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

Epileptic seizures are associated with increases in hippocampal excitability, but the mechanisms that render the hippocampus hyperexcitable chronically (in epilepsy) or acutely (in status epilepticus) are poorly understood. Recent evidence suggests that substance P (SP), a peptide that has been implicated in cardiovascular function, inflammatory responses, and nociception, also contributes to hippocampal excitability and status epilepticus, in part by enhancing glutamate release. Here we report that mice with disruption of the preprotachykinin A gene, which encodes SP and neurokinin A, are resistant to kainate excitoxicity. The mice show a reduction in the duration and severity of seizures induced by kainate or pentylenetetrazole, and both necrosis and apoptosis of hippocampal neurons are prevented. Although kainate induced the expression of bax and caspase 3 in the hippocampus of wild-type mice, these critical intracellular mediators of cell death pathways were not altered by kainate injection in the mutant mice. These results indicate that the reduction of seizure activity and the neuroprotection observed in preprotachykinin A null mice are caused by the extinction of a SP/neurokinin A-mediated signaling pathway that is activated by seizures. They suggest that these neurokinins are critical to the control of hippocampal excitability, hippocampal seizures, and hippocampal vulnerability.
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PMID:Resistance to excitotoxin-induced seizures and neuronal death in mice lacking the preprotachykinin A gene. 1051 82

In the aftermath of prolonged continuous seizure activity (status epilepticus, SE), neuronal cell death occurs in the brain regions through which the seizure propagates. Recent studies have implicated apoptotic processes in this seizure-related injury. Because activation of caspase-3-like cysteine proteases plays a crucial role in mammalian neuronal apoptosis, we explored the possibility that activation of caspase-3 is involved in the neuronal apoptotic cell death that occurs in rat brain following SE induced by systemic kainic acid. Caspase-3 activity was determined immunocytochemically using CM1 antibodies specific for catalytically active subunit (p17) of the enzyme. We found an induction of caspase-3 activity in rhinal cortex and amygdala at 24 h after SE. To determine whether activation of caspase-3-like proteases is a necessary component of the injury process, we delivered a caspase-3 inhibitor, z-DEVD-fmk, into the lateral ventricle prior to, and following SE. z-DEVD-fmk treatment substantially attenuated apoptotic cell death after SE, both in hippocampus and rhinal cortex, as evaluated by analysis of internucleosomal DNA fragmentation and neuronal nuclear morphology. Our findings implicate caspase-3 cysteine protease in the neurodegenerative response to SE and suggest that this degeneration can be attenuated by inhibition of caspase-3-like enzyme activity.
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PMID:Intracerebral injection of caspase-3 inhibitor prevents neuronal apoptosis after kainic acid-evoked status epilepticus. 1068 42

The cysteine protease caspase-3 may be involved in the mechanism of cell death following seizures. Using a rat model of focally evoked limbic epilepsy with continuous electroencephalography monitoring, we investigated seizure-induced changes in caspase-3 protein expression and processing, enzyme activity, and the in vivo effect of caspase-3 inhibition. Seizures were induced by intraamygdaloid injection of kainic acid (0.1 microg) and were terminated after 45 min by diazepam (30 mg/kg) administration. Animals were killed 0-72 h following diazepam administration. Levels of the 32-kDa proenzyme form of caspase-3 were unaffected by seizures. Levels of the 17-kDa cleaved (active) fragment of caspase-3 were almost undetectable in control brain, but were increased significantly at 4 and 24 h within ipsilateral hippocampus and cortex in seizure animals. Caspase-3-like protease activity was increased within the ipsilateral hippocampus at 8 and 24 h following seizures. Caspase-3 immunoreactivity was increased within the vulnerable ipsilateral CA3/CA4 subfield at 24 and 72 h following seizures and was associated predominantly, but not exclusively, with neurons exhibiting DNA fragmentation. The putatively selective caspase-3 inhibitor N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone significantly improved neuronal survival bilaterally within the hippocampal CA3/CA4 subfields following seizures. Collectively, these data suggest that caspase-3 may play a significant role in the mechanism by which neurons die following seizures.
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PMID:Involvement of caspase-3-like protease in the mechanism of cell death following focally evoked limbic seizures. 1069 54

