Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary and secondary epileptogenesis involves multiple genetic and acquired factors. Epileptogenesis is a complex result of combined factors including membrane factors, neurotransmitter and environmental factors. Ion channel-related diseases, GABA and glutamate dysfunction, and glial reaction intervene in different epileptic conditions. The understanding of the mechanisms which emphasize initiation and maintenance of status epilepticus (SE) are in progress. Prognosis of SE is related to the duration of epileptic activity and to the acute cerebral and systemic consequences. Delayed cellular and molecular alterations after SE are responsible for secondary epileptogenesis. Glutamate receptor activation is the main key point leading to an excessive intraneuronal accumulation of ionic calcium by which a cascade of reactions is induced. Apoptotic neuronal death, glial reaction axonal sprouting and neurogenesis contribute to a state of hyperexcitability and hypersynchrony. A better understanding of underlying mechanisms of epileptogenesis may serve the development of new drugs with both anticonvulsant and antiepileptic (prevention or neuroprotection) actions.
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PMID:[Pathophysiology of epileptic seizures and status epilepticus]. 1127 Feb 45

Ca2+ currents are thought to enhance glutamate excitotoxicity. To investigate whether reduced expression of the Ca2+ limiting GluR2(B) subunit enhances seizure-induced vulnerability to either CA1 or CA3 neurons, we delivered GluR2(B) oligodeoxynucleotides (AS-ODNs) to the dorsal hippocampus of adult rats before inducing kainate (KA) seizures. After knockdown, no changes in behavior, electrographic activity, or histology were observed. In contrast, GluR2(B) knockdown and KA-induced status epilepticus produced accelerated histological injury to the ipsilateral CA3a-b and hilar subregions. At 8 to 12 h, the CA3a was preferentially labeled by both silver and TUNEL methods. TUNEL staining revealed 2 types of nuclei. They were round with uniform label, features of necrosis, or had DNA clumping or speckled chromatin deposits within surrounding cytosol, features of apoptosis. At 16 to 24 h, many CA3a-c neurons were shrunken, eosinophilic, argyrophilic, or completely absent. Immunohistochemistry revealed marked decreases in GluR2(B) subunits throughout the hippocampus, NR1 immunoreactivity was also reduced but to a lesser extent. In contrast, GluR1 and NR2A/B immunohistochemistry was relatively uniform except in regions of cell loss or within close proximity to the CA1 infusion site. At 144 h, the CA3 was still preferentially injured although bilateral CA1 injury was also observed in some AS-ODN-, S-ODN-, and KA-only-treated animals. Glutamate receptor antibodies revealed generalized decreases in the CA3 with all probes tested at this delayed time. In contrast, GluR2(B) expression was increased within CA1 irregularly shaped, injured neurons. Therefore, hippocampal deprivation of GluR2(B) subunits is insufficient to induce cell death in mature animals but may accelerate the already known CA3/hilar lesion, possibly by triggering apoptosis within CA3 neurons. CA1 and DG survive the first week despite their loss of GluR2(B) subunits, suggesting that other intrinsic properties such as increased Na+ conductance and reduced ability of the GluR2(B) subunit to interact with certain cytoplasmic proteins may be responsible for the augmented cell death rather than changes in AMPA receptor-mediated Ca2+ permeability. Alternatively, changes in allosteric interactions that affect other receptor classes of high density at the mossy fiber synapse (e.g. KA receptors) may augment KA neurotoxicity. Latent GluR2(B) increases in CA1 injured neurons support a role for AMPA receptor subunit alterations in seizure-induced tolerance.
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PMID:GluR2(B) knockdown accelerates CA3 injury after kainate seizures. 1290

Glutamate receptor-mediated excitotoxicity is a common pathogenic process in many neurological conditions including epilepsy. Prolonged seizures induce elevations in extracellular glutamate that contribute to excitotoxic damage, which in turn can trigger chronic neuroinflammatory reactions, leading to secondary damage to the brain. Blocking key inflammatory pathways could prevent such secondary brain injury following the initial excitotoxic insults. Prostaglandin E2 (PGE2) has emerged as an important mediator of neuroinflammation-associated injury, in large part via activating its EP2 receptor subtype. Herein, we investigated the effects of EP2 receptor inhibition on excitotoxicity-associated neuronal inflammation and injury in vivo. Utilizing a bioavailable and brain-permeant compound, TG6-10-1, we found that pharmacological inhibition of EP2 receptor after a one-hour episode of kainate-induced status epilepticus (SE) in mice reduced seizure-promoted functional deficits, cytokine induction, reactive gliosis, blood-brain barrier impairment, and hippocampal damage. Our preclinical findings endorse the feasibility of blocking PGE2/EP2 signaling as an adjunctive strategy to treat prolonged seizures. The promising benefits from EP2 receptor inhibition should also be relevant to other neurological conditions in which excitotoxicity-associated secondary damage to the brain represents a pathogenic event.
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PMID:Suppressing pro-inflammatory prostaglandin signaling attenuates excitotoxicity-associated neuronal inflammation and injury. 3076 57