Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis.
Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis.
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DOI：
10.1186/s12974-016-0620-9
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发表时间：
2016-07-11
影响因子：
9.3
通讯作者：
Barbeito L
中科院分区：
文献类型：
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作者：
Trias E;Ibarburu S;Barreto-Núñez R;Babdor J;Maciel TT;Guillo M;Gros L;Dubreuil P;Díaz-Amarilla P;Cassina P;Martínez-Palma L;Moura IC;Beckman JS;Hermine O;Barbeito L
在肌萎缩侧索硬化症 (ALS) 的 SOD1G93A 突变大鼠模型中，神经元死亡和快速麻痹进展与退化脊髓中增殖的活化异常神经胶质细胞的出现有关。对这种异常神经胶质细胞的药理学下调是否会减少运动神经元死亡并延长生存尚不清楚。我们假设异常神经胶质细胞的增殖依赖于激酶受体激活，因此酪氨酸激酶抑制剂马赛替尼 (AB1010) 可以潜在地控制 ALS 大鼠模型中的神经炎症。在从老年有症状 SOD1G93A 大鼠中分离的小胶质细胞的细胞培养物中，分析了马赛替尼对酪氨酸激酶的药理学抑制的细胞效应。为了确定马赛替尼是否可以预防异常神经胶质细胞的出现或改变麻痹后的存活率，在麻痹发作后开始以 30 mg/kg/天的剂量口服该药物。我们发现马赛替尼在纳摩尔浓度下选择性抑制酪氨酸激酶受体集落刺激因子 1R (CSF-1R)。在来自有症状的 SOD1G93A 脊髓的小胶质细胞培养物中，马赛替尼可阻止脑脊液诱导的增殖、细胞迁移和炎症介质的表达。相对于媒介物治疗的大鼠，在瘫痪发作后开始对 SOD1G93A 大鼠口服马赛替尼可减少退化脊髓中异常神经胶质细胞、小胶质细胞增生和运动神经元病理学的数量。麻痹发作后 7 天开始马赛替尼治疗可将麻痹后存活率延长 40%。这些数据表明，马赛替尼能够控制小胶质细胞增生和异常神经胶质细胞的出现/扩张，从而为其用于控制 ALS 中的神经炎症提供了强有力的生物学原理。值得注意的是，在瘫痪发作后使用马赛替尼可显着延长生存期，这在 ALS 临床前模型中具有前所未有的效果，因此似乎非常适合治疗 ALS。本文的在线版本 (doi:10.1186/s12974-016-0620-9) 包含补充材料，可供授权用户使用。
In the SOD1G93A mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS. The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1G93A rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset. We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1G93A spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1G93A rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %. These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS. The online version of this article (doi:10.1186/s12974-016-0620-9) contains supplementary material, which is available to authorized users.