IJPPP Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Physiol Pathophysiol Pharmacol 2011;3(2):120-132.

Original Article
Suppression of TNF receptor-1 signaling in an in vitro model of epileptic tolerance

Simon J. Thompson, Michelle D. Ashley, Sabine Stöhr, Clara Schindler, Minghua Li, Kristin A. McCarthy, Andrea N. Pearson, Zhi-Gang
Xiong, Roger P. Simon, David C. Henshall, Robert Meller

RS Dow Neurobiology Laboratories, Legacy Research, 1225 NE 2nd Ave, Portland, Oregon, 97232, USA. 2Department of Physiology &
Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

Received May 25, 2011; accepted June 10, 2011; Epub June 13, 2011; Published June 30, 2011

Abstract: Tumor necrosis factor (TNF ) is a pleiotropic cytokine that can regulate cell survival, inflammation or, under certain
circumstances, trigger cell death. Previous work in rat seizure models and analysis of temporal lobe samples from epilepsy patients
has suggested seizures activate TNF receptor 1 (TNFR1). Here we explored the activation and functional significance of TNFR1
signaling in the mouse hippocampus using in vitro and in vivo models of seizureinduced neuronal injury. Focal-onset status
epilepticus in mice upregulated TNFR1 levels and led to formation of TNFR1-TNFR-associated death domain (TRADD) and
TRADD-Fasassociated death domain (FADD) binding. Seizure-like injury modeled in vitro by removal of chronic excitatory blockade in
mouse hippocampal neurons also activated this TNFR1 signaling pathway. Prior exposure of hippocampal neurons to a non-harmful
seizure episode, via NMDA receptor blockade, 24 h prior to injurious seizures significantly reduced cell death and modeled epileptic
tolerance in vitro. TNFR1 complex formation with TRADD and TRADD-FADD binding were reduced in tolerant cells. Finally, TNFR1
signaling and cell death were reduced by PKF- 242-484, a dual matrix metaloproteinase/TNF converting enzyme inhibitor. The present
study shows that TNFR1 signaling is activated in mouse seizure models and may contribute to neuropathology in vitro and in vivo while
suppression of this pathway may underlie neuroprotection in epileptic tolerance. (IJPPP1105002).

Key words: Seizure, epileptic tolerance, preconditioning, TACE, PKF242-484, cell death, neuroprotection, TNF

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Address all correspondence to:
Robert Meller, PhD
Neuroscience Institute, Morehouse School of Medicine
720 Westview Drive, Atlanta, GA, 30310-1495, USA.