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)

The present study sought to evaluate the neuroprotective effects of apocynin, an NADPH oxidase assembly inhibitor, on seizure-induced neuronal death. Apocynin, also known as acetovanillone, is a natural organic compound isolated from the root of Canadian hemp (Apocynum cannabium). It has been extensively studied to determine its disease-fighting capabilities and application in several brain insults, such as traumatic brain injury and stroke. Here we tested the hypothesis that post-treatment of apocynin may prevent seizure-induced neuronal death by suppression of NADPH oxidase-mediated superoxide production. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25mg/kg) in male rats. Apocynin (30mg/kg, i.p.) was injected into the intraperitoneal space two hours after seizure onset. A second injection was performed 24h after seizure. To test whether apocynin inhibits NADPH oxidase activation-induced reactive oxygen species (ROS) production, dihydroethidium (dHEt, 5mg/kg, i.p.) was injected before onset of seizure and ROS production was detected five hours after seizure onset. Neuronal oxidative injury (4HNE), neuronal death (Fluoro Jade-B), blood brain barrier (BBB) disruption (IgG leak), neurotrophil infiltration (MPO) and microglia activation (CD11b) in the hippocampus was evaluated at three days after status epilepticus (SE). Pilocarpine-induced seizure increased p47 immunofluorescence in the plasma membrane of hippocampal neurons at 12h post-insult and apocynin treatment prevented this increase. The present study found that apocynin post-treatment decreased ROS production and lipid peroxidation after seizure and decreased the number of degenerating hippocampal neurons. Apocynin also reduced seizure-induced BBB disruption, neurotrophil infiltration and microglial activation. Taken together, the present results suggest that inhibition of NADPH oxidase by apocynin may have a high therapeutic potential to reduce seizure-induced neuronal dysfunction.
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PMID:Post-treatment of an NADPH oxidase inhibitor prevents seizure-induced neuronal death. 2331 82

Progranulin (PGRN) haploinsufficiency accounts for up to 10% of frontotemporal lobe dementia. PGRN has also been implicated in neuroinflammation in acute and chronic neurological disorders. Here we report that both protein and mRNA levels of cortical and hippocampal PGRN are significantly enhanced following pilocarpine-induced status epilepticus. We also identify intense PGRN immunoreactivity that colocalizes with CD11b in seizure-induced animals, suggesting that PGRN elevation occurs primarily in activated microglia and macrophages. To test the role of PGRN in activation of microglia/macrophages, we apply recombinant PGRN protein directly into the hippocampal formation, and observe no change in the number of CD11b(+) microglia/macrophages in the dentate gyrus. However, with pilocarpine-induced status epilepticus, PGRN application significantly increases the number of CD11b(+) microglia/macrophages in the dentate gyrus, without affecting the extent of hilar cell death. In addition, the number of CD11b(+) microglia/macrophages induced by status epilepticus is not significantly different between PGRN knockout mice and wildtype. Our findings suggest that status epilepticus induces PGRN expression, and that PGRN potentiates but is not required for seizure-induced microglia/macrophage activation.
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PMID:Progranulin promotes activation of microglia/macrophage after pilocarpine-induced status epilepticus. 2388 54

Non-synaptic mechanisms are being considered the common factor of brain damage in status epilepticus and alcohol intoxication. The present work reports the influence of the chronic use of ethanol on epileptic processes sustained by non-synaptic mechanisms. Adult male Wistar rats administered with ethanol (1, 2 e 3 g/kg/d) during 28 days were compared with Control. Non-synaptic epileptiform activities (NEAs) were induced by means of the zero-calcium and high-potassium model using hippocampal slices. The observed involvement of the dentate gyrus (DG) on the neurodegeneration promoted by ethanol motivated the monitoring of the electrophysiological activity in this region. The DG regions were analyzed for the presence of NKCC1, KCC2, GFAP and CD11b immunoreactivity and cell density. The treated groups showed extracellular potential measured at the granular layer with increased DC shift and population spikes (PS), which was remarkable for the group E1. The latencies to the NEAs onset were more prominent also for the treated groups, being correlated with the neuronal loss. In line with these findings were the predispositions of the treated slices for neuronal edema after NEAs induction, suggesting that restrict inter-cell space counteracts the neuronal loss and subsists the hyper-synchronism. The significant increase of the expressions of NKCC1 and CD11b for the treated groups confirms the existence of conditions favorable to the observed edematous necrosis. The data suggest that the ethanol consumption promotes changes on the non-synaptic mechanisms modulating the NEAs. For the lower ethanol dosage the neurophysiological changes were more effective suggesting to be due to the less intense neurodegenertation.
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PMID:Alcohol abuse promotes changes in non-synaptic epileptiform activity with concomitant expression changes in cotransporters and glial cells. 2423 60

