title: 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.affiliation: Department of Anatomy & Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon, Kangwon-Do 200-702, South Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Hea Jin
authors.initials: HJ
authors.lastname: Ryu
authors.forename: Tae-Cheon
authors.initials: TC
authors.lastname: Kang
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010862:Pilocarpine / Q000494:pharmacology; D058913:Purinergic Agonists / Q000494:pharmacology; D058914:Purinergic Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C515928:(N-(1-(((cyanoimino)(5-quinolinylamino) methyl) amino)-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide); C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D000081:Acetamides; D018721:Muscarinic Agonists; D058913:Purinergic Agonists; D058914:Purinergic Antagonists; D011725:Pyridines; D011804:Quinolines; D058486:Receptors, Purinergic P2X7; C498145:Rela protein, rat; D013777:Tetrazoles; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D010862:Pilocarpine; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate