title: Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Cellular Biology and Neurobiology Institute, CNR, Via del Fosso di Fiorano, 65, 00143 Rome, Italy Santa Lucia Foundation, IRCCS, Via Ardeatina, 306, 00179 Rome, Italy.
authors.forename: Savina
authors.initials: S
authors.lastname: Apolloni
authors.affiliation: Santa Lucia Foundation, IRCCS, Via Ardeatina, 306, 00179 Rome, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Amadio
authors.affiliation: Cellular Biology and Neurobiology Institute, CNR, Via del Fosso di Fiorano, 65, 00143 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Parisi
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Matteucci
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Rosa L
authors.initials: RL
authors.lastname: Potenza
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Armida
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Popoli
authors.affiliation: Cellular Biology and Neurobiology Institute, CNR, Via del Fosso di Fiorano, 65, 00143 Rome, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: D'Ambrosi
authors.affiliation: Cellular Biology and Neurobiology Institute, CNR, Via del Fosso di Fiorano, 65, 00143 Rome, Italy Santa Lucia Foundation, IRCCS, Via Ardeatina, 306, 00179 Rome, Italy cinzia.volonte@cnr.it.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Volonté
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D009046:Motor Neurons / Q000473:pathology; D016133:Polymerase Chain Reaction; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D012394:Rosaniline Dyes / Q000494:pharmacology*; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: D015415:Biomarkers; D017931:DNA Primers; D058920:Purinergic P2X Receptor Antagonists; D012394:Rosaniline Dyes; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C004692:coomassie Brilliant Blue
keywords: ALS; Brilliant Blue G; Microglia; Motor neuron; P2X7