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The Journal of Neuroscience, May 2, 2007, 27(18):4957-4968; doi:10.1523/JNEUROSCI.5417-06.2007

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Neurobiology of Disease
Modulation of the Purinergic P2X₇ Receptor Attenuates Lipopolysaccharide-Mediated Microglial Activation and Neuronal Damage in Inflamed Brain

Hyun B. Choi,^1,2 * Jae K. Ryu,^1 * Seung U. Kim,^2,3 and James G. McLarnon¹

¹Department of Anesthesiology, Pharmacology, and Therapeutics and ²Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3, and ³Brain Disease Research Center, Ajou University, Suwon, Korea 443-749

Correspondence should be addressed to Dr. James G. McLarnon, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Email: mclarnon{at}interchange.ubc.ca

We investigated the involvement and roles of the ionotropic purinergic receptor P2X₇R in microglia in mediating lipopolysaccharide (LPS)-induced inflammatory responses and neuronal damage in rat striatum. A detailed in vivo study showed that LPS injection into striatum markedly increased the expression of P2X₇R in microglia compared with control (saline)-injected animals. Additionally, LPS injection upregulated a broad spectrum of proinflammatory mediators, including inducible nitric oxide synthase (nitric oxide production marker), 3-nitrotyrosine (peroxynitrite-mediated nitration marker), 4-hydroxynonenal (lipid peroxidation marker), and 8-hydroxy-2'-deoxyguanosine (oxidative DNA damage marker), and reduced neuronal viability. The P2X₇R antagonist oxidized ATP (oxATP) was effective in attenuating expressions of all inflammatory mediators and in addition inhibited LPS-induced activation of the cellular signaling factors p38 mitogen-activated protein kinase and transcriptional factor nuclear factor B. Most importantly, in vivo, oxATP blockade of P2X₇R also reduced numbers of caspase-3-positive neurons and increased neuronal survival in LPS-injected brain. In vitro, LPS stimulation of cultured human microglia enhanced cellular expressions of a host of proinflammatory factors, including cyclooxygenase-2, interleukin-1ß (IL-1ß), IL-6, IL-12, and tumor necrosis factor-; all factors were inhibited by oxATP. A novel finding was that LPS potentiated intracellular [Ca²⁺]_i mobilization induced by the P2X₇R ligand 2',3'-O-(4-benzoyl-benzoyl) ATP, which could serve as a mechanistic link for P2X₇R amplification of inflammatory responses. Our results suggest critical roles for P2X₇R in mediating inflammation and inhibition of this subtype purinergic receptor as a novel therapeutic approach to reduce microglial activation and confer neuroprotection in inflamed and diseased brain.

Key words: P2X₇ receptor; lipopolysaccharide; microglia; inflammation; cytokines; oxidized ATP

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Received Dec. 14, 2006; revised March 13, 2007; accepted March 28, 2007.

Correspondence should be addressed to Dr. James G. McLarnon, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Email: mclarnon{at}interchange.ubc.ca

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