Neuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), produced by the chronic activation of microglia in the CNS. This process is triggered by the persistent activation of the ATP-gated P2X7 receptor (P2RX7, hereafter referred to as P2X7R). The present study aimed to evaluate the effects of the chronic treatment with the P2X7R antagonist JNJ-47965567 in the development and progression of ALS in the SOD1^G93A murine model. SOD1^G93A mice were intraperitoneally (i.p.) injected with either 30 mg/kg of JNJ-47965567 or vehicle 4 times per week, from pre-onset age (here, postnatal day 60; P60) until study endpoint. Body weight, motor coordination, phenotypic score, disease onset and survival were measured throughout the study, and compared between vehicle- and drug-injected groups. Treatment with the P2X7R antagonist JNJ-47965567 delayed disease onset, reduced body weight loss and improved motor coordination and phenotypic score in female SOD1^G93A mice, although it did not increase lifespan. Interestingly, neither beneficial nor detrimental effects were observed in males in any of the analyzed parameters. Treatment did not affect motor neuron survival or ChAT, Iba-1 and P2X7R protein expression in endpoint individuals of mixed sexes. Overall, chronic administration of JNJ-47965567 for 4 times per week to SOD1^G93A mice from pre-onset stage altered disease progression in female individuals while it did not have any effect in males. Our results suggest a partial, yet important, effect of P2X7R in the development and progression of ALS.

中文翻译：

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P2X7 受体拮抗剂 JNJ-47965567 的长期给药可延迟疾病的发作和进展，并改善 ALS SOD1G93A 雌性小鼠的运动表现。

神经炎症是肌萎缩侧索硬化 (ALS) 的主要病理生理机制之一，由 CNS 中小胶质细胞的慢性激活产生。该过程由 ATP 门控 P2X7 受体（P2RX7，以下简称 P2X7R）的持续激活触发。本研究旨在评估 P2X7R 拮抗剂 JNJ-47965567 长期治疗对 SOD1 ^G93A鼠模型中 ALS 发展和进展的影响。SOD1 ^G93A从发病前年龄（此处，出生后第 60 天；P60）到研究终点，小鼠每周 4 次腹膜内 (ip) 注射 30 mg/kg JNJ-47965567 或载体。在整个研究过程中测量体重、运动协调性、表型评分、疾病发作和存活率，并在载体和药物注射组之间进行比较。用 P2X7R 拮抗剂 JNJ-47965567 治疗女性 SOD1 ^G93A延迟疾病发作，减少体重减轻并改善运动协调性和表型评分老鼠，虽然它没有增加寿命。有趣的是，在任何分析参数中，在男性中均未观察到有益或有害影响。治疗不影响混合性别的终点个体的运动神经元存活或 ChAT、Iba-1 和 P2X7R 蛋白表达。总体而言，每周 4 次对来自发病前阶段的SOD1 ^G93A小鼠慢性施用 JNJ-47965567改变了女性个体的疾病进展，而它对男性没有任何影响。我们的结果表明 P2X7R 在 ALS 的发展和进展中具有部分但重要的作用。