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)

Neuronal loss and irreversible brain damage often cause the worsening of symptoms and the decreased efficacy of pharmacological treatment occurring in epileptic patients and animal models of kindling. Recently we reported that the neurotransmitter/neuromodulatory peptide Cholecystokinin-8 (CCK-8) is able to induce the structural and functional neuronal recovery of chemical- and surgical-induced lesions when i.p. injected in rodents. The present study therefore, was aimed at verifying the hypothesis that treatment with a CCK-8 dose having a neuroprotective action might affect brain alterations and the development of kindling in adult rats receiving the convulsant agent pentylenetetrazole (PTZ). Compared to rats receiving Saline prior to PTZ, which manifested clonic-tonic seizures (Class 5 behavioural change scale) after three weeks of treatment, rats pre-treated with CCK-8 showed an improvement of behavioural score exhibiting myoclonus and occasionally tonic seizures (Class 3/4). This decreased susceptibility to develop convulsions was associated with the recovery of PTZ-induced reduction of ChAT levels in forebrain and GABA/GAD expression in the hippocampus. Furthermore, NPY immunoreactivity distribution and NPY mRNA levels were also increased in the hippocampus of rats receiving CCK-8 injection before each PTZ treatment. These data indicate that CCK-8 possesses the ability to prevent and/or suppress the convulsant effects of PTZ by stimulating the synthesis of neurotransmitters/peptides involved in the inhibition of hippocampal hyper-excitability. Our findings suggest that CCK-8 may have anticonvulsant and neuroprotective properties that merit further investigation.
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PMID:CCK-8 prevents the development of kindling and regulates the GABA and NPY expression in the hippocampus of pentylenetetrazole (PTZ)-treated adult rats. 1581 7

In this study we tested the hypothesis that the 65-kDa isoform of glutamate decarboxylase (GAD(65)) mediates activity-dependent GABA synthesis as invoked by seizures in anesthetized rats. GABA synthesis was measured following acute GABA-transaminase inhibition by gabaculine using spatially localized (1)H NMR spectroscopy before and after bicuculline-induced seizures. Experiments were conducted with animals pre-treated with vigabatrin 24 h earlier in order to reduce GAD(67) protein and also with non-treated controls. GAD isoform content was quantified by immunoblotting. GABA was higher in vigabatrin-treated rats compared to non-treated controls. In vigabatrin-treated animals, GABA synthesis was 28% lower compared to controls [p < 0.05; vigabatrin-treated, 0.043 +/- 0.011 micromol/(g min); non-treated, 0.060 +/- 0.014 micromol/(g min)] and GAD(67) was 60% lower. No difference between groups was observed for GAD(65). Seizures increased GABA synthesis in both control [174%; control, 0.060 +/- 0.014 micromol/(g min) vs. seizures, 0.105 +/- 0.043 micromol/(g min)] and vigabatrin-treated rats [214%; control, 0.043 +/- 0.011 micromol/(g min); seizures, 0.092 +/- 0.018 micromol/(g min)]. GAD(67) could account for at least half of basal GABA synthesis but only 20% of the two-fold increase observed in vigabatrin-treated rats during seizures. The seizure-induced activation of GAD(65) in control cortex occurs concomitantly with a 2.3-fold increase in inorganic phosphate, known to be a potent activator of apoGAD(65)in vitro. Our results are consistent with a major role for GAD(65) in activity-dependent GABA synthesis.
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PMID:Evidence that GAD65 mediates increased GABA synthesis during intense neuronal activity in vivo. 1653 72

