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)

Bcl-2 family gene products are critical to the integration of cell death stimuli that target the mitochondrion. Proapoptotic BAD (Bcl-2-associated death protein) has been shown to dissociate from its sequestered site with the molecular chaperone protein 14-3-3 and displace proapoptotic BAX (Bcl-2-associated X protein) from antiapoptotic BCL-Xl. BAX subsequently translocates to the mitochondrion and induces cytochrome c release and caspase activation. Herein we report the response of the key members of this proposed pathway after seizures. Seizures evoked by microinjection of kainic acid into the amygdala of the rat induced unilateral CA3 pyramidal neuron death with features of apoptosis. In control hippocampus and cortex, BAD was found constitutively bound to 14-3-3, whereas BCL-Xl bound BAX. Within damaged hippocampus, seizures induced the dissociation of BAD from 14-3-3 and the subsequent dimerization of BAD with BCL-Xl as determined by immunoprecipitation and immunohistochemical colocalization. 14-3-3 was found to translocate to the nucleus of degenerating neurons, whereas BAX accumulated at mitochondrial membranes. In contrast, the primarily uninjured cortex exhibited increased phosphorylation of Akt (protein kinase B), which may phosphorylate and inhibit BAD, and no altered binding of BAD to BCL-Xl. Finally, administration of an inhibitor of phosphatidylinositol 3-kinase (LY294002), thought to be an upstream activator of Akt, exacerbated cortical apoptosis after seizures. These data suggest that seizures elicit divergent cell death and survival responses within neuronal populations and that the BAD cell death pathway may perform an instigator or reinforcement role in seizure-induced neuronal death.
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PMID:Activation of Bcl-2-associated death protein and counter-response of Akt within cell populations during seizure-induced neuronal death. 1235 20

Growth factors including insulin-like growth factor-1 (IGF-1) promote cell survival in ischemic brain injury. Stimulation of IGF-1 receptor coupled with tyrosine kinase activates phosphatidylinositol 3-kinase and subsequently, protein kinase B (Akt) in hippocampal neurons. Here we introduce a new approach of signal transduction therapy for brain damage occurring in ischemic insult. As has been shown for IGF-1, intracerebroventricular injection of sodium orthovanadate, a protein tyrosine phosphatase inhibitor, prior to ischemic insult blocked delayed neuronal death in the CA1 region. The neuroprotective effects of orthovanadate and IGF-1 were associated with an increased Akt activity in the CA1 region. We discuss here potential targets for Akt relevant to such neuroprotective activity. Our findings lead to the conclusion that Akt activity is a potential target for neuroprotective drugs in brain ischemic insult and other episodes of excitotoxic neuronal apoptosis such as seizure and Huntington's and Parkinson's diseases.
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PMID:Akt is a molecular target for signal transduction therapy in brain ischemic insult. 1293 16

Hyponatremia leads to hyperexcitability of neurons, seizures, and coma. It is well established that uptake of neurotransmitters is a sodium-dependent process. Therefore, we suggest that inhibition of neurotransmitter uptake can lead to the clinical manifestations of hyponatremia. Decreasing of sodium concentration down to 92 mM in incubation medium, which corresponds to lowering the osmolarity down to 230 mOsm/l, leads to a 45% decrease in glutamate uptake and a 46% decrease in gamma-aminobutyric acid (GABA) uptake. However, this effect was mediated by the nonspecific lowering of osmolarity rather than by decreasing sodium concentration. Hypotonic shock was able to reduce glutamate uptake in the presence of protein kinase inhibitors staurosporine and genistein, the phosphatase inhibitor okadaic acid, the phosphatidylinositol 3-kinase inhibitor wortmannin, and cytoskeleton modulators colchicine and cytochalasin B. Therefore, we suggest that intracellular signaling is not mediating the effect of osmolarity reduction on neurotransmitter uptake.
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PMID:Influence of hypotonic shock on glutamate and GABA uptake in rat brain synaptosomes. 1545 59

