的是，活化的MG也具有神经保护功能，包括碎片吞噬和生长因子分泌。MS的进展形式可以通过在成年小鼠中长期给予铜螯合剂（CPZ）来模拟，因为CPZ通过少突胶质细胞（OLG）凋亡诱导不同脑区高度可重复的脱髓鞘，同时伴有MG和AST激活以及轴突损伤。因此，我们的目标是评估通过口服具有脑渗透性的集落刺激因子-1受体（CSF-1R）抑制剂BLZ945（BLZ）来减少小胶质细胞激活对神经变性的影响，以及其与脱髓鞘、星形胶质细胞激活和慢性CPZ诱导的脱髓鞘模型中行为的相关性。我们的结果表明，BLZ治疗成功减少了小胶质细胞数量和髓鞘损失。然而，在髓鞘保存和神经变性之间未发现相关性，因为在BLZ治疗后轴突变性更为突出。同时，BLZ未能显著抵消CPZ诱导的星形胶质细胞激活和行为改变。在设计与脱髓鞘疾病相关的治疗方法时，提出调节小胶质细胞激活时应考虑这些结果。本期封面图片：https://doi.org/10.1111/jnc.15394 。