Activation of microglial cells (brain macrophages) soon after status epilepticus has been suggested to be critical for the pathogenesis of mesial temporal lobe epilepsy (MTLE). However, microglial activation in the chronic phase of experimental MTLE has been scarcely addressed. In this study, we questioned whether microglial activation persists in the hippocampus of pilocarpine-treated, epileptic Wistar rats and to which extent it is associated with segmental neurodegeneration. Microglial cells were immunostained for the universal microglial marker, ionized calcium-binding adapter molecule-1 and the activation marker, CD11b (also known as OX42, Mac-1). Using quantitative morphology, i.e., stereology and Neurolucida-based reconstructions, we investigated morphological correlates of microglial activation such as cell number, ramification, somatic size and shape. We find that microglial cells in epileptic rats feature widespread, activation-related morphological changes such as increase in cell number density, massive up-regulation of CD11b and de-ramification. The parameters show heterogeneity in different hippocampal subregions. For instance, de-ramification is most prominent in the outer molecular layer of the dentate gyrus, whereas CD11b expression dominates in hilus. Interestingly, microglial activation only partially correlates with segmental neurodegeneration. Major neuronal death in the hilus, CA3 and CA1 coincides with strong up-regulation of CD11b. However, microglial activation is also observed in subregions that do not feature neurodegeneration, such as the molecular and granular layer of the dentate gyrus. This in vivo study provides solid experimental evidence that microglial cells feature widespread heterogeneous activation that only partially correlates with hippocampal segmental neuronal loss in experimental MTLE.
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PMID:Widespread activation of microglial cells in the hippocampus of chronic epileptic rats correlates only partially with neurodegeneration. 2487 24

Non-convulsive status epilepticus (NCSE) is a prolonged epileptic seizure with subtle symptoms that may delay clinical diagnosis. Emerging experimental evidence shows brain pathology and epilepsy development following NCSE. New diagnostic/prognostic tools are therefore needed for earlier and better stratification of treatment. Here we examined whether NCSE initiates a peripheral immune response in blood serum from rats that experienced electrically-induced NCSE. ELISA analysis showed an acute transient increase in serum protein levels including interleukin-6 6 h post-NCSE, similar to the immune reaction in the brain. At 4 weeks post-NCSE, when 75% of rats subjected to NCSE had also developed spontaneous seizures, several immune proteins were altered. In particular, markers associated with microglia, macrophages and antigen presenting cells, such as CD68, MHCII, and galectin-3, were increased and the T-cell marker CD4 was decreased in serum compared to both non-stimulated controls and NCSE rats without spontaneous seizures, without correlation to interictal epileptiform activity. Analyses of serum following intracerebral injection of lipopolysaccharide (LPS) showed an acute increase in interleukin-6, but at 4 weeks unaltered levels of MHCII and galectin-3, an increase in CD8 and CD11b and a decrease in CD68. None of the increased serum protein levels after NCSE or LPS could be confirmed in spleen tissue. Our data identifies the possibility to detect peripheral changes in serum protein levels following NCSE, which may be related to the development of subsequent spontaneous seizures.
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PMID:Immune Profile in Blood Following Non-convulsive Epileptic Seizures in Rats. 3133 61

A multidimensional inflammatory response ensues after status epilepticus (SE), driven partly by cyclooxygenase-2 mediated activation of prostaglandin EP2 receptors. The inflammatory response is typified by astrocytosis, microgliosis, erosion of the blood-brain barrier (BBB), formation of inflammatory cytokines, and brain infiltration of blood-borne monocytes. Our previous studies have shown that inhibition of monocyte brain invasion or systemic administration of an EP2 receptor antagonist relieves multiple deleterious consequences of SE. Here we identify those effects of EP2 antagonism that are reproduced by conditional ablation of EP2 receptors in immune myeloid cells and show that systemic EP2 antagonism blocks monocyte brain entry in male mice. The induction of hippocampal IL-6 after pilocarpine SE was nearly abolished in EP2 conditional knockout mice. Serum albumin levels in the cortex, a measure of BBB breakdown, were significantly higher after SE in EP2-sufficient mice but not in EP2 conditional knockouts. EP2 deficiency in innate immune cells accelerated the recovery from sickness behaviors following SE. Surprisingly, neurodegeneration was not alleviated in myeloid conditional knockouts. Systemic EP2 antagonism prevented monocyte brain infiltration and provided broader rescue of SE-induced effects than myeloid EP2 ablation, including neuroprotection and broader suppression of inflammatory mediators. Reporter expression indicated the cellular target of CD11b-driven Cre was circulating myeloid cells but, unexpectedly, not microglia. These findings indicate that activation of EP2 receptors on immune myeloid cells drives substantial deficits in behavior and disrupts the BBB after SE. The benefits of systemic EP2 antagonism can be attributed, in part, to blocking brain recruitment of blood-borne monocytes.SIGNIFICANCE STATEMENTUnabated seizures reduce quality of life, promote the development of epilepsy, and can be fatal. We previously identified activation of prostaglandin EP2 receptors as a driver of undesirable consequences of seizures. However, the relevant EP2-expressing cell types remain unclear. Here we identify peripheral innate immune cells as a driver of the EP2-related negative consequences of seizures. Removal of EP2 from peripheral immune cells was beneficial, abolishing production of a key inflammatory cytokine, accelerating weight regain, and limiting behavioral deficits. These findings provide evidence that EP2 engagement on peripheral immune and brain endothelia contributes to the deleterious effects of SE, and will assist in the development of beneficial therapies to enhance quality of life in individuals who suffer prolonged seizures.
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PMID:Peripheral myeloid cell EP2 activation contributes to the deleterious consequences of status epilepticus. 3329 58