After intracerebral hemorrhage (ICH), many changes of gene transcription occur that may be important because they will contribute to understanding mechanisms of injury and recovery. Therefore, gene expression was assessed using Affymetrix microarrays in the striatum and the overlying cortex at 24 h after intracranial infusions of blood into the striatum of adult rats. Intracerebral hemorrhage regulated 369 of 8,740 transcripts as compared with saline-injected controls, with 104 regulated genes shared by the striatum and cortex. There were 108 upregulated and 126 downregulated genes in striatum, and 170 upregulated and 69 downregulated genes in the cortex. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed upregulation of IL-1-beta, Lipcortin 1 (annexin) and metallothionein 1,2, and downregulation of potassium voltage-gated channel, shaker-related subfamily, beta member 2 (Kcnab2). Of the functional groups of genes modulated by ICH, many metabolism and signal-transduction-related genes decreased in striatum but increased in adjacent cortex. In contrast, most enzyme, cytokine, chemokine, and immune response genes were upregulated in both striatum and in the cortex after ICH, likely in response to foreign proteins from the blood. A number of these genes may contribute to brain edema and cellular apoptosis caused by ICH. In addition, downregulation of growth factor pathways and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway could also contribute to perihematoma cell death/apoptosis. Intracerebral hemorrhage-related downregulation of GABA-related genes and potassium channels might contribute to perihematoma cellular excitability and increased risk of post-ICH seizures. These genomic responses to ICH potentially provide new therapeutic targets for treatment.
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PMID:Brain genomics of intracerebral hemorrhage. 1603 71

Glutamate transporters (also called excitatory amino acid transporters, EAAT) participate in maintaining extracellular homeostasis of glutamate, a major excitatory neurotransmitter, and regulating glutamate neurotransmission. EAAT3, the major neuronal EAAT, may also regulate gamma-aminobutyric acid-mediated inhibitory neurotransmission. Dysfunction of EAAT3 has been shown to induce seizure in rats. We hypothesize that carbamazepine, a commonly used antiepileptic agent, enhances EAAT3 activity. We tested this hypothesis using oocytes artificially expressing EAAT3 and C6 rat glioma cells expressing endogenous EAAT3. In oocytes, carbamazepine dose-dependently enhanced EAAT3 activity. The EC50 of this carbamazepine effect was 12.2muM. The concentrations of carbamazepine to significantly enhance EAAT3 activity were within the therapeutic serum levels (17-51muM) of carbamazepine for the antiepileptic effect. Carbamazepine decreased the Km but did not change the maximal response of EAAT3 to glutamate. Carbamazepine-increased EAAT3 activity was inhibited by wortmannin or LY-294002, phosphatidylinositol 3-kinase (PI3K) inhibitors, but was not affected by staurosporine, chelerythrine or calphostin C, protein kinase C inhibitors. In C6 cells, carbamazepine also enhanced the endogenous EAAT3 activity. However, carbamazepine did not affect the activity of EAAT4 expressed in Cos7 cells. These results suggest that carbamazepine at clinically relevant concentrations specifically enhances the affinity of EAAT3 for glutamate to increase EAAT3 activity via a PI3K-dependent pathway. EAAT3 may be a therapeutic target for carbamazepine in the central nervous system.
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PMID:Carbamazepine enhances the activity of glutamate transporter type 3 via phosphatidylinositol 3-kinase. 1615 May 75

Proneurotrophins bind with high affinity to p75 neurotrophin receptor (p75NTR) and lack the capacity to bind Trk receptors, suggesting that proneurotrophins can elicit apoptosis via p75NTR even in cells expressing survival-promoting Trk receptors. In the CNS, basal forebrain (BF) neurons are particularly vulnerable to degeneration in Alzheimer's disease, and are among the few populations of brain neurons that express p75NTR throughout life. These neurons also express Trk receptors and may be concomitantly exposed to both proneurotrophins and mature neurotrophins during development, disease, or after injury. We investigated the interaction of mature and proneurotrophin signaling in these CNS neurons. Kainic acid-induced seizures elicited production of pro-NGF by BF astrocytes before caspase activation in p75NTR-positive BF neurons, demonstrating local production of proneurotrophins under pathological conditions and suggesting apoptotic signaling in vivo. Mechanisms of proneurotrophin-induced death were analyzed in cultured BF neurons, and required both p75NTR and its coreceptor sortilin. Surprisingly, exposure to both mature neurotrophins and proneurotrophins demonstrated that Trk phosphorylation did not prevent pro-NGF-induced apoptosis via p75NTR. However, activation of PI3K (phosphatidylinositol 3-kinase)/Akt and MEK (mitogen-activated protein kinase kinase)/Erk pathways prevented pro-NGF-induced apoptosis, revealing a novel critical checkpoint in survival versus apoptotic signaling downstream of Trk activation, and suggesting that pro-NGF blocks survival signaling by preventing Akt and Erk activation. This study shows that proneurotrophins are produced in the brain under pathological conditions, and can elicit apoptosis of BF neurons even when Trk receptors are activated.
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PMID:Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and proneurotrophins. 1685 3