Glutamate receptor overactivation contributes to neuron death after stroke, trauma, and epileptic seizures. Exposure of cultured rat hippocampal neurons to the selective glutamate receptor agonist N-methyl-d-aspartate (300 microm, 5 min) or to the apoptosis-inducing protein kinase inhibitor staurosporine (300 nm) induced a delayed neuron death. In both cases, neuron death was preceded by the mitochondrial release of the pro-apoptotic factor cytochrome c. Unlike staurosporine, the N-methyl-d-aspartate-induced release of cytochrome c did not lead to significant activation of caspase-3, the main caspase involved in the execution of neuronal apoptosis. In contrast, activation of the Ca(2+)-activated neutral protease calpain I was readily detectable after the exposure to N-methyl-d-aspartate. In a neuronal cell-free apoptosis system, calpain I prevented the ability of cytochrome c to activate the caspase cascade by inhibiting the processing of procaspase-3 and -9 into their active subunits. In the hippocampal neuron cultures, the inhibition of calpain activity restored caspase-3-like protease activity after an exposure to N-methyl-d-aspartate. Our data demonstrate the existence of signal transduction pathways that prevent the entry of cells into a caspase-dependent cell death program after the mitochondrial release of cytochrome c.
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PMID:Activation of calpain I converts excitotoxic neuron death into a caspase-independent cell death. 1082 77

Metallothioneins (MTs) are major zinc binding proteins in the CNS that could be involved in the control of zinc metabolism as well as in protection against oxidative stress. Mice lacking MT-I and MT-II (MT-I + II deficient) because of targeted gene inactivation were injected with kainic acid (KA), a potent convulsive agent, to examine the neurobiological importance of these MT isoforms. At 35 mg/kg KA, MT-I + II deficient male mice showed a higher number of convulsions and a longer convulsion time than control mice. Three days later, KA-injected mice showed gliosis and neuronal injury in the hippocampus. MT-I + II deficiency decreased both astrogliosis and microgliosis and potentiated neuronal injury and apoptosis as shown by terminal deoxynucleotidyl transferase-mediated in situ end labelling (TUNEL), detection of single stranded DNA (ssDNA) and by increased interleukin-1beta-converting enzyme (ICE) and caspase-3 levels. Histochemically reactive zinc in the hippocampus was increased by KA to a greater extent in MT-I + II-deficient compared with control mice. KA-induced seizures also caused increased oxidative stress, as suggested by the malondialdehyde (MDA) and protein tyrosine nitration (NITT) levels and by the expression of MT-I + II, nuclear factor-kappaB (NF-kappaB), and Cu/Zn-superoxide dismutase (Cu/Zn-SOD). MT-I + II deficiency potentiated the oxidative stress caused by KA. Both KA and MT-I + II deficiency significantly affected the expression of MT-III, granulocyte-macrophage colony stimulating factor (GM-CSF) and its receptor (GM-CSFr). The present results indicate MT-I + II as important for neuron survival during KA-induced seizures, and suggest that both impaired zinc regulation and compromised antioxidant activity contribute to the observed neuropathology of the MT-I + II-deficient mice.
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PMID:Enhanced seizures and hippocampal neurodegeneration following kainic acid-induced seizures in metallothionein-I + II-deficient mice. 1094 10

Clusterin, also known as apolipoprotein J, is a ubiquitously expressed molecule thought to influence a variety of processes including cell death. In the brain, it accumulates in dying neurons following seizures and hypoxic-ischemic (H-I) injury. Despite this, in vivo evidence that clusterin directly influences cell death is lacking. Following neonatal H-I brain injury in mice (a model of cerebral palsy), there was evidence of apoptotic changes (neuronal caspase-3 activation), as well as accumulation of clusterin in dying neurons. Clusterin-deficient mice had 50% less brain injury following neonatal H-I. Surprisingly, the absence of clusterin had no effect on caspase-3 activation, and clusterin accumulation and caspase-3 activation did not colocalize to the same cells. Studies with cultured cortical neurons demonstrated that exogenous purified astrocyte-secreted clusterin exacerbated oxygen/glucose-deprivation-induced necrotic death. These results indicate that clusterin may be a new therapeutic target to modulate non-caspase-dependent neuronal death following acute brain injury.
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PMID:Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia. 1153 82

Domoic acid (DA), a potent neurotoxin, administered intravenously (0.75 mg/kg body weight) in adult rats evoked seizures accompanied by nerve cell damage in the present study. Neuronal degeneration and microglial reaction in the hippocampus were investigated, and the temporal profile of bcl-2, bax, and caspase-3 genes in cell death or survival was assessed following the administration of DA. Nissl staining showed darkly stained degenerating neurons in the hippocampus following the administration of DA at 1-21 days, the degeneration being most severe at 5 days. Ultrastructural study in CA1 and CA3 regions of hippocampus revealed two types of neuronal degeneration, cells that exhibited swollen morphology and shrunken electron-dense cells. Immunoreactivity of Bcl-2 and Bax was increased considerably at 16 hr and 24 hr in the neurons of the hippocampus following DA administration. No significant change was observed in the immunoreactivity of caspase-3 in the controls and DA-treated rats at any time interval. Microglial cells in the hippocampus showed intense immunoreaction with the antibodies OX-42 and OX-6 at 1-21 days after DA administration, indicating the up-regulation of complement type 3 receptors and major histocompatibility complex type II antigens for increased phagocytic activity and antigen presentation, respectively. Terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) showed occasional positive neurons in the CA1 and CA3 regions at 5 days after DA administration, with no positive cells in the controls. RT-PCR analysis revealed that bcl-2 and bax mRNA transcripts in the hippocampus were significantly increased at 16 hr and gradually decreased at 24 hr following the administration of DA. Although bax and bcl-2 mRNA expression is rapidly induced at early stages, in situ hybridization analysis revealed complete loss of bcl-2, bax, and caspase-3 mRNA at 24 hr after DA administration in the region of neuronal degeneration in the hippocampus. These results indicate that the pattern of neuronal degeneration observed during DA-induced excitotoxic damage is mostly necrotic.
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PMID:Domoic acid-induced neuronal damage in the rat hippocampus: changes in apoptosis related genes (bcl-2, bax, caspase-3) and microglial response. 1159 13

