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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The basal ganglia system is thought to play a key role in the control of absence-seizures and there is ample evidence that epileptic seizures modify brain dopamine function. We recently reported that local injections of dopamine D1 or D2 agonists in the core of the nucleus accumbens suppressed absence-seizures in a spontaneous, genetic rodent model of absence-epilepsy whereas injections of D1 or D2 antagonists had aggravating effects. These findings raised the possibility that the dopaminergic system may be altered in absence-epilepsy prone rats. Therefore, we studied by in situ hybridization histochemistry the expression of pre- and postsynaptic components of the dopaminergic system in this strain of rats. When compared to non-epileptic control rats, epileptic rats displayed no change in the expression of mRNAs coding for the neuronal dopaminergic markers (tyrosine hydroxylase, membraneous and vesicular dopamine transporters). In addition, there was no difference between the two strains concerning the expression of the dopamine receptor transcripts D1, D2 and D5. In adult absence-epilepsy prone rat with an overt epileptic phenotype, however, an elevated level of D3 mRNA expression was observed in neurons of the core of the nucleus accumbens (+23% increase in silver grain density compared to non-epileptic control rats). D3 transcripts were not increased in juvenile epileptic rats without seizures. These findings suggests that up-regulation of D3 receptor mRNA is part of the epileptic phenotype in absence-epilepsy prone rats. Its localization in the core of the nucleus accumbens bears close resemblance to the dopamine-sensitive antiepileptic sites in ventral striatum and further support the involvement of ventral structures of the basal ganglia system in the control of absence-seizures.
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PMID:Up-regulation of D3 dopaminergic receptor mRNA in the core of the nucleus accumbens accompanies the development of seizures in a genetic model of absence-epilepsy in the rat. 1159 77

The dopamine-releasing and depleting substance amphetamine (AMPH) can make cortical neurons susceptible to damage, and the prevention of hyperthermia, seizures and stroke is thought to block these effects. Here we report a 2-day AMPH treatment paradigm which affected only interneurons in three cortical regions with average or below-average dopamine input. AMPH (six escalating doses/day ranging from 5 to 30 mg/kg for 2 days) was given at 17-18 degrees C ambient temperature (T) to adult male rats. During the 2-day AMPH treatment, peak body T stayed below 38.9 degrees C in 40% of the AMPH treated rats. In 60% of the rats, deliberate cooling suppressed (<39.5 degrees C) or minimized (<40.0 degrees C) hyperthermia. Escalation of stereotypes to seizure-like behaviors was rare and post-mortem morphological signs of stroke were absent. Neurons labeled with the anionic, neurodegeneration-marker dye Fluoro-Jade (F-J) were seen 1 day after dosing, peaked 3 days later, but were barely detectable 14 days after dosing. Only nonpyramidal neurons in layer IV of the somatosensory barrel cortex and in layer II of the piriform cortex and posterolateral cortical amygdaloid nucleus were labeled with Fluoro-Jade. Isolectin B-labeled activated microglia were only detected in their neighborhood. F-J labeled neurons were extremely rare in cortical regions rich in dopamine (e.g. cingulate cortex), and were absent in cortical regions with no dopamine (e.g. visual cortex). Parvalbumin was seen in some Fluoro-Jade-labeled neurons and parvalbumin immunostaining in local axon plexuses intensified. This AMPH paradigm affected fewer cortical regions, and caused smaller reduction in striatal tyrosine hydroxylase (TH) immunoreactivity than previous 1-day AMPH regimens generating seizures or severe (above 40 degrees C) hyperthermia. Correlation between peak or mean body T and the extent of neurodegeneration or microgliosis was below statistical significance. Astrogliosis (elevated levels of the astroglia-marker, glial fibrillary acidic protein (GFAP)) was detected in many brain regions. In the striatum and midbrain, F-J labeled neurons and activated microglia were absent, but astrogliosis, decreased TH immunolabel, and swollen TH fibers were detected. In sum, after this AMPH treatment, cortical pyramidal neurons were spared, but astrogliosis was brain-wide and some interneurons and microglia in three cortical regions with average or below-average dopamine input remained sensitive to AMPH exposure.
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PMID:Parvalbumin neuron circuits and microglia in three dopamine-poor cortical regions remain sensitive to amphetamine exposure in the absence of hyperthermia, seizure and stroke. 1246 30

