Spinal cord pathology is ameliorated by P2X7 antagonism in SOD1-G93A mouse model of amyotrophic lateral sclerosis

Abstract

Abstract In recent years there has been an increasing awareness on the role of P2X7 receptor for extracellular ATP in modulating physiopathological mechanisms in the CNS. In particular, P2X7 was shown to be implicated in neuropsychiatry, chronic pain, neurodegeneration, neuroinflammation. Remarkably, P2X7 was shown to be a "gene modifier" in amyotrophic lateral sclerosis (ALS): the receptor is up-regulated in spinal cord microglia in human and rat at advanced stages of the disease; in vitro, activation of P2X7 exacerbates pro-inflammatory responses in ALS-microglia, as well as toxicity towards neuronal cells. Despite this detrimental in vitro role of P2X7, in P2X7−/−/SOD1-G93A mice 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 already proven to reduce neuroinflammation in traumatic brain injury, cerebral ischemia/reperfusion, neuropathic pain and experimental autoimmune encephalitis. We tested BBG in SOD1-G93A ALS mouse model at asymptomatic, pre-symptomatic and late pre-symptomatic phases of disease. BBG at late pre-onset significantly enhances motoneuron survival and reduces 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 is accompanied by delayed onset and improved general conditions and motor performance, in both male and female mice, although survival appears not affected. 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.