Extracellular ATP and the P2X7receptor in astrocyte-mediated motor neuron death: Implications for amyotrophic lateral sclerosis

Background: during pathology of the nervous system,increased extracellular atp acts both as a cytotoxic factor and pro-inflammatory mediator through p2x7receptors. in animal models of amyotrophic lateral sclerosis (als),astrocytes expressing superoxide dismutase 1 (sod1g93a) mutations display a neuroinflammatory phenotype and contribute to disease progression and motor neuron death. here we studied the role of extracellular atp acting through p2x7receptors as an initiator of a neurotoxic phenotype that leads to astrocyte-mediated motor neuron death in non-transgenic and sod1g93aastrocytes.methods: we evaluated motor neuron survival after co-culture with sod1g93aor non-transgenic astrocytes pretreated with agents known to modulate atp release or p2x7receptor. we also characterized astrocyte proliferation and extracellular atp degradation.results: repeated stimulation by atp or the p2x7-selective agonist bzatp caused astrocytes to become neurotoxic,inducing death of motor neurons. involvement of p2x7receptor was further confirmed by brilliant blue g inhibition of atp and bzatp effects. in sod1g93aastrocyte cultures,pharmacological inhibition of p2x7receptor or increased extracellular atp degradation with the enzyme apyrase was sufficient to completely abolish their toxicity towards motor neurons. sod1g93aastrocytes also displayed increased atp-dependent proliferation and a basal increase in extracellular atp degradation.conclusions: here we found that p2x7receptor activation in spinal cord astrocytes initiated a neurotoxic phenotype that leads to motor neuron death. remarkably,the neurotoxic phenotype of sod1g93aastrocytes depended upon basal activation the p2x7receptor. thus,pharmacological inhibition of p2x7receptor might reduce neuroinflammation in als through astrocytes. © 2010 gandelman et al; licensee biomed central ltd.