JOURNAL OF NEUROINFLAMMATION Gandelman et al. Journal of Neuroinflammation 2010, 7:33 http://www.jneuroinflammation.com/content/7/1/33 Open Access RESEARCH © 2010 Gandelman et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Com- mons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduc- tion in any medium, provided the original work is properly cited. Research Extracellular ATP and the P2X 7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis Mandi Gandelman 1,2 , Hugo Peluffo 1,2 , Joseph S Beckman 3 , Patricia Cassina 2 and Luis Barbeito* 1,4 Abstract Background: During pathology of the nervous system, increased extracellular ATP acts both as a cytotoxic factor and pro-inflammatory mediator through P2X 7 receptors. In animal models of amyotrophic lateral sclerosis (ALS), astrocytes expressing superoxide dismutase 1 (SOD1 G93A ) mutations display a neuroinflammatory phenotype and contribute to disease progression and motor neuron death. Here we studied the role of extracellular ATP acting through P2X 7 receptors as an initiator of a neurotoxic phenotype that leads to astrocyte-mediated motor neuron death in non- transgenic and SOD1 G93A astrocytes. Methods: We evaluated motor neuron survival after co-culture with SOD1 G93A or non-transgenic astrocytes pretreated with agents known to modulate ATP release or P2X 7 receptor. We also characterized astrocyte proliferation and extracellular ATP degradation. Results: Repeated stimulation by ATP or the P2X 7 -selective agonist BzATP caused astrocytes to become neurotoxic, inducing death of motor neurons. Involvement of P2X 7 receptor was further confirmed by Brilliant blue G inhibition of ATP and BzATP effects. In SOD1 G93A astrocyte cultures, pharmacological inhibition of P2X 7 receptor or increased extracellular ATP degradation with the enzyme apyrase was sufficient to completely abolish their toxicity towards motor neurons. SOD1 G93A astrocytes also displayed increased ATP-dependent proliferation and a basal increase in extracellular ATP degradation. Conclusions: Here we found that P2X 7 receptor activation in spinal cord astrocytes initiated a neurotoxic phenotype that leads to motor neuron death. Remarkably, the neurotoxic phenotype of SOD1 G93A astrocytes depended upon basal activation the P2X 7 receptor. Thus, pharmacological inhibition of P2X 7 receptor might reduce neuroinflammation in ALS through astrocytes. Background Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spi- nal cord, brainstem and motor cortex, leading to respira- tory failure and death of affected patients within a few years of diagnosis [1]. The discovery of mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase-1 (SOD1) in a subset of patients with familial ALS has led to the development of transgenic animal models expressing different SOD1 mutations [2]. These animal models recapitulate the human disease, exhibiting aberrant oxidative chemistry [3,4], neuroinflammation [5], endoplasmic reticulum stress [6], glutamate excito- toxicity [7], mitochondrial dysfunction [8] and protein misfolding and aggregation [9]. However, the mecha- nisms behind motor neuron death are unknown. Accumulating evidence indicates that non-neuronal cells contribute to motor neuron dysfunction and death in ALS by the maintenance of a chronic inflammatory response [10-12]. Activated microglia accumulate in the spinal cord, producing inflammatory mediators and reac- tive oxygen and nitrogen species [11]. Astrocytes, the most abundant cells in the adult nervous system, also * Correspondence: barbeito@pasteur.edu.uy 1 Neurodegeneration Laboratory, Institut Pasteur, Montevideo, Uruguay Full list of author information is available at the end of the article