A large body of experimental evidence suggests that the basal ganglia circuitry may be part of a remote control system modulating the spread of epileptic seizures. In the kindling model of temporal lobe epilepsy, this endogenous inhibitory control mechanism seems to be impaired. Neurochemical and neurophysiological studies have indicated that the activity of the GABAergic projection from the striatum to the substantia nigra pars reticulata is reduced in kindled rats, but the exact mechanisms involved in this observation are not known. Possible explanations include a kindling-induced loss of striatal GABAergic projection neurons to the substantia nigra or enhanced inhibition of these neurons by GABAergic interneurons. In the present experiments, the GABAergic system of the striatum (caudate-putamen) of amygdala-kindled rats and controls was studied immunohistochemically with a monoclonal antibody to GABA and with nonisotopic in situ hybridization with cRNA probes selective for glutamic acid decarboxylase 65 (GAD65) and GAD67, respectively. Compared to sham controls, an increased density of neurons heavily labeled for GAD67 mRNA was observed in the anterior striatum of kindled rats when cells were counted 6 weeks after the last kindled seizure. This subgroup of striatal GABAergic neurons has been suggested previously to correspond to the medium-sized aspiny interneurons in the striatum, indicating that kindling is associated with an increased activity of these neurons. Our previous finding of reduced GAD and GABA levels in synaptosomes isolated from the substantia nigra of kindled rats together with the present observation of increased density of GABAergic striatal interneurons in such rats suggest that kindling affects the regulation of the GABAergic projections from the striatum to the substantia nigra rather than directly damaging GABAergic neurons in the striatum.
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PMID:Distribution of GABAergic neurons in the striatum of amygdala-kindled rats: an immunohistochemical and in situ hybridization study. 1654 83

The septal region of the basal forebrain plays a critical role modulating hippocampal excitability and functional states. Septal circuits may also play a role in controlling abnormal hippocampal hyperexcitability in epilepsy. Both lateral and medial septal neurons are targets of hippocampal axons. Since the hippocampus is an important epileptogenic area in temporal lobe epilepsy, we hypothesize that excessive excitatory output will promote sustained neurodegeneration of septal region neurons. Pilocarpine-induced status epilepticus (SE) was chosen as a model to generate chronic epileptic animals. To determine whether septal neuronal populations are affected by hippocampal seizures, immunohistochemical assays were performed in brain sections obtained from age-matched control, latent period (7 days post-SE) and chronically epileptic (more than one month post-SE survival) rats. An anti-NeuN (neuronal nuclei) antibody was used to study total neuronal numbers. Anti-ChAT (choline acetyltransferase), anti-GAD (glutamic acid decarboxylase) isoenzymes (65 and 67), and anti-glutamate antibodies were used to reveal cholinergic, GABAergic and glutamatergic neurons, respectively. Our results revealed a significant atrophy of medial and lateral septal areas in all chronically epileptic rats. Overall neuronal density in the septum (medial and lateral septum), assessed by NeuN immunoreactivity, was significantly reduced by approximately 40% in chronically epileptic rats. The lessening of neuronal numbers in both regions was mainly due to the loss of GABAergic neurons (80-97% reduction in medial and lateral septum). In contrast, populations of cholinergic and glutamatergic neurons were spared. Overall, these data indicate that septal GABAergic neurons are selectively vulnerable to hippocampal hyperexcitability, and suggest that the processing of information in septohippocampal networks may be altered in chronic epilepsy.
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PMID:Septal GABAergic neurons are selectively vulnerable to pilocarpine-induced status epilepticus and chronic spontaneous seizures. 1693 46

