Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kainic acid-induced seizures in the rat brain cause severe brain damage that is thought to result, in part, from oxidative stress. In this study, we examine the consequences of systemic administration of kainic acid on expression of several genes that encode proteins thought to play roles in protection from oxidative stress, including metallothionein-I, and -III. Kainic acid causes an increase in metallothionein-I and heme oxygenase-I mRNAs, as well as an increase in c-fos, heat shock protein-70, and interleukin-1 beta mRNAs. The induction of these mRNAs is seizure dependent, and is greater in brain areas with extensive damage (e.g. piriform cortex) than in areas with minimal damage (e.g. frontal cortex and cerebellum). In contrast, little or no change in mRNA for metallothionein-III, manganese superoxide dismutase, copper-zinc superoxide dismutase, glutathione-s-transferase ya subunit or glutathione peroxidase occur. The prolonged and robust concordant induction of the metallothionein-I and heme oxygenase-I genes may reflect the oxidative stress produced by kainic acid-induced seizures. In addition, the induction of interleukin-1 beta gene expression suggests an inflammatory response in brain regions damaged by kainic acid-induced seizures. Delineating the regulation of genes associated with oxidative and inflammatory responses can contribute to a fuller understanding of seizures and associated brain damage.
 ...
PMID:Temporalspatial patterns of expression of metallothionein-I and -III and other stress related genes in rat brain after kainic acid-induced seizures. 765 48

Changes in gene expression in the brain in response to adverse conditions, such as ischemia or excitotoxin exposure, may be part of the injury process or represent an adaptive response which may be protective during subsequent stressful events. In this review we have considered the regulation, functions and potential relationships to the pathophysiology of ischemia of several major groups of stress-induced genes, including those of the M(r) 27,000, 32,000 (heme oxygenase), 70,000 and 90,000 heat shock protein families, the glucose-regulated proteins, glucose transporters and ubiquitin. Patterns of gene expression in several injury models, including focal and global ischemia, excitotoxin/ seizure-related injury and hyperthermia are reviewed. In vitro expression studies and the phenomenon of ischemic tolerance are also discussed. It is concluded that stress gene expression provides a useful marker of cellular injury, and that disjunction of mRNA and protein expression may be indicative of imminent death in cells which survive the initial insult. Though other stress proteins may play a role, it seems unlikely that neuronal hsp70 expression is a major contributor to ischemic tolerance.
 ...
PMID:The stress gene response in brain. 872 84

The role of nitric oxide (NO) in the pathogenesis of viral encephalitis was investigated by using an experimental model of herpes simplex virus type 1 (HSV-1) encephalitis in Lewis rats. The expression of inducible NO synthase (iNOS) mRNA determined by Northern blotting was observed first in the olfactory bulb and the brain stem on day 5 after intranasal inoculation of HSV-1, and thereafter iNOS mRNA was detected in other brain regions, i.e., cerebrum and cerebellum. In various parts of the brain, excessive NO production was identified by electron spin resonance spectroscopy. The temporal and spatial patterns of iNOS expression coincided with those of viral propagation, as demonstrated by polymerase chain reaction for HSV-1 gene expression as well as by the plaque-forming assay. Immunohistochemical study determined that iNOS was localized mainly in monocyte-derived macrophages. Treatment of virus-infected animals with the NOS inhibitor Nomega-monomethyl-l-arginine (l-NMMA), but not Nomega-monomethyl-d-arginine, significantly ameliorated not only clinical symptoms such as paralysis and seizures but also mortality. Virus yield from brain tissue was not affected by l-NMMA treatment. It is of interest that increased expression of the antioxidant enzyme heme oxygenase-1 was observed in the HSV-1-infected brain; this increased expression was strongly inhibited by l-NMMA treatment. These data suggest that the high level of NO produced by iNOS is a pathogenic factor in HSV-1-induced encephalitis in rats.
 ...
PMID:Role of nitric oxide in pathogenesis of herpes simplex virus encephalitis in rats. 1019 Nov 85

Global hypoxia preconditioning provides neuroprotection against a subsequent, normally damaging challenge. While the mechanistic pathways are unknown, changes in the expression of stress-related proteins are implicated. Hypoxia preconditioning attenuates the brain edema and neuropathology associated with kainic acid-induced status epilepticus in a protein synthesis-dependent manner when a kainic acid challenge is given up to one week post-preconditioning. Kainic acid initiates a glutamate-driven status epilepticus causing a Ca2+ and oxidative stress, resulting in injury to the piriform cortex and hippocampus. Stress-related gene expression [e.g. metallothioneins (MTs), heme oxygenase-1 (HO-1)] is enhanced during seizures in vulnerable brain areas, (e.g. piriform cortex). This study explores the effects of hypoxia preconditioning on expression of MT-1, MT-2 and HO-1 before and after kainic acid-induced seizures. Analysis of MT-1, MT-2 and HO-1 expression, through Western and Northern blotting, indicates that there is a variable pattern of induction and suppression of these two genes following hypoxia preconditioning alone as well as after kainic acid-induced seizures compared to non-preconditioned animals. These findings suggest that hypoxia preconditioning induces an adaptive response that prevents kainic acid seizure-associated neuropathology even when robust seizures occur. This may involve a variety of stress-related proteins, working in concert, each with their own individual expression profiles. Induction of this type of neuroprotection pharmacologically, or through preconditioning, will provide a better understanding of the stress response in brain.
 ...
PMID:Effects of hypoxia preconditioning on expression of metallothionein-1,2 and heme oxygenase-1 before and after kainic acid-induced seizures. 1087 48

