Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis.
Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis.
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DOI：
10.1242/dmm.017038
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发表时间：
2014-09
影响因子：
4.3
通讯作者：
Volonté C
中科院分区：
文献类型：
--
作者：
Apolloni S;Amadio S;Parisi C;Matteucci A;Potenza RL;Armida M;Popoli P;D'Ambrosi N;Volonté C
近年来，人们对细胞外ATP受体P2X7在调节中枢神经系统生理病理机制中的作用的认识越来越高。特别是，P2X7已被证明与神经精神病学、慢性疼痛、神经变性和神经炎症有关。值得注意的是，P2X7也被证明是肌萎缩性侧索硬化症（ALS）的“基因修饰剂”：在疾病晚期的人和大鼠中，该受体在脊髓小胶质细胞中上调；在体外，P2X7的激活加剧了具有ALS表型的小胶质细胞的促炎反应，以及对神经元细胞的毒性。尽管P2X7在体外具有这种有害的作用，但在缺乏P2X7的SOD1-G93A小鼠中，ALS的临床发病明显加快，疾病进展恶化，从而表明该受体可能具有一些有益的作用，至少在疾病的某些阶段。为了阐明P2X7在ALS发病机制中的双重作用，在本工作中，我们使用了拮抗剂Brilliant Blue G (BBG)，这是一种可穿透血脑屏障的安全药物，已被证明可以减轻创伤性脑损伤、脑缺血再灌注、神经性疼痛和实验性自身免疫性脑炎的神经炎症。我们在SOD1-G93A ALS小鼠模型的无症状、症状前和症状前晚期检测了BBG。发作前晚期BBG可显著提高运动神经元存活率，减少腰椎小胶质细胞增生，调节NF-κB、NADPH氧化酶2、白细胞介素-1β、白细胞介素-10和脑源性神经营养因子等炎症标志物。在雄性和雌性小鼠中，这伴随着延迟发作和改善的一般状况和运动表现，尽管存活率似乎没有受到影响。我们的研究结果证明了P2X7在ALS病程中的双重作用，并确定P2X7调节可能通过干扰疾病的神经炎症成分代表了一种有希望的治疗策略。
In recent years there has been an increasing awareness of the role of P2X7, a receptor for extracellular ATP, in modulating physiopathological mechanisms in the central nervous system. In particular, P2X7 has been shown to be implicated in neuropsychiatry, chronic pain, neurodegeneration and neuroinflammation. Remarkably, P2X7 has also been shown to be a ‘gene modifier’ in amyotrophic lateral sclerosis (ALS): the receptor is upregulated in spinal cord microglia in human and rat at advanced stages of the disease; in vitro, activation of P2X7 exacerbates pro-inflammatory responses in microglia that have an ALS phenotype, as well as toxicity towards neuronal cells. Despite this detrimental in vitro role of P2X7, in SOD1-G93A mice lacking P2X7, the clinical onset of ALS was significantly accelerated and disease progression worsened, thus indicating that the receptor might have some beneficial effects, at least at certain stages of disease. In order to clarify this dual action of P2X7 in ALS pathogenesis, in the present work we used the antagonist Brilliant Blue G (BBG), a blood-brain barrier permeable and safe drug that has already been proven to reduce neuroinflammation in traumatic brain injury, cerebral ischemia-reperfusion, neuropathic pain and experimental autoimmune encephalitis. We tested BBG in the SOD1-G93A ALS mouse model at asymptomatic, pre-symptomatic and late pre-symptomatic phases of disease. BBG at late pre-onset significantly enhanced motor neuron survival and reduced microgliosis in lumbar spinal cord, modulating inflammatory markers such as NF-κB, NADPH oxidase 2, interleukin-1β, interleukin-10 and brain-derived neurotrophic factor. This was accompanied by delayed onset and improved general conditions and motor performance, in both male and female mice, although survival appeared unaffected. Our results prove the twofold role of P2X7 in the course of ALS and establish that P2X7 modulation might represent a promising therapeutic strategy by interfering with the neuroinflammatory component of the disease.
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