Epileptogenesis

About: Epileptogenesis is a research topic. Over the lifetime, 4218 publications have been published within this topic receiving 170809 citations.

Up-regulation of hippocampal metabotropic glutamate receptor 5 in temporal lobe epilepsy patients.

Abstract: Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors involved in the regulation of glutamatergic transmission. Recent studies indicate that excitatory group I mGluRs (mGluR1 and mGluR5) contribute to neurotoxicity and hyperexcitability during epileptogenesis. In this study, we examined the distribution of mGluR1α and mGluR5 immunoreactivity (IR) in hippocampal resection tissue from pharmaco-resistant temporal lobe epilepsy (TLE) patients. IR was detected with panels of receptor subtype specific antisera in hippocampi from TLE patients without (non-HS group) and with hippocampal sclerosis (HS group) and was compared with that of non-epileptic autopsy controls (control group). By immunohistochemistry and immunoblot analysis, we found a marked increase of mGluR5 IR in hippocampi from the non-HS compared with the control group. High mGluR5 IR was most prominent in the cell bodies and apical dendrites of hippocampal principal neurons and in the dentate gyrus molecular layer. In the HS group, this increase in neuronal mGluR5 IR was even more pronounced, but owing to neuronal loss the number of mGluR5-immunoreactive neurons was reduced compared with the non-HS group. IR for mGluR1α was found in the cell bodies of principal neurons in all hippocampal subfields and in stratum oriens and hilar interneurons. No difference in mGluR1α IR was observed between neurons in both TLE groups and the control group. However, owing to neuronal loss, the number of mGluR1α-positive neurons was markedly reduced in the HS group. The up-regulation of mGluR5 in surviving neurons is probably a consequence rather than a cause of the epileptic seizures and may contribute to the hyperexcitability of the hippocampus in pharmaco-resistant TLE patients. Thus, our data point to a prominent role of mGluR5 in human TLE and indicate mGluR5 signalling as potential target for new anti-epileptic drugs.

High Mobility Group Box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy

Abstract: Approximately 30% of epilepsy patients experience seizures that are not controlled by the available drugs. Moreover, these drugs provide mainly a symptomatic treatment since they do not interfere with the disease's mechanisms. A mechanistic approach to the discovery of key pathogenic brain modifications causing seizure onset, recurrence and progression is instrumental for designing novel and rationale therapeutic interventions that could modify the disease course or prevent its development. In this regard, increasing evidence shows that neuroinflammation is a pathogenic factor in drug-resistant epilepsies. The High Mobility Group Box 1 (HMGB1)/Toll-like receptor 4 axis is a key initiator of neuroinflammation following brain injuries leading to epilepsy, and its activation contributes to seizure mechanisms in animal models. Recent findings have shown dynamic changes in HMGB1 and its isoforms in the brain and blood of animals exposed to acute brain injuries and undergoing epileptogenesis, and in surgically resected epileptic foci in humans. HMGB1 isoforms reflect different pathophysiological processes, and the disulfide isoform, which is generated in the brain during oxidative stress, is implicated in seizures, cell loss and cognitive dysfunctions. Interfering with disulfide HMGB1-activated cell signaling mediates significant therapeutic effects in epilepsy models. Moreover, both clinical and experimental data suggest that HMGB1 isoforms may serve as mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy. These novel findings suggest that the HMGB1 system could be targeted to prevent seizure generation and may provide clinically useful prognostic biomarkers which may also predict the patient's response to therapy.

Granule Cell Neurogenesis After Status Epilepticus in the Immature Rat Brain

Abstract: Purpose: Several experimental paradigms of seizure induction that produce epilepsy as a consequence have been shown to be associated with the proliferation of dentate granule cells. In developing animals, the acute sequela of hilar damage and the chronic sequelae of spontaneous seizures and mossy fiber synaptic reorganization, in response to status epilepticus, occur in an age-dependent manner. We investigated seizure-induced granule cell neurogenesis in developing rat pups to study the association between hilar injury, granule cell neurogenesis, and epilepsy. Methods: Rat pups of 2 and 3 weeks postnatal age were subjected to lithium-pilocarpine status epilepticus (LiPC SE). Rats were given bromodeoxyuridine (BrdU; 50 mg/kg intraperitoneal) twice daily for 4 days beginning 3 days after SE to label dividing cells. Routine immunocytochemistry and quantification of BrdU labeling by image analysis were performed. Results were compared with previously reported data on cellular injury, mossy fiber sprouting, and spontaneous seizures in rat pups of these ages after LiPC SE. Results: In 3-week-old pups, which demonstrate SE-induced hilar damage and develop spontaneous seizures accompanied by mossy fiber sprouting, the BrdU-immunoreactive area (percent) in the subgranular proliferative zone increased to 10.6 ± 2.5 compared with 1.4 ± 0.5 in the control animals (p < 0.05). The 2-week-old animals, which show neither hilar damage nor sprouting and rarely develop spontaneous seizures, also showed a comparable extent of SE-induced neurogenesis [8.0 ± 1.4 (LiPC SE) versus 0.4 ± 0.2 (control), p < 0.05]. Conclusions; Seizure-induced granule cell neurogenesis does not appear to be a function of seizure-induced hilar cellular damage. Granule cell neurogenesis induced by SE does not determine epileptogenesis in the developing rat.

δ Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter Channel Gating and Surface Expression of α4β2δ GABAA Receptors

Abstract: Most human idiopathic generalized epilepsies (IGEs) are polygenic, but virtually nothing is known of the molecular basis for any of the complex epilepsies. Recently, two GABA A receptor δ subunit variants (E177A, R220H) were proposed as susceptibility alleles for generalized epilepsy with febrile seizures plus and juvenile myoclonic epilepsy. In human embryonic kidney 293T cells, recombinant hα1β2δ(E177A) and hα1β2δ(R220H) receptor currents were reduced, but the basis for the current reduction was not determined. We examined the mechanistic basis for the current reduction produced by these variants using the hα4β2δ receptor, an isoform more physiologically relevant and linked to epileptogenesis, by characterizing the effects of these variants on receptor cell surface expression and single-channel gating properties. Expression of variant α4β2δ(R220H) receptors resulted in a decrease in surface receptor proteins, and a smaller, but significant, reduction was observed for variant α4β2δ(E177A) receptors. For both variants, no significant alterations of surface expression were observed for mixed population of wild-type and variant receptors. The mean open durations of α4β2δ(E177A) and α4β2δ(R220H) receptor single-channel currents were both significantly decreased compared to wild-type receptors. These data suggest that both δ(E177A) and δ(R220H) variants may result in disinhibition in IGEs by similar cellular and molecular mechanisms, and in heterozygously affected individuals, a reduction in channel open duration of δ subunit-containing GABA A receptors may be the major contributor to the epilepsy phenotypes.