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

Abstract

BACKGROUND:

The release of tumor necrosis factor-α (TNF-α) appears depend on the P2X7 receptor, a purinergic receptor. In the present study, we addressed the question of whether P2X7 receptor-mediated TNF-α 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-α and NF-κB subunit phosphorylations.

RESULTS:

Following SE, P2X7 receptor agonist (BzATP) infusion increased TNF-α immunoreactivity in dentate granule cells as compared with that in saline-infused animals. In addition, TNF-α immunoreactivity was readily apparent in the mossy fibers, while TNF-α immunoreactivity in CA1-3 pyramidal cells was unaltered. However, P2X7 receptor antagonist (OxATP-, A-438079, and A-740003) infusion reduced SE-induced TNF-α 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-κB 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-α induction by P2X7 receptor activation may ameliorate SE-induced CA3 neuronal damage via enhancing NF-κB p65-Ser276 and p65-Ser311 phosphorylations.

• Authors: Ji-Eun Kim, Hea Jin Ryu, Tae-Cheon Kang
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 8 Pg. 62 (Jun 02 2011) ISSN: 1742-2094 [Electronic] England
• PMID: 21631954 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (N-(1-(((cyanoimino)(5-quinolinylamino) methyl) amino)-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide)
• 3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine
• Acetamides
• Muscarinic Agonists
• Purinergic Agonists
• Purinergic Antagonists
• Pyridines
• Quinolines
• Receptors, Purinergic P2X7
• Rela protein, rat
• Tetrazoles
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha
• Pilocarpine
• 3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
• Adenosine Triphosphate

Topics

• Acetamides (pharmacology)
• Adenosine Triphosphate (analogs & derivatives, pharmacology)
• Animals
• CA3 Region, Hippocampal (cytology, drug effects, metabolism, pathology)
• Male
• Muscarinic Agonists (pharmacology)
• Neurons (drug effects, metabolism, pathology)
• Pilocarpine (pharmacology)
• Purinergic Agonists (pharmacology)
• Purinergic Antagonists (pharmacology)
• Pyridines (pharmacology)
• Quinolines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Purinergic P2X7 (metabolism)
• Signal Transduction (physiology)
• Status Epilepticus (chemically induced, metabolism)
• Tetrazoles (pharmacology)
• Transcription Factor RelA (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)