Soman, a potent acetylcholinesterase inhibitor, induces status epilepticus in rats followed by conspicuous neuropathology, most prominent in piriform cortex and the CA3 region of the hippocampus. Cholinergic seizures originate in striatal-nigral pathways and with fast-acting agents (soman) rapidly spread to limbic related areas and finally culminate in a full-blown status epilepticus. This leads to neurochemical changes, some of which may be neuroprotective whereas others may cause brain damage. Pretreatment with lithium sensitizes the brain to cholinergic seizures. Likewise, other agents that increase limbic hyperactivity may sensitize the brain to cholinergic agents. The hyperactivity associated with the seizure state leads to an increase in intracellular calcium, cellular edema and metal delocalization producing an oxidative stress. These changes induce the synthesis of stress-related proteins such as heat shock proteins, metallothioneins and heme oxygenases. We show that soman-induced seizures cause a depletion in tissue glutathione and an increase in tissue 'catalytic' iron, metallothioneins and heme oxygenase-1. The oxidative stress induces the synthesis of stress-related proteins, which are indicators of 'stress' and possibly provide neuroprotection. These findings suggest that delocalization of iron may catalyze Fenton-like reactions, causing progressive cellular damage via free radical products.
 ...
PMID:Soman-induced seizures: limbic activity, oxidative stress and neuroprotective proteins. 1192 Sep 27

Carbon monoxide (CO) and the excitatory amino acid glutamate both dilate cerebral arterioles in newborn pigs. The key enzyme in CO synthesis is heme oxygenase, which is highly expressed in neurons with glutamatergic receptor activity as well as cerebral microvessels. During seizures the extracellular level of glutamate is increased, which results in excessive depolarization of neurons. We hypothesized that CO is a mediator of excitatory amino acid-induced dilation of the cerebral microvasculature during seizures. Three groups of piglets were examined: 1) i.v. normal saline (sham control), 2) topical chromium mesoporphyrin (Cr-MP, 15 x 10(-6) M), and 3) i.v. tin-protoporphyrin (Sn-PP, 4 mg/kg). Synthetic metalloporphyrins (Cr-MP and Sn-PP) are heme oxygenase inhibitors, thereby reducing CO synthesis. Implanted closed cranial windows were used to monitor changes in pial arteriolar diameters. Seizures were induced by administration of i.v. bicuculline. Changes in pial arteriolar diameters were monitored during 30 min of status epilepticus. The percent increase in pial arteriolar dilation in the saline group during seizures was 68 +/- 3%. In the metalloporphyrin groups, the pial arteriolar dilation was markedly reduced (35 +/- 3% and 13 +/- 1%, for Cr-MP and Sn-PP, respectively; p < 0.05, compared with the saline group). We conclude that metalloporphyrins by inhibition of heme oxygenase and prevention of CO synthesis attenuate pial arteriolar dilation during seizures. Therefore, CO appears to be involved in cerebral vasodilation caused by glutamatergic seizures.
 ...
PMID:Cerebrovasodilatory contribution of endogenous carbon monoxide during seizures in newborn pigs. 1197 80

In newborn pigs, the mechanism of seizure-induced cerebral hyperemia involves carbon monoxide (CO), the vasodilator product of heme catabolism by heme oxygenase (HO). We hypothesized that seizures cause cerebral vascular dysfunction when HO activity is inhibited. With the use of cranial window techniques, we examined cerebral vascular responses to endothelium-dependent (hypercapnia and bradykinin) and endothelium-independent (isoproterenol and sodium nitroprusside) dilators during the recovery from bicuculline-induced seizures in saline controls and in animals pretreated with a HO inhibitor, tin protoporphyrin (SnPP). SnPP (3 mg/kg iv) blocked dilation to heme and reduced the CO level in cortical periarachnoid cerebrospinal fluid, indicating HO inhibition in the cerebral microcirculation. In saline control piglets, seizures increased the CO level, which correlated with the time-dependent cerebral vasodilation; during the recovery (2 h after seizure induction), responses to all vasodilators were preserved. In SnPP-treated animals, cerebral vasodilation and the CO responses to seizures were greatly reduced, and cerebral vascular reactivity was severely impaired during the recovery. These findings suggest that HO in the cerebral microcirculation is rapidly activated during seizures and provides endogenous protection against seizure-induced vascular injury.
 ...
PMID:Endogenous heme oxygenase prevents impairment of cerebral vascular functions caused by seizures. 1291 92

