P2X7 receptor activation ameliorates CA3 neuronal damage via a tumor necrosis factor-α-mediated pathway in the rat hippocampus following status epilepticus

Background: The release of tumor necrosis factor-alpha (TNF-alpha) appears depend on the P2X7 receptor, a purinergic receptor. In the present study, we addressed the question of whether P2X7 receptor-mediated TNF-alpha regulation is involved in pathogenesis and outcome of status epilepticus (SE). Methods: SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, 2',3'-O-(4-benzoylbenzoyl)-adenosine 5'-triphosphate (BzATP), adenosine 5'-triphosphate-2',3'-dialdehyde (OxATP), A-438079, or A-740003 prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-alpha and NF-kappa B subunit phosphorylations. Results: Following SE, P2X7 receptor agonist (BzATP) infusion increased TNF-alpha immunoreactivity in dentate granule cells as compared with that in saline- infused animals. In addition, TNF-alpha immunoreactivity was readily apparent in the mossy fibers, while TNF-alpha immunoreactivity in CA1-3 pyramidal cells was unaltered. However, P2X7 receptor antagonist (OxATP-, A-438079, and A-740003) infusion reduced SE-induced TNF-alpha expression in dentate granule cells. In the CA3 region, BzATP infusion attenuated SE-induced neuronal damage, accompanied by enhancement of p65-Ser276 and p65-Ser311 NF-kappa B subunit phosphorylations. In contrast, OxATP-, A-438079, and A-740003 infusions increased SE-induced neuronal death. Soluble TNF p55 receptor (sTNFp55R), and cotreatment with BzATP and sTNFp55R infusion also increased SE-induced neuronal damage in CA3 region. However, OxATP-, sTNFp55R or BzATP+sTNFp55R infusions could not exacerbate SE-induced neuronal damages in the dentate gyrus and the CA1 region, as compared to BzATP infusion. Conclusions: These findings suggest that TNF-alpha induction by P2X7 receptor activation may ameliorate SE-induced CA3 neuronal damage via enhancing NF-kappa B p65-Ser276 and p65-Ser311 phosphorylations.