The dentate gyrus (DG) is one of the few regions in the brain that continues to produce new neurons throughout adulthood. Seizures not only increase neurogenesis, but also lead to death of DG neurons. We investigated the relationship between cell death and neurogenesis following seizures in the DG of adult rats by blocking caspases, which are key components of apoptotic cell death. Multiple intracerebroventricular infusions of caspase inhibitors (pancaspase inhibitor zVADfmk, and caspase 3 and 9 inhibitor) prior to, just after, 1 day after, and 1 week following 2 h of lithium-pilocarpine-induced status epilepticus reduced the number of terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labelled (TUNEL) cells and increased the number of bromodeoxyuridine (BrdU) -stained proliferated cells in the subgranular zone at 1 week. The caspase inhibitor-treated group did not differ from control at 2 days or 5 weeks following the epileptic insult. Our findings suggest that caspases modulate seizure-induced neurogenesis in the DG, probably by regulating apoptosis of newly born neurons, and that this action can be suppressed transiently by caspase inhibitors. Furthermore, although previous studies have indicated that increased neuronal death can trigger neurogenesis, we show here that reduction in apoptotic death may be associated with increased neurogenesis.
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PMID:Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus. 1159 32

Hypoxic-ischemic encephalopathy (HIE) in neonates is a disorder of excessive neuronal excitation that includes seizures, abnormal EEG activity, and delayed failure of oxidative metabolism with elevated levels of lactic acid in the brain. Evidence from experimental models and clinical investigation indicates that HIE is triggered by a profound disruption in the function of glutamate synapses so that re-uptake of glutamate from the synapse is impaired and post-synaptic membranes containing glutamate receptors are depolarized. Severe hypoxemia preferentially depolarizes neuronal membranes, while ischemia probably has greater impact on the activity of glial glutamate re-uptake. Together, severe hypoxia and ischemia trigger a delayed cascade of events that may result in cell death by necrosis and/or apoptosis. Apoptosis is far more prominent in the neonate than in the adult and activation of cysteine proteases such as caspase-3 is a very important pathway in excitotoxic neonatal injury. Understanding the complex molecular networks triggered by an excitotoxic insult in the neonate provides insight into patterns of selective neuronal vulnerability and potential therapeutic strategies.
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PMID:Excitotoxicity in neonatal hypoxia. 1175 16

Specific biochemical hallmarks of apoptosis, namely internucleosomal DNA fragmentation and caspase-3 activation, appear in the aftermath of status epilepticus (SE). This led us to hypothesize that caspase-activated DNase (CAD) is involved in DNA fragmentation and apoptotic neuronal cell death following SE. The present study aimed to determine whether SE is associated with an activation of CAD, as reflected in the degradation of the CAD inhibitor, ICAD. SE was induced in adult male Sprague-Dawley rats by kainic acid (12 mg/kg i.p.) and seizures were terminated with diazepam after 2 h. At 24, 48, or 72 h after SE termination, protein levels of CAD and ICAD were measured by Western blotting (after sodium dodecyl sulfate-polyacrylamide gel electrophoresis) using specific antibodies. At 48 and 72 h after SE termination, ICAD protein levels significantly decreased (by more than 60%) in rhinal cortex and hippocampus as compared with those in the same tissue from animals not experiencing SE. No changes were detected in total CAD protein levels at any time point, resulting in an increase in the ratio of CAD to its inhibitor. The loss of ICAD following SE is indicative of a disinhibition of CAD, leading to DNA fragmentation. Consistent with this, we observed that the decrease in ICAD between 24 and 48 h was accompanied by a marked increase in DNA fragmentation. Our results support the proposal that CAD participates in caspase-3-mediated internucleosomal DNA fragmentation in the aftermath of SE.
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PMID:Status epilepticus leads to the degradation of the endogenous inhibitor of caspase-activated DNase in rats. 1183 14


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