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)

Several factors involved in the regulation of ornithine decarboxylase (ODC) activity in adult rat brain tissue have been identified by using the in vitro hippocampal slice preparation. The same amino acids that have previously been reported to induce ODC in tissue culture, i.e., asparagine and glutamine, were found to produce a concentration- and time-dependent increase in ODC activity that reached a 100 fold the control value after 6 h of incubation. The effect of asparagine was totally blocked by inhibition of either protein or RNA synthesis, suggesting that the inducing amino acids increase ODC activity by stimulating the transcription of genes directly or indirectly regulating ODC activity. The effect of the inducing amino acids was potentiated by a variety of factors which by themselves did not modify ODC activity. In particular, opioid peptides markedly potentiated the effect of asparagine. Although the opiate antagonists naloxone and naltrexone totally blocked the effects of the opioid peptides on ODC induction, they also produced an inhibition of the asparagine-mediated increase in ODC activity. Other factors like dibutyryl cyclic AMP and insulin also potentiated the effects of asparagine on ODC activity. These results provide the first description of ODC induction in an in vitro preparation of adult brain tissue and indicate that the hippocampal slice preparation could be used to study the molecular mechanisms which regulate the expression and activity of ODC in the adult central nervous system. Moreover the data suggest possible mechanisms which may be involved in the induction of ODC in hippocampus by seizure activity.
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PMID:Induction of ornithine decarboxylase in adult rat hippocampal slices. 285 84

Levels of ornithine decarboxylase activity were measured in brain regions and in adrenal glands of adult male rats exposed to electroshock. Five hours after shock at levels causing transient loss of consciousness and fore and hindlimb tonic extensor seizures, major increases in ornithine decarboxylase activity were found in adrenals, hippocampus, brain stem, frontal cortex, and cerebellum, but striatal levels were unchanged. These increases were reversed by 24 h after electroshock. When lower levels of shock, which caused no loss of consciousness, were also used, a clear dose-response relationship of shock intensity and ornithine decarboxylase activity was found for hippocampus and brain stem. The ornithine decarboxylase response in brain increased with higher shock levels. However, the changes of ornithine decarboxylase in adrenal glands were maximal at intermediate, and diminished at maximal shock values, as were levels of circulating testosterone. These data suggest a differing role for cerebral and adrenal ornithine decarboxylase in the mature rat. The brain enzyme may be primarily related to metabolic repair processes, whereas adrenal ornithine decarboxylase may function in the activation of secretion.
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PMID:Regional variation in the response of cerebral ornithine decarboxylase to electroconvulsive shock. 312 46

Small electrolytic lesions placed in the hilus of the dentate gyrus have been shown to induce behavioral seizures, an elevation in the concentration of the opioid peptide enkephalin, and an increase in the transcription of the gene coding for the peptide precursor of enkephalin. Since polyamines and ornithine decarboxylase (ODC), the rate-limiting enzyme in their synthesis, have been shown to play critical roles in the growth and differentiation of several types of tissue, we tested for changes in ODC activity at various times following the initiation of seizures. ODC activity is significantly increased 3 hr after the lesions, reaches maximal (50-fold) levels about 12 hr later, and returns to control values after 48 hr. The increase occurs in both hippocampi following unilateral electrolytic lesions, is blocked by treatments that suppress limbic seizures, and does not occur after lesions that fail to elicit seizures; accordingly, we conclude that the increase in ODC activity results from epileptiform activity rather than some other consequence of the hilar lesion (e.g., deafferentation). The increase in ODC activity precedes the increase in the amount of mRNA coding for the enkephalin prohormone, which, in turn, precedes the increase in enkephalin levels. These results are consistent with the hypothesis that the early induction of ODC following the initiation of seizures leads to an alteration in genomic expression, which, in turn, changes neuropeptide levels. Adult brains thus appear to possess trophic responses of a type found in a variety of developing cell types and organs, and the possibility exists that these are involved in the control of seizure susceptibility.
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PMID:Induction of ornithine decarboxylase as a possible mediator of seizure-elicited changes in genomic expression in rat hippocampus. 379 81