Previous epilepsy-related gene screen identified a spontaneous recurrent seizure (SRS)-related gene named epilepsy-related gene (ERG1) that encodes N-ethylmaleimide-sensitive fusion protein (NSF). To explore whether spatial learning memory deficits are relevant to SRS and whether hippocampal NSF expression is altered by SRS, we used the kainic acid (KA)-induced epilepsy animal model. SRS was monitored for 3 weeks after injection of a single convulsive dose of KA. KA-treated rats with SRS, KA-treated rats without SRS, and saline-treated rats were then measured in Morris water maze. In this spatial learning task, KA-treated rats with SRS performed poorer compared to those without SRS and those treated with saline. During the subsequent probe trials, KA-treated rats with SRS spent less swim path and time in the target quadrant but more swim path and time in the opposite quadrant, and showed fewer platform crossings. Moreover, in situ hybridization and immunohistochemistry showed that both ERG1/NSF mRNA and NSF immunoreactive expression were down-regulated in the CA1 and dorsal dentate gyrus cells (dDGCs) of the hippocampus, and interestingly, tyrosine hydroxylase (TH) immunoreactive dopamine (DA) neurons were lost in ventral tegmental area (VTA) in the KA rats with SRS. These data demonstrate that SRS impairs spatial learning memory and suggest that the down-regulation of NSF expression pattern in the hippocampus and the loss of DA neurons in VTA might contribute to the spatial learning memory deficits induced by SRS.
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PMID:Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid. 1603 22

TCH-346, an anti-apoptotic compound, is under development by Novartis for the potential treatment of Parkinson's disease (PD) and motor neuron disease [271447,342937]. By September 1999, phase I clinical trials for PD were underway [342937]. The compound was discovered in a screen for molecules with both norepinephrine uptake and MAO inhibiting properties but, although it had anti-apoptotic properties, it did not inhibit MAOA or MAO-B [333136,332004]. The compound increases lifespan in the progressive motorneuropathy mouse model and prevents ischemia in models of ischemia and seizure [288893]. In vivo, it shows neurorescuing and anti-apoptotic properties in PC12 cells and cerebellar granule cells, among others, at concentrations of 0.1 pM to 10 microM, suggesting that its action might prove potentially useful against Alzheimer's and/or Parkinson's disease [332004]. The compound has also shown neurorescuing properties in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia and mouse nigral dopaminergic (DA) neurons after treatment with MPTP in doses ranging between 0.0003 and 0.1 mg/kg po or sc, depending on the model [333136]. Data presented by the University of Nijmengen and the Free University of Amsterdam show that TCH-346 improves the behavioral and enzymatic outcome in the rat 6-OH-dopamine model of Parkinson's disease. TCH-346 (0.0014 mg/kg sc bid) prevented abnormal stepping (open field test) and prevented increases in fore and hind-paw retraction time. TCH-346 also improved acquisition in the Morris water maze task and, at doses between 0.0014 and 0.14 mg/kg, prevented reduction in tyrosine hydroxylase immunoreactivity [345259]. Affinity binding studies with TCH-346 showed that GAPDH is the target [294902,283200]. Differential display RT-PCR also showed that protein-isoaspartyl-methyl transferase is induced by the drug [283200].
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PMID:TCH-346 (Novartis). 1610 Jun 86

Multiple intracellular and extracellular regulatory factors affect transcription of the tyrosine hydroxylase (TH) gene encoding the rate-limiting enzyme in the biosynthesis of the neurotransmitters dopamine, norepinephrine and epinephrine. Short chain fatty acids like butyrate are known to alter TH gene expression, but the mechanism of action is unknown. In this report, transient transfection assays identified the proximal TH promoter to contain sufficient genetic information to confer butyrate responsiveness to a reporter gene. Deletion studies and gel shift analyses revealed that the promoter region spanning the cAMP response element is an absolute requirement for transcriptional activation by butyrate. The branched short chain fatty acid valproate is used for seizure control in humans. Significantly, it has a similar aliphatic structure to butyrate, and it was found to have similar effects on TH in PC12 cells. Site-directed mutagenesis indicated that the effects of both fatty acids were mediated through the canonical CRE. Butyrate treatment also resulted in CREB phosphorylation without changing CREB protein levels. The increased phosphorylation of CREB correlated with accumulation of TH mRNA. The adenylate cyclase inhibitor dideoxyadenosine blocked both CREB phosphorylation and accumulation of TH mRNA. The data are consistent with the conclusion that butyrate induces post-translational modifications of pre-existing CREB molecules in a cAMP/PKA-dependent manner to alter TH transcription. These results support the role of butyrate as a novel exogenous regulatory factor in TH gene expression. Our data delineate a molecular mechanism through which diet-derived environmental signals (e.g. butyrate) can modulate catecholaminergic systems by affecting TH gene transcription.
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PMID:Short chain fatty acids regulate tyrosine hydroxylase gene expression through a cAMP-dependent signaling pathway. 1621 87

