Abstract:
:Delineating the molecular pathways underlying seizure-induced neuronal death may yield novel strategies for brain protection against prolonged or repetitive seizures. Glutamate-mediated excitotoxicity and necrosis is a primary contributing mechanism but seizures also activate programmed (apoptotic) cell death pathways. Apoptosis signalling pathways are typically initiated following perturbation of intracellular organelle function (intrinsic pathway) or by activated cell-surface-expressed death receptors (extrinsic pathway), with signalling cascades orchestrated in part by the Bcl-2 and caspase gene families. In this review, evidence for these pathways from experimental seizure modelling and clinical material from patients with intractable temporal lobe epilepsy is examined. Seizures cause mitochondrial dysfunction and activate intrinsic pathway components including pro-apoptotic Bcl-2 family proteins and caspases, processes that may be partly calcium-induced. The ER (endoplasmic reticulum) has emerged as a major intrinsic pathway trigger for apoptosis and its function may also be compromised following seizures and in epilepsy. The extrinsic, death-receptor-dependent pathway is also rapidly engaged following experimental seizures and in patient brain, supporting a previously unexpected apical role for a calcium-independent pathway. When considered alongside emerging functions of apoptosis-regulatory proteins in non-cell-death processes, including regulating intracellular calcium release and neuronal (re)structuring, apoptosis signalling pathways can be viewed as an important developing focus of research into how to obviate the deleterious impact of seizures on the brain.
journal_name
Biochem Soc Transjournal_title
Biochemical Society transactionsauthors
Henshall DCdoi
10.1042/BST0350421subject
Has Abstractpub_date
2007-04-01 00:00:00pages
421-3issue
Pt 2eissn
0300-5127issn
1470-8752pii
BST0350421journal_volume
35pub_type
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