We have studied the role of putrescine by using transgenic mouse lines overexpressing the human ornithine decarboxylase gene in most of their tissues. The aberrant expression of the transgene is most strikingly manifested in the brain, leading to an increase of up to 20-fold in putrescine content. We report that the transgenic mice with grossly elevated putrescine in all brain regions analysed (cortex, striatum, hippocampus and cerebellum) showed a significantly elevated seizure threshold to chemical and electrical stimuli, and impaired performance in spatial learning and memory tests. The view that putrescine may be primarily responsible for these changes was supported by the fact that the concentrations of the major neurotransmitter amino acids, glutamate and GABA in the brain, were not changed in the transgenic animals, and by the finding that a further increase in brain putrescine, achieved by inhibition of the catabolism of L-ornithine, appeared to provide additional protection against electroshock-induced seizures. These results suggest that the commonly observed increase in ornithine decarboxylase activity and the massive increase in brain putrescine in connection with neuron damage is a neuroprotective measure rather than a cause of the damage.
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PMID:Elevated seizure threshold and impaired spatial learning in transgenic mice with putrescine overproduction in the brain. 828 26

Ornithine decarboxylase (ODC) is the rate-limiting enzyme in polyamine synthesis and is regulated by both transcription-dependent and transcription-independent mechanisms. We compared the effects of asparagine, an amino acid previously shown to increase ODC activity in adult hippocampal slices, on ODC mRNA and activity in adult and neonatal hippocampal slices. In addition, we evaluated the effects of asparagine on ODC activity following seizure activity elicited by systemic administration of kainic acid (KA) in both adult and neonatal rats. Asparagine produced an increase in ODC gene expression and activity in both adult and neonatal hippocampal slices. The increase in ODC activity elicited by asparagine in hippocampal slices was the same in control animals as in animals sacrificed 16 h after KA-induced seizure activity. The asparagine-elicited increase in ODC activity in neonatal and adult hippocampal slices was blocked by the RNA synthesis inhibitor, actinomycin D. Finally, polyamines produced an inhibition of ODC activity in neonatal hippocampal slices. The results indicate that the regulation of the expression and activity of ODC is similar in neonatal and adult hippocampus.
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PMID:Transcriptional activation of ornithine decarboxylase in adult and neonatal hippocampal slices. 840 82

We have characterised the induction of the mitogen-inducible form of cyclooxygenase, COX-2, in the rat cerebral cortex in response to excitotoxin injection into the nucleus basalis. This model is associated with intense stimulation of the ascending pathway to the cerebral cortex, seizure activity, and subsequent ipsilateral cortical induction of various immediate early genes (IEGs), including c-fos, c-jun, and zif268, and ornithine decarboxylase enzyme activity and mRNA, all of which processes are sensitive to treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. In this study we show that excitotoxin injection also causes a marked induction of COX-2 mRNA in ipsilateral cortex detectable at 1 h and peaking at 4 h, where COX-2 mRNA levels were 19 times those in unoperated animals. Levels of COX-2 mRNA remained significantly elevated at 24 h. The early induction of COX-2 at 1 h was also seen in sham-operated animals, but at 4 h the COX-2 mRNA level was significantly increased (4.4-fold) in animals injected with excitotoxin compared with sham-operated animals. The induction at this time point (4 h) was explored pharmacologically and found to be significantly attenuated by treatment with MK-801 (1.5 mg/kg), lamotrigine (10 mg/kg), which prevents presynaptic glutamate release by blocking voltage-sensitive Na+ channels, and the glucocorticoid dexamethasone (3 mg/kg), which has an indirect inhibitory effect on phospholipase A2 and COX activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclooxygenase-2 induction in cerebral cortex: an intracellular response to synaptic excitation. 852 90

Natural polyamines, putrescine, spermidine and spermine, exhibit a number of neurophysiological and metabolic effects in brain preparations. In the in vitro studies, several specific sites of action have been identified such as ion channels, transmitter release and Ca2+ homeostasis. Polyamines have been linked to the development of neuronal degeneration caused by, for instance, epileptic seizures and stroke. The role of endogenous polyamines in the functioning brain is not clear, however. We review the work carried out using state-of-the-art transgenic animal models for polyamine research. A number of transgenic mouse lines carrying human ornithine decarboxylase, spermidine synthase and S-adenosylmethionine decarboxylase gene have been generated. Of these animals those with ornithine decarboxylase transgene show an extensive and constitutive expression of the enzyme in the brain with an exceedingly high putrescine concentration, a phenotype that is not encountered under physiological conditions. In this article we review the neurometabolic, behavioural and histological data that has been obtained from these transgenic mice.
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PMID:Transgenic animals as models in the study of the neurobiological role of polyamines. 878 35