Conditional deletion of Pten (phosphatase and tensin homolog on chromosome ten) in differentiated cortical and hippocampal neurons in the mouse results in seizures, macrocephaly, social interaction deficits and anxiety, reminiscent of human autism spectrum disorder. Here we extended our previous examination of these mice using electroencephalogram/electromyogram (EEG/EMG) monitoring and found age-related increases in spontaneous seizures, which were correlated with cellular dispersion in the hippocampal dentate gyrus. Increased spontaneous locomotor activity in the open field on the first and the second day of a 3-day continuous study suggested heightened anxiety in Pten mutant mice. In contrast, the mutants exhibited decreased wheel running activity, which may reflect reduced adaptability to a novel environment. Synchronization to the light-dark cycle was normal, but for up to 28 days under constant darkness, the Pten mutants maintained a significantly lengthened and remarkably constant free-running period of almost exactly 24 h. This result implies the involvement of Pten in the maintenance of circadian rhythms, which we interpret as being due to an effect on the phosphatidylinositol 3-kinase (PI3K) signaling cascade.
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PMID:A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice. 1770 14

Low-grade glioneuronal lesions involving tumors such as gangliogliomas and focal cortical dysplasias (FCD) predispose individuals to pharmacoresistant epilepsy. A frequent variant of FCD is composed of dysplastic cytomegalic neurons and Taylor-type balloon cells (FCD(IIb)). Those are similar to cellular elements, which are present in cortical tubers in the autosomal dominant inherited tuberous sclerosis complex (TSC). This phacomatosis is caused by mutations in the TSC1 or TSC2 genes. Recent data have indicated accumulation of distinct allelic variants of TSC1 also in FCD(IIb). TSC1 represents a key factor in the phosphatidylinositol 3-kinase (PI3K) pathway. A variety of alterations in the PI3K-pathway have been recently reported in epilepsy-associated glioneuronal malformations. Here, we discuss pathogenetic similarities and differences between cortical dysplasias as well epilepsy-associated glioneuronal tumors and TSC-associated cortical tubers with a focus on PI3K-pathway components including ezrin, radixin and moesin (ERM), which represent downstream effectors involved in cytoskeleton-membrane interference. No evidence has been found for mutational events of ERM genes to play a major pathogenetic role in epilepsy-associated glioneuronal malformations. In contrast, aberrant expression of ERM proteins in FCDs and gangliogliomas was observed. These alterations may relate to compromised interactions of dysplastic cellular components in epilepsy-associated glioneuronal lesions and be involved in aberrant PI3K-pathway signaling in epilepsy-associated malformations. However, the underlying cause of PI3K-pathway activation and the functional relationship of PI3K-pathway activity to generation of seizures in epilepsy-associated glioneuronal lesions will need to be determined in the future.
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PMID:Alterations of phosphatidylinositol 3-kinase pathway components in epilepsy-associated glioneuronal lesions. 1791 May 83

Leptin plays a pivotal role in the regulation of energy homeostasis and metabolism, primarily by acting on neurons in the hypothalamus that control food intake. However, leptin receptors are more widely expressed in the brain suggesting additional, as yet unknown, functions of leptin. Here we show that both embryonic and adult hippocampal neurons express leptin receptors coupled to activation of STAT3 and phosphatidylinositol 3-kinase-Akt signaling pathways. Leptin protects hippocampal neurons against cell death induced by neurotrophic factor withdrawal and excitotoxic and oxidative insults. The neuroprotective effect of leptin is antagonized by the JAK2-STAT3 inhibitor AG-490, STAT3 decoy DNA, and phosphatidylinositol 3-kinase/Akt inhibitors but not by an inhibitor of MAPK. Leptin induces the production of manganese superoxide dismutase and the anti-apoptotic protein Bcl-xL, and stabilizes mitochondrial membrane potential and lessens mitochondrial oxidative stress. Leptin receptor-deficient mice (db/db mice) are more vulnerable to seizure-induced hippocampal damage, and intraventricular administration of leptin protects neurons against seizures. By enhancing mitochondrial resistance to apoptosis and excitotoxicity, our findings suggest that leptin signaling serves a neurotrophic function in the developing and adult hippocampus.
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PMID:Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. 1799 59

The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of neuronal and synaptic structures and subsequently synaptic function.
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PMID:Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. 1808 64


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