The substantia nigra pars reticulata (SNR) is involved in movement and seizure control. In male but not female postnatal day 15 (PN15) rats, GABAA receptor agonists depolarize the SNR neurons and increase the expression of the calcium-regulated gene KCC2 (potassium/chloride cotransporter). Moreover, in PN15 rat SNR, 7beta-estradiol down-regulates KCC2 expression only in the presence of depolarizing GABAA receptor responses. The hypothesis tested here was that GABAA receptors and estradiol also regulate the expression of the phosphorylated form of the transcription factor cAMP responsive element binding protein (phosphoCREB), in PN15 rat SNR and substantia nigra pars compacta (SNC). Rats were injected with muscimol or 17beta-estradiol or their vehicles, and killed 1 h later. Sections were stained with an antibody specific for phosphoCREB alone or counterstained with either tyrosine hydroxylase (TH)- or parvalbumin (PRV)-specific antibodies. Muscimol increased phosphoCREB-ir in male but not in female SN neurons. Using gramicidin perforated patch clamp of PN14-15 SNC neuron, it was shown that muscimol bath application depolarized male SNC neurons but did not significantly alter membrane potential in females. In males, 17beta-estradiol decreased phosphoCREB expression in all studied cell types. In females, 17beta-estradiol did not influence phosphoCREB expression in PRV-ir SNR cells, but increased it in the dopaminergic SN neurons. These data suggest that GABAA receptor activation and estradiol promote the sexual differentiation of the SN in a cell-type-specific manner, by influencing calcium-regulated gene transcription, and therefore promoting the acquisition of sex-specific roles of the SN in movement and seizure control.
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PMID:Sex- and cell-type-specific patterns of GABAA receptor and estradiol-mediated signaling in the immature rat substantia nigra. 1670 49

The neurotransmitter disorders represent an enigmatic and enlarging group of neurometabolic conditions caused by abnormal neurotransmitter metabolism or transport. A high index of clinical suspicion is important, given the availability of therapeutic strategies. This article covers disorders of monoamine (catecholamine and serotonin) synthesis, glycine catabolism, pyridoxine dependency, and gamma-aminobutyric acid (GABA) metabolism. The technological aspects of appropriate cerebrospinal fluid (CSF) collection, shipment, study, and interpretation merit special consideration. Diagnosis of disorders of monoamines requires analysis of CSF homovanillic acid, 5-hydroxyindoleacetic acid, ortho-methyldopa, BH4, and neopterin. The delineation of new disorders with important therapeutic implications, such as cerebral folate deficiency and PNPO deficiency, serves to highlight the value of measuring CSF neurotransmitter precursors and metabolites. The impressive responsiveness of Segawa fluctuating dystonia to levodopa is a hallmark feature of previously unrecognized neurologic morbidity becoming treatable at any age. Aromatic amino acid decarboxylase and tyrosine hydroxylase deficiency have more severe phenotypes and show variable responsiveness to levodopa. Glycine encephalopathy usually has a poor outcome; benzoate therapy may be helpful in less affected cases. Pyridoxine-dependent seizures are a refractory but treatable group of neonatal and infantile seizures; rare cases require pyridoxal-5-phosphate. Succinic semialdehyde dehydrogenase deficiency is relatively common in comparison to the remainder of this group of disorders. Treatment directed at the metabolic defect with vigabatrin has been disappointing, and multiple therapies are targeted toward specific but protean symptoms. Other disorders of GABA metabolism, as is true of the wide spectrum of neurotransmitter disorders, will require increasing use of CSF analysis for diagnosis, and ultimately, treatment.
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PMID:Diagnosis and treatment of neurotransmitter disorders. 1703 64

