Cumulative evidence suggests that programmed cell death (apoptosis) may contribute to the progressive hippocampal sclerosis seen in patients with refractory mesial temporal lobe epilepsy (MTLE). The endoplasmic reticulum (ER) stress-mediated cell apoptotic pathway has recently emerged as a vital intrinsic pathway, but the molecular mechanisms underlying this process in the epileptic brain remain unclear. We investigated inositol-requiring protein 1α (IRE1α)-mediated ER stress pro-and anti-apoptotic signaling pathways in resected hippocampi from 32 patients with intractable MTLE. Immunoreactivity for the ER stress markers glucose-regulated proteins 78 and 94 was significantly higher in MTLE hippocampi than in controls. The levels of IRE1α, tumor necrosis factor receptor associated factor 2 (TRAF2), apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK), which together constitute the IRE1α/TRAF2/ASK1/JNK pro-apoptotic signaling pathway, were significantly upregulated in patients with MTLE. Immunoreactivity for caspase-4, a homologue of caspase-12 that is possibly activated by IRE1α via TRAF2 following ER stress, and caspase-3 which was a downstream effector of caspase-4, were both detected in MTLE tissue samples. In contrast, immunoreactivity for caspase-4 and caspase-3 were low or absent in control samples. Simultaneously, the X-box binding protein 1 (XBP1), a basic leucine zipper (bZIP) family transcription factor downstream of IRE1α which can promote cell survival by upregulation of multiple ER-targeted genes, was also overexpressed and activated in MTLE hippocampi. Our data suggest that chronic epilepsy is associated with ER stress, as well as induction of both IRE1α-mediated pro- and anti-apoptotic signaling pathways.
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