Abstract
BackgroundThe 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).MethodsSE 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.ResultsFollowing 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.ConclusionsThese 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.
Highlights
The release of tumor necrosis factor-a (TNF-a) appears depend on the P2X7 receptor, a purinergic receptor
Salinetreated animals showed the beginning of epileptiform discharges 768 s after pilocarpine injection (i.p.)
These findings indicate that BzATP, oxidized ATP (OxATP), sTNFp55R or BzATP +sTNFp55R-infusion did not affect pilocarpine-induced status epilepticus (SE) in rats (Figure 1)
Summary
The release of tumor necrosis factor-a (TNF-a) appears depend on the P2X7 receptor, a purinergic receptor. We addressed the question of whether P2X7 receptor-mediated TNF-a regulation is involved in pathogenesis and outcome of status epilepticus (SE). Tumor necrosis factor-a (TNF-a) is a 17-kDa protein signaling via TNFp75R involves activation of p38 mitogen-activated protein kinase to promote neuronal survival [10]. TNFp55R deficiency enhances KA-induced excitotoxic hippocampal injury in mice [11]. Marchetti et al [12] has reported that TNFp75R-induced persistent NF-B activity is essential for neuronal survival against excitotoxic stress. TNF-a clearly possesses the ability to simultaneously activate both cell death and cell survival pathways, and this balance determines whether TNF-a promotes neurodegeneration or neuroprotection
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.