Concerns regarding the side effects of pharmacological approaches have recently increased interest in the use of acupuncture for treatment of epilepsy. Although clinical evidence for the acupunctural anti-epileptic effect has been demonstrated, the precise mechanism still remains unknown. The purpose of this study was to investigate the effect of electroacupuncture (EA) on spontaneous recurrent seizure (SRS) and expression of GAD(67) mRNA in dentate gyrus (DG) in epileptic rats. EA at bilateral acupoints of Zusanli (St36) was administered. Two sham EA controls were set: sham EA at bilateral nearby nonacupoints in the hamstring muscles, and sham EA at bilateral St36 without electrical stimulation. Lithium-pilocarpine injection was performed to establish the rat model of epilepsy at the 1st day. Three time points were set according to the day when the rats were killed (30th, 45th, 60th day). The results showed that EA at St36 significantly reduced the times of spontaneous recurrent seizure, neither of the two sham EA controls displayed significant effect on spontaneous recurrent seizure. Moreover, EA at St36 significantly elevated the expression of GAD(67) mRNA in DG granule cell layer (GCL), but not in the hilus; neither of the two sham controls showed significant effect on the expression of GAD(67) mRNA in granule cell layer or hilus. The findings suggest that EA at St36 possess some curative effect on epileptic rats, related with change of GAD(67) mRNA level in DG region.
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PMID:The effect of electroacupuncture on spontaneous recurrent seizure and expression of GAD(67) mRNA in dentate gyrus in a rat model of epilepsy. 1802 44

GABA is the major inhibitory neurotransmitter in the central nervous system, and its concentration in the brain in associated with a variety of neurological disorders, including seizures, convulsions, and epilepsy. The concentration of GABA is modulated by the pyridoxal-5'-phosphate (PLP)-dependent enzymes, GAD and GABA-T. In this study, we generated pyridoxyl-gamma-aminobutyrate (PL-GABA), a novel GABA analogue composed of pyridoxyl and GABA, and have also characterized its anticonvulsant and pharmacological functions in vitro. The results of biodistribution studies revealed that PL-GABA is capable of crossing the blood-brain barrier. PL-GABA evidenced anticonvulsant activity in a wide range of epilepsy models, some of which were electrically-based (MES seizures) and some chemically-based (bicuculline, pentylenetetrazol (PTZ), picrotoxine, 3-mercaptopropionic acid). Following a timed subcutaneous administration of PTZ to mice, PL-GABA consistently increased the latencies to first twitch and clonus. In addition, PL-GABA displayed no signs of tolerance after subchronic (10 day) treatment. PL-GABA appears to exert its anticonvulsant effects by influencing seizure spread and by raising the seizure threshold. Therefore, our results indicate that PL-GABA exerts a broad-spectrum anticonvulsant effect, and identify the potential for reduced PL-GABA tolerance as an additional positive profile for novel antiepileptic drugs.
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PMID:Anticonvulsant characteristics of pyridoxyl-gamma-aminobutyrate, PL-GABA. 1834 62

Neural transplantation has been investigated experimentally and clinically for the purpose of developing new treatment options for intractable epilepsy. In the present study we assessed the anticonvulsant efficacy and safety of bilateral allotransplantation of genetically engineered striatal GABAergic rat cell lines into the substantia nigra pars reticulata (SNr). Rats with previously-established seizures, induced by amygdala kindling, were used as a model of temporal lobe epilepsy. Three cell lines were transplanted: (1) immortalized GABAergic cells (M213-2O) derived from embryonic rat striatum; (2) M213-2O cells (CL4) transfected with human GAD67 cDNA to obtain higher GABA synthesis than the parent cell line; and (3) control cells (121-1I), also derived from embryonic rat striatum, but which did not show GAD expression. A second control group received injections of medium alone. Transplantation of M213-2O cells into the SNr of kindled rats resulted in significant but transient anticonvulsant effects. Neither control cells nor medium induced anticonvulsant effects. Strong tissue reactions were, however, induced in the host brain of kindled but not of non-kindled rats, and only in animals that received grafts of genetically modified CL4 cells. These tissue reactions included graft rejection, massive infiltration of inflammatory immune cells, and gliosis. The anticonvulsant effect of M213-2O cells emphasizes the feasibility of local manipulations of seizures by intranigral transplantation of GABA-producing cells. On the other hand, the present data suggest that kindling-induced activation of microglia in the SNr can enhance immune reactions to transplanted cells. In this case, under conditions of further immunological stimulation by CL4 cells, transfected with a human cDNA, substantial immune reactions occurred. Thus, it appears that the condition of the host brain and the production of foreign proteins by transplanted cells have to be considered in estimating the risks of rejection of transplants into the brain.
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PMID:Benefits and risks of intranigral transplantation of GABA-producing cells subsequent to the establishment of kindling-induced seizures. 1863 80