The aim of the study was to investigate the interaction between nitric oxygenase (NOS)/nitric oxide (NO) and heme oxygenase (HO)/carbon monoxide (CO) system in the pathogenesis of recurrent febrile seizures (FS). On a rat model of recurrent FS, the ultrastructure of hippocampal neurons was observed under electron microscopy, and expression of neuronal NOS (nNOS) in hippocampus and NO formation in plasma were examined after treatment with ZnPP-IX, an HO-1 inhibitor. In the ultrastructure of hippocampal neurons, the expression of HO-1 in hippocampus and CO formation in plasma were examined after treatment with L-NAME, a NOS inhibitor. We found that hippocampal neurons were injured after recurrent FS. The gene and protein expression of nNOS and HO-1 increased markedly in hippocampus in FS rats, while CO formation in plasma increased markedly and the concentration of NO in plasma increased slightly. ZnPP-IX could worsen the neuronal damage of recurrent FS rats. However, it further increased the expression of nNOS and endogenous production of NO obviously. L-NAME alleviated the neuronal damage of recurrent FS rats, but decreased the expression of HO-1 and CO formation. The results of this study suggested that endogenous NOS/NO and HO/CO systems might interact with each other and therefore play an important regulating role in recurrent FS brain damage.
 ...
PMID:Interaction between endogenous nitric oxide and carbon monoxide in the pathogenesis of recurrent febrile seizures. 1476 14

Carbon monoxide (CO) is a product of heme degradation by heme oxygenase (HO) that is highly expressed in the brain. The present study addresses the hypothesis that CO can be involved in brain neuronal function. The effects of the HO inhibitor, tin protoporphyrin (SnPP), on brain electrical activity and pial arteriolar diameter were examined using quantitative electroencephalography (EEG) and cranial window techniques in the bicuculline model of sustained generalized seizures in newborn pigs. SnPP (3 mg/kg i.v.) inhibits brain HO as indicated by blocking cerebral vasodilation to heme and decreasing CO concentration in cortical periarachnoid cerebrospinal fluid. The quantitative spectral analysis of digitalized scalp EEG recordings was performed to determine the EEG amplitude and spectral power within a 1-15-Hz frequency range. SnPP did not affect basal brain EEG parameters. Bicuculline (3 mg/kg i.v.) immediately (in <1 min) evoked bursts of brain electrical activity characterized by four- to seven-fold increases in EEG amplitude and power in all analyzed frequency bands that occurred simultaneously with cerebral vasodilation. Increased EEG activity and cerebral vasodilation were sustained for a 2h period. SnPP inhibited cerebral vasodilation but did not affect the EEG amplitude evoked by bicuculline. However, 20-40% reductions of the power in 7.5 Hz (theta), 10 and 12.5 Hz (alpha), and a 15-Hz (beta) bands, the major evoked EEG spectral components, were observed for the duration of seizures in SnPP-treated animals. These findings suggest that endogenous CO can have proconvulsant action and affect neuronal activation during seizures.
 ...
PMID:Heme oxygenase inhibition reduces neuronal activation evoked by bicuculline in newborn pigs. 1521 95

Although there is evidence that astrocytes support neuronal function, the contribution of astrocytes to seizure onset and termination is not known. To determine whether there are changes in seizure susceptibility or neuronal damage when the ability of astrocytes to generate ATP is reduced, 0.5 nmol of fluorocitrate (FC) was injected into the right ventricle. Injection of FC alone did not produce electrographic or behavioral seizures and did not stress or injure neurons or astrocytes, as measured with silver stain and immunohistochemistry for HSP32 or HSP72. However, in animals pretreated with FC, administration of kainic acid, at a dose that does not initiate seizures in control animals (7 mg/kg), caused wet dog shakes and neuronal damage in the hilus. Wet dog shakes did not cause any neuronal damage in control animals. If the dose of FC was increased to 0.75 nmol, then subsequent administration of the same dose of kainic acid (7 mg/kg) caused stage 3-5 seizures. Injection of FC also reduced the dose of pilocarpine needed to produce seizures. Given simultaneously with FC, isocitrate, which bypasses the biochemical inhibition of aconitase, blocked the effects of FC in both kainic acid and pilocarpine treated animals. The data demonstrate that inhibition of aconitase in astrocytes lowers the doses of both kainic acid and pilocarpine that will cause behavioral seizures and may increase neuronal vulnerability to seizures.
 ...
PMID:Inhibition of aconitase in astrocytes increases the sensitivity to chemical convulsants. 1527 69


1 2 3 4 Next >>