Natural polyamines, spermidine and spermine, and their precursor putrescine, are of considerable importance for the developing and mature nervous system. They exhibit a number of neurophysiological and metabolic effects in the nervous system, including control of nucleic acid and protein synthesis, modulation of ionic channels and calcium-dependent transmitter release. The polyamine system is also known to be involved in various brain pathologic events (seizures, stroke, Alzheimer's disease and others). While cerebral polyamine concentrations and the activities of polyamine-metabolizing enzymes have been studied in great detail, much less is known about the cells that are responsible for cerebral polyamine synthesis and interconversion. With the present review the attempt is made to show how exact knowledge about the regional distribution and cellular localization of polyamines and the polyamine-synthesizing enzymatic machinery (and especially of L-ornithine decarboxylase) may help to better understand the functional interplay between polyamines and other endogenous agents (transmitters, receptors, growth factors neuroactive drugs etc.). Polyamines have been localized both in neurones and glial cells. However, the main cellular locus of the ODC is the neuron--both in the immature and adult central nervous system. Each period of normal brain development and ageing seems to have its own, characteristic temporo-spatial pattern of neuronal ODC expression. During strong functional activation (kindling, epileptic seizures, neural transplantation) astrocytes and other non-neuronal cells do also express ODC and other polyamine-metabolizing enzymes. Astroglial expression of ODC is accompanied by an increase in glial fibrillary acidic protein in these cells. This shift in the cellular mechanisms of polyamine metabolism is currently far from being understood. In human brain diseases (Alzheimer's disease, schizophrenia) certain neurones show an increased expression of ODC, the first and rate-limiting enzyme of polyamine metabolism. Since polyamines are structurally related to psychoactive drugs (neuroleptics, antidepressants) the polyamine system might be of importance as a putative target for drug intervention in psychiatry.
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PMID:The cellular localization of the L-ornithine decarboxylase/polyamine system in normal and diseased central nervous systems. 1021 98

In kainate-induced neurotoxicity, the stimulation of kainate receptors results in the activation of phospholipase A(2) and a rapid release of arachidonic acid from neural membrane glycerophospholipids. This process raises arachidonic acid levels and produces alterations in membrane fluidity and permeability. These result in calcium influx and stimulation of lipolysis and proteolysis, production of lipid peroxides, depletion of ATP, and loss of reduced glutathione. As well as the above neurochemical changes, stimulation of ornithine decarboxylase, altered activities of protein kinase C isozymes, and expression of immediate early genes, cytokines, growth factors, and heat shock proteins have also been reported. Kainate-induced stimulation of arachidonic acid release, calcium influx, accumulation of lipid peroxides and products of their decomposition, especially 4-hydroxynonenal (4-HNE), along with alterations in cellular redox state and ATP depletion may play important roles in kainate-induced cell death. Thus the consequences of altered glycerophospholipid metabolism in kainate-induced neurotoxicity can lead to cell death. Kainate-induced neurotoxicity initiates apoptotic as well as necrotic cell death depending upon the intensity of oxidative stress and abnormality in mitochondrial function. Other neurochemical changes may be related to synaptic reorganization following kainate-induced seizures and may be involved in recapitulation of hippocampal development and synaptogenesis.
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PMID:Neurochemical consequences of kainate-induced toxicity in brain: involvement of arachidonic acid release and prevention of toxicity by phospholipase A(2) inhibitors. 1175 Sep 27

Loss-of-function mutations of the spermine synthase gene (SMS) result in Snyder-Robinson Syndrome (SRS), a recessive X-linked syndrome characterized by intellectual disability, osteoporosis, hypotonia, speech abnormalities, kyphoscoliosis, and seizures. As SMS catalyzes the biosynthesis of the polyamine spermine from its precursor spermidine, SMS deficiency causes a lack of spermine with an accumulation of spermidine. As polyamines, spermine, and spermidine play essential cellular roles that require tight homeostatic control to ensure normal cell growth, differentiation, and survival. Using patient-derived lymphoblast cell lines, we sought to comprehensively investigate the effects of SMS deficiency on polyamine homeostatic mechanisms including polyamine biosynthetic and catabolic enzymes, derivatives of the natural polyamines, and polyamine transport activity. In addition to decreased spermine and increased spermidine in SRS cells, ornithine decarboxylase activity and its product putrescine were significantly decreased. Treatment of SRS cells with exogenous spermine revealed that polyamine transport was active, as the cells accumulated spermine, decreased their spermidine level, and established a spermidine-to-spermine ratio within the range of wildtype cells. SRS cells also demonstrated elevated levels of tissue transglutaminase, a change associated with certain neurodegenerative diseases. These studies form a basis for further investigations into the leading biochemical changes and properties of SMS-mutant cells that potentially represent therapeutic targets for the treatment of Snyder-Robinson Syndrome.
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PMID:Polyamine Homeostasis in Snyder-Robinson Syndrome. 3054 65


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