A variety of autoantibodies have been identified with complex neurological disorders including limbic encephalitis. The underlying trigger for the immune-mediated process and the role of autoantibodies in the pathogenesis of limbic encephalitis remain to be clarified. Here, we report a 16-year-old female who was diagnosed with acute-onset non-neoplastic limbic encephalitis. The initial treatment with pulse doses of i.v. methylprednisolone improved the neurological symptoms. During the next 12 months, progressive decline was reported in her academic functioning and seizure control. Additional diagnostic evaluation revealed no evidence of malignancy or central nervous system infection but circulating anti-GAD antibodies were present in the serum and cerebrospinal fluid. Intravenous gammaglobulin infusion was initiated and continued monthly. Intravenous and oral steroids were added to the intravenous immunoglobulin treatment because of the worsening course and seizures, despite treatment with antiepileptic medications. Screening for quantitative immunoglobulins demonstrated hypogammaglobulinaemia with low immunoglobulin M and G in addition to low immunoglobulin A levels. There was a lack of protective pneumococcal antibody titers before and after immunization. Therefore, common variable immunodeficiency was suspected despite there being no history of recurrent infections. To our knowledge, this is the first report describing a possible link between immune-mediated limbic encephalitis and immune deficiency.
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PMID:Limbic encephalitis associated with anti-GAD antibody and common variable immune deficiency. 1953 23

The subtle mechanisms of post-traumatic epileptogenesis remain unknown, although the incidence of chronic epilepsy after penetrating cortical wounds is high. Here, we investigated whether the increased frequency of seizures occurring within 6 weeks following partial deafferentation of the suprasylvian gyrus in cats is accompanied with a change in the ratio between the number of excitatory and inhibitory neurons. Immuno-histochemical labeling of all neurons with neuronal-specific nuclear protein (NeuN) antibody, and of the GABAergic inhibitory neurons with either gamma-aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD 65&67) antibodies, was performed on sections obtained from control and epileptic animals with chronically deafferented suprasylvian gyrus. Quantification of the labeled neurons was performed in control animals and at 2, 4, and 6 weeks following cortical deafferentation, in the suprasylvian and marginal gyri, both ipsi- and contra-lateral to the cortical trauma. In all epileptic animals, the neuronal loss was circumscribed to the deafferented suprasylvian gyrus. Inhibitory GABAergic neurons were particularly more sensitive to cortical deafferentation than excitatory ones, leading to a progressively increasing ratio between excitation and inhibition towards excitation, potentially explaining the increased propensity to seizures in chronic undercut cortex.
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PMID:Neocortical post-traumatic epileptogenesis is associated with loss of GABAergic neurons. 1942 94

Limbic encephalitis (LE) associated with glutamic acid decarboxylase antibodies (GAD-Ab) is rare. We describe a 30-year-old male with acute LE and GAD-Ab, with follow-up during 2 years of cognitive status including verbal episodic memory, number of seizures recorded by high-resolution video-EEG, brain MRI, 2-[18F]-fluoro-2-deoxyglucose PET and GAD-Ab titres. Treatment with corticosteroids, IV immunoglobulins, immunosuppressors and antiepileptic drugs resulted in improved memory status, disappearance of seizures and decreased GAD-Ab titres. Review of the other cases of literature and this case is in favour of the existence of autoimmune LE associated with GAD-Ab and supports the link between memory, temporal seizures and possibly GAD-Ab titres.
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PMID:Acute limbic encephalitis and glutamic acid decarboxylase antibodies: a reality? 1978 84


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