The mouse mutant ducky and its allele ducky(2J) represent a model for absence epilepsy characterized by spike-wave seizures and cerebellar ataxia. These mice have mutations in Cacna2d2, which encodes the alpha2delta-2 calcium channel subunit. Of relevance to the ataxic phenotype, alpha2delta-2 mRNA is strongly expressed in cerebellar Purkinje cells (PCs). The Cacna2d2(du2J) mutation results in a 2 bp deletion in the coding region and a complete loss of alpha2delta-2 protein. Here we show that du(2J)/du(2J) mice have a 30% reduction in somatic calcium current and a marked fall in the spontaneous PC firing rate at 22 degrees C, accompanied by a decrease in firing regularity, which is not affected by blocking synaptic input to PCs. At 34 degrees C, du(2J)/du(2J) PCs show no spontaneous intrinsic activity. Du(2J)/du(2J) mice also have alterations in the cerebellar expression of several genes related to PC function. At postnatal day 21, there is an elevation of tyrosine hydroxylase mRNA and a reduction in tenascin-C gene expression. Although du(2J)/+ mice have a marked reduction in alpha2delta-2 protein, they show no fall in PC somatic calcium currents or increase in cerebellar tyrosine hydroxylase gene expression. However, du(2J)/+ PCs do exhibit a significant reduction in firing rate, correlating with the reduction in alpha2delta-2. A hypothesis for future study is that effects on gene expression occur as a result of a reduction in somatic calcium currents, whereas effects on PC firing occur as a long-term result of loss of alpha2delta-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma.
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PMID:The ducky(2J) mutation in Cacna2d2 results in reduced spontaneous Purkinje cell activity and altered gene expression. 1713 19

The pediatric neurotransmitter disorders represent an enlarging group of neurological syndromes characterized by abnormalities of neurotransmitter synthesis and breakdown. The disorders of dopamine and serotonin synthesis are aromatic amino acid decarboxylase deficiency, tyrosine hydroxylase deficiency, and disorders of tetrahydrobiopterin synthesis. Amino acid decarboxylase, tyrosine hydroxylase, sepiapterin reductase, and guanosine triphosphate cyclohydrolase (Segawa disease) deficiencies do not feature elevated serum phenylalanine and require cerebrospinal fluid analysis for diagnosis. Segawa disease is characterized by dramatic and lifelong responsiveness to levodopa. Glycine encephalopathy is typically manifested by refractory neonatal seizures secondary to a defect of the glycine degradative pathway. gamma-amino butyric acid (GABA) metabolism is associated with several disorders, including glutamic acid decarboxylase deficiency with nonsyndromic cleft lip/ palate, GABA-transaminase deficiency, and succinic semialdehyde dehydrogenase deficiency. The latter is characterized by elevated gamma-hydroxybutyric acid and includes a wide range of neuropsychiatric symptoms as well as epilepsy. Pyridoxine-dependent seizures have now been associated with deficiency of alpha-aminoadipic semialdehyde dehydrogenase, as well as a new variant requiring therapy with pyridoxal-5-phosphate, the biologically active form of pyridoxine.
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PMID:The pediatric neurotransmitter disorders. 1769 69

Changes in the histological morphology of the caudate-putamen (CPu) were determined after a high-dose methamphetamine (METH) exposure in an effort to elucidate whether BBB disruption plays a role in CPu neurotoxicity. This was accomplished by evaluating the tyrosine hydroxylase immunoreactivity (TH-IR), isolectin B4 reactivity, Black Gold II (BG-II) and Fluoro-Jade C (FJ-C) staining, and immunoreactivity to mouse immunoglobulin G (IgG-IR) in adult male mice at 90-min, 4-h, 12-h, 1-day, and 3-day post-METH exposure. The IgG-IR indicated that the BBB was only modestly altered in the CPu at time points after neurodegeneration occurred and dependent on hyperthermia and status epilepticus. The modest CPu IgG-IR changes observed in the perivascular areas indicated that immunoglobulins were present on some CPu microglia 1 day or more after METH. The first signs of CPu damage were swellings in the TH-IR axons, myelin damage, and a few degenerating neurons at 4-h post-METH. The loss of TH-IR was dependent on hyperthermia but not seizures or CPu neurodegeneration, and the TH-IR was virtually absent throughout the CPu within 12 h. Surprisingly, signs of FJ-C labeling (degenerating) axons in the CPu were seen only in the regions of pronounced somatic neurodegeneration and independent of TH-IR loss. Microglial activation did not occur until 1 day or more post-METH. In summary, a major BBB disruption within the CPu does not directly contribute to neurotoxicity in this single high-dose METH exposure. However, seizure activity produced or exacerbated by amygdalar BBB disruption can significantly increase CPu somatic neurodegeneration (but not affect dopamine (DA) terminal damage). The time course of microglial activation indicates a response to the neurodegeneration, myelin damage, and/or damaged DA terminals after loss of TH-IR.
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PMID:Neurotoxic-related changes in tyrosine hydroxylase, microglia, myelin, and the blood-brain barrier in the caudate-putamen from acute methamphetamine exposure. 1808 Nov 84


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