Calpain activation is involved in early caspase‐independent neurodegeneration in the hippocampus following status epilepticus

Araújo, Inês M.; Gil, Joana; Carreira, Bruno P.; Mohapel, Paul; Petersén, Åsa; Pinheiro, Paulo S.; Soulet, Denis; Bahr, Ben A.; Brundin, Patrik; Carvalho, Caetana M.

doi:10.1111/j.1471-4159.2007.05181.x

Cited by 48 publications

(59 citation statements)

References 50 publications

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“…VGAT cleavage in the hippocampus of rats following systemic injection of kainate may also arise from calpain activation. In fact, activation of calpains was shown to contribute to neurodegeneration in the hippocampus in this model of temporal lobe epilepsy (Goodman, 1998;Araú jo et al, 2008). Interestingly, 24 h after MCAO there was a recovery of fulllength VGAT protein levels, suggesting that the functional consequences of the cleavage of the transporter may be more relevant in the first hours after ischemia, when excitotoxicity takes place, and alterations in GABAergic synaptic transmission may interfere in the balance excitation/inhibition.…”

Section: Discussionmentioning

confidence: 84%

Cleavage of the Vesicular GABA Transporter under Excitotoxic Conditions Is Followed by Accumulation of the Truncated Transporter in Nonsynaptic Sites

Gomes¹,

Lobo²,

Melo³

et al. 2011

J. Neurosci.

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GABA is the major inhibitory neurotransmitter in the CNS and changes in GABAergic neurotransmission affect the overall activity of neuronal networks. The uptake of GABA into synaptic vesicles is mediated by the vesicular GABA transporter (VGAT), and changes in the expression of the transporter directly regulate neurotransmitter release. In this work we investigated the changes in VGAT protein levels during ischemia and in excitotoxic conditions, which may affect the demise process. We found that VGAT is cleaved by calpains following excitotoxic stimulation of hippocampal neurons with glutamate, giving rise to a stable truncated cleavage product (tVGAT). VGAT cleavage was also observed after transient middle cerebral artery occlusion in mice, a cerebral ischemia model, and following intrahippocampal injection of kainate, but no effect was observed in transgenic mice overexpressing calpastatin, a calpain inhibitor. Incubation of isolated cerebrocortical synaptic vesicles with recombinant calpain also induced the cleavage of VGAT and formation of stable tVGAT. Immunoblot experiments using antibodies targeting different regions of VGAT and N-terminal sequencing analysis showed that calpain cleaves the transporter in the N-terminal region, at amino acids 52 and 60. Immunocytochemistry of GABAergic striatal neurons expressing GFP fusion proteins with the full-length VGAT or tVGAT showed that cleavage of the transporter induces a loss of synaptic delivery, leading to a homogeneous distribution of the protein along neurites. Our results show that excitotoxicity downregulates full-length VGAT, with a concomitant generation of tVGAT, which is likely to affect GABAergic neurotransmission and may influence cell death during ischemia.

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Section: Discussionmentioning

confidence: 84%

Cleavage of the Vesicular GABA Transporter under Excitotoxic Conditions Is Followed by Accumulation of the Truncated Transporter in Nonsynaptic Sites

Gomes¹,

Lobo²,

Melo³

et al. 2011

J. Neurosci.

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“…4D). The choice of antibodies for immunoblots was indicated by previous studies that linked cytoskeletal and synaptic compromise to events of excitotoxic brain damage [13,33,38,44]. The better protective influence of AM6701 vs. AM6702 is evident across the 3 synaptic proteins (see post hoc tests of Fig.…”

Section: Resultsmentioning

confidence: 99%

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

et al. 2012

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Advances in the understanding of the endogenous cannabinoid system have led to several therapeutic indications for new classes of compounds that enhance cannabinergic responses. Endocannabinoid levels are elevated during pathogenic conditions, and inhibitors of endocannabinoid inactivation promote such on-demand responses. The endocannabinoids anandamide and 2-arachidonoyl glycerol have been implicated in protective signaling against excitotoxic episodes, including seizures. To better understand modulatory pathways that can exploit such responses, we used the new generation compound AM6701 that blocks both the anandamide-deactivating enzyme fatty acid amide hydrolase (FAAH) and the 2-arachidonoyl glycerol-deactivating enzyme monoacylglycerol lipase (MAGL) with equal potency. Also studied was the structural isomer AM6702 which is 44-fold more potent for inhibiting FAAH versus MAGL. When applied before and during kainic acid (KA) exposure to cultured hippocampal slices, AM6701 protected against the resulting excitotoxic events of calpain-mediated cytoskeletal damage, loss of presynaptic and postsynaptic proteins, and pyknotic changes in neurons. The equipotent inhibitor was more effective than its close relative AM6702 at protecting against the neurodegenerative cascade assessed in the slice model. In vivo, AM6701 was also the more effective compound for reducing the severity of KA-induced seizures and protecting against behavioral deficits linked to seizure damage. Corresponding with the behavioral improvements, cytoskeletal and synaptic protection was elicited by AM6701, as found in the KA-treated hippocampal slice model. It is proposed that the influence of AM6701 on FAAH and MAGL exerts a synergistic action on the endocannabinoid system, thereby promoting the protective nature of cannabinergic signaling to offset excitotoxic brain injury.

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“…Other enzymes that have been implicated include the calpains -calcium-dependent, non-lysosomal cysteine proteases [67]. Members of the calpain family, however, have different targets and their activation results in a complex array of protein degradation with calpain 1 activation having predominantly neuroprotective effects whilst calpain 2 activation is neurotoxic [68,69].…”

Section: Enzymes Activated By Intracellular Calcium Accumulationmentioning

confidence: 99%

Pathophysiology of status epilepticus

Walker¹

2018

Neuroscience Letters

109

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Status epilepticus (SE) is the maximal expression of epilepsy with a high morbidity and mortality. It occurs due to the failure of mechanisms that terminate seizures.Both human and animal data indicate that the longer a seizure lasts, the less likely it is to stop. Recent evidence suggests that there is a critical transition from an ictal to a post-ictal state, associated with a transition from a spatio-temporally desynchronized state to a highly synchronized state, respectively.As SE continues, it becomes progressively resistant to drugs, in particular benzodiazepines due partly to NMDA receptor-dependent internalization of GABA (A) receptors. Moreover, excessive calcium entry into neurons through excessive NMDA receptor activation results in activation of nitric oxide synthase, calpains, and NADPH oxidase. The latter enzyme plays a critical part in the generation of seizuredependent reactive oxygen species. Calcium also accumulates in mitochondria resulting in mitochondrial failure (decreased ATP production), and opening of the mitochondrial permeability transition pore. Together these changes result in status epilepticus-dependent neuronal death via several pathways. Multiple downstream mechanisms including inflammation, break down of the blood-brain barrier, and changes in gene expression can contribute to later pathological processes including chronic epilepsy and cognitive decline.

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Calpain activation is involved in early caspase‐independent neurodegeneration in the hippocampus following status epilepticus

Cited by 48 publications

References 50 publications

Cleavage of the Vesicular GABA Transporter under Excitotoxic Conditions Is Followed by Accumulation of the Truncated Transporter in Nonsynaptic Sites

Cleavage of the Vesicular GABA Transporter under Excitotoxic Conditions Is Followed by Accumulation of the Truncated Transporter in Nonsynaptic Sites

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

Pathophysiology of status epilepticus

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