Apoptosis signalling pathways in seizure-induced neuronal death and epilepsy

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.

Neuroprotective Effect of Piperine on Primarily Cultured Hippocampal Neurons

“…35) Glutamate receptor antagonists protect against seizure damage, but their therapeutic value is unlikely to be realized because of neurotoxic side effects, particularly in the young, and the profound disturbance these drugs impart on normal brain function. 36) Accordingly, alternative approaches to targeting seizure-induced neuronal death are required.…”

“…Apoptosis may be triggered by two main pathways: activation of cell surfaceexpressed death receptors of the tumor necrosis factor TNF, superfamily and disruption to intracellular organelle homeostasis or DNA damage. 35) Seizure-induced mitochondrial dysfunction and activation of Bcl-2 family are calcium dependent or at least partly of calcium dependent, 38,39) whereas a role for death receptors contributing to seizure-induced neuronal death is less likely because there is no apparent requirement for calcium in the activation mechanism. 35,40) Our results suggest that the neuroprotective effect of PIP should be calcium dependent and participate in protecting intracellular organelles, such as mitochondrion and endoplasmic reticulum (ER).…”

Temporal Lobe Epilepsy: Cell Death and Molecular Targets

“…Several studies have indicated that seizures can activate the intrinsic and extrinsic apoptotic pathways in the brain (Henshall, 2007). The release of cytochrome c, Apaf-1, activated caspase-9 and -3 and subsequent DNA fragmentation in the rat hippocampus after a short SE duration indicate activation of the intrinsic pathway (Turski et al, 1983;Leite et al, 1990).…”

“…This ultimately culminates with cell necrosis (Fujikawa, 2005(Fujikawa, , 2006. The glutamate-mediated excitotoxicity and necrosis are primary contributing factors, but seizures also activate programmed cell death pathways, such as apoptosis (Henshall 2007(Henshall , 2008.…”

“…Activation of the cell surface-expressed death receptors, such as the TNF superfamily (TNFR1; TNF receptor 1) or Fas, causes the death effector domains (DED) within the prodomain to bind to homologous regions on the death receptor (DR) adaptor proteins, such as Fas-associated death domain (FADD), which forms an intracellular complex known as the DISC (death-inducing signaling complex), leading to caspase-8 activation (Henshall, 2005, Thornberry andLazebnik, 1998). The caspase cascade is initiated by caspase-8 and culminates with the activation of executioner caspases, such as caspase-3, which cleave intracellular structural and survival proteins and activate enzymes responsible for DNA fragmentation (Henshall andSimon, 2005, Thornberry andLazebnik, 1998). The intrinsic pathway is triggered following the disruption of intracellular organelle homoeostasis or DNA damage (Verhagen et al, 2000).…”