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)

Solid pieces of fetal locus coeruleus (LC) or superior cervical ganglion (SCG) were placed into a fimbria-fornix lesion cavity in 6-hydroxydopamine-treated, noradrenaline (NA)-denervated rats. Six to 8 months later, all animals were subjected to electrical kindling stimulations in the hippocampus until they had reached the fully kindled state. Nongrafted lesioned animals showed markedly increased kindling rate which was partly attenuated by LC but not SCG grafts. In both LC- and SCG-grafted animals, dopamine beta-hydroxylase immunocytochemistry demonstrated a high density of graft-derived noradrenergic fibers in the dorsal hippocampus, whereas reinnervation of the ventral hippocampus was much more sparse. Subregional distribution of these fibers within the hippocampus was different in the two grafted groups. Both grafts partly restored basal extracellular NA levels in the hippocampus and reacted to generalized seizures by a significant (two- to threefold) increase of NA release, as measured by intracerebral microdialysis. Our data indicate (i) that seizure activity can regulate transmitter release from noradrenergic neurons in both LC and SCG grafts, (ii) that only fetal LC grafts retard seizure development in kindling, and (iii) that the inability of SCG implants to influence kindling epileptogenesis could be due to a lack of synaptic contacts between the graft-derived ganglionic fibers and host hippocampal neurons.
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PMID:Seizure development and noradrenaline release in kindling epilepsy after noradrenergic reinnervation of the subcortically deafferented hippocampus by superior cervical ganglion or fetal locus coeruleus grafts. 786 65

The neuropharmacological activity profile of total fungal extract of F. oxysporum (FO) was investigated. FO enhanced spontaneous locomotor activity, exploratory behaviour and reduced pentobarbitone hypnosis. It had per se anticonvulsant action against maximal electroshock seizure (MES) and potentiated phenobarbitone and phenytoin in MES and also potentiated pentylenetetrazol (PTZ) convulsion. It antagonised morphine, tetrabenazine and haloperidol catalepsy. FO did not show per se analgesia or potentiation of morphine antinociception in mice, while both effects were present in rats. The effect of FO on body temperature was complex. It produced per se reduction in rectal temperature and potentiated the hypothermic responses of reserpine, apomorphine, PEA and I-dopa, and also the hyperthermic response of 5-HTP. The hyperthermic response of haloperidol was reversed by FO. It potentiated amphetamine and morphine lethality, amphetamine, PEA and apomorphine stereotypy, 5-HTP headtwitch response and post-swim grooming response. On swim-stress immobility, while the time of onset of immobility was reduced, FO did not modify the duration of immobility. On foot-shock induced aggression in paired rats, FO produced a decrease in the latency to onset of fighting behaviour and increased the total contact period and the cumulative aggressive score. FO potentiated clonidine automutilation. It has, thus, facilitated aggressive behaviour. The effects are likely to be due to the presence of fusaric acid in FO, which inhibits dopamine beta-hydroxylase and is known to have dopaminergic effects. This investigation has practical implications. since F. oxysporum is a common food contaminant.
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PMID:Neuropharmacological studies on Fusarium toxins--II: Total toxin extract from F. oxysporum. 906 74

Kainic acid-triggered seizures (KATS) induce Fos-like immunoreactivity (FLI) in limbic structures, which send efferents to the locus coeruleus (LC). Following KATS, brain stem sections were stained for Fos immunocytochemistry and double immunostained for Fos and dopamine beta-hydroxylase (DBH). KA-treated animals showed significantly greater numbers of FLI neurons in the LC than control animals (p < 0.05). Co-localization of DBH/Fos was observed in 89.7% of the LC neurons in KA-treated animals and in 1.4% of LC neurons in control animals. Thus, KATS heavily induce Fos in DBH-containing neurons in the LC, which are known to project to the hippocampus. However, the role of activation of the LC noradrenergic neurons during KATS is not well understood at this present time.
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PMID:Seizures in rats treated with kainic acid induce Fos-like immunoreactivity in locus coeruleus. 963 28

Several lines of evidence suggest that norepinephrine (NE) can modulate seizure activity. However, the experimental methods used in the past cannot exclude the possible role of other neurotransmitters coreleased with NE from noradrenergic terminals. We have assessed the seizure susceptibility of genetically engineered mice that lack NE. Seizure susceptibility was determined in the dopamine beta-hydroxylase null mutant (Dbh -/-) mouse using four different convulsant stimuli: 2,2,2-trifluroethyl ether (flurothyl), pentylenetetrazol (PTZ), kainic acid, and high-decibel sound. Dbh -/- mice demonstrated enhanced susceptibility (i.e., lower threshold) compared with littermate heterozygous (Dbh +/-) controls to flurothyl, PTZ, kainic acid, and audiogenic seizures and enhanced sensitivity (i.e., seizure severity and mortality) to flurothyl, PTZ, and kainic acid. c-Fos mRNA expression in the cortex, hippocampus (CA1 and CA3), and amygdala was increased in Dbh -/- mice in association with flurothyl-induced seizures. Enhanced seizure susceptibility to flurothyl and increased seizure-induced c-fos mRNA expression were reversed by pretreatment with L-threo-3, 4-dihydroxyphenylserine, which partially restores the NE content in Dbh -/- mice. These genetically engineered mice confirm unambiguously the potent effects of the noradrenergic system in modulating epileptogenicity and illustrate the unique opportunity offered by Dbh -/- mice for elucidating the pathways through which NE can regulate seizure activity.
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PMID:Norepinephrine-deficient mice have increased susceptibility to seizure-inducing stimuli. 1059 79

It has been known for many years that norepinephrine (NE) is a potent endogenous anticonvulsant, yet there is confusion as to which receptor(s) mediate this effect. This is probably due to multiple factors, including the importance of distinct signaling pathways for different seizure paradigms, a lack of comprehensive pharmacological studies, and difficulty in interpreting existing pharmacological results due to the presence of endogenous NE. We sought to circumvent these problems by testing the anticonvulsant activity of selective agonists for most known adrenoreceptors (ARs) in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack endogenous NE. Dbh -/- mice are hypersensitive to pentylenetetrazole (PTZ)-induced seizures, demonstrating that endogenous NE inhibits PTZ-induced seizures in the wild type. Pretreatment of Dbh -/- mice with an alpha(1)AR or beta(2)AR, but not an alpha(2)AR or beta(1)AR agonist significantly protected against PTZ-induced seizures. In contrast, only the beta(2)AR agonist showed anticonvulsant activity in heterozygous controls. Furthermore, an alpha(1)AR antagonist exacerbated PTZ-induced seizures in control mice, whereas a beta(2)AR antagonist had no effect. We conclude that activation of the alpha(1)AR is primarily responsible for the anticonvulsant activity of endogenous NE in the murine PTZ model of epilepsy. Endogenous NE probably does not activate the beta(2)AR under these conditions, but exogenous activation of the beta(2)AR produces an anticonvulsant effect.
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PMID:Alpha(1) and beta(2) adrenoreceptor agonists inhibit pentylenetetrazole-induced seizures in mice lacking norepinephrine. 1150 1

Ketogenic diet (KD) is a high fat, low carbohydrate diet used to treat children with epilepsy that are refractory to conventional antiepileptic drugs (AEDs). The anticonvulsant mechanism of the KD is unknown. To determine if the noradrenergic system has a role in mediating the anticonvulsant action of the KD, dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack norepinephrine (NE) and Dbh +/- littermates that have normal NE content were fed either a standard rodent chow or the KD. When exposed to the convulsant flurothyl, Dbh +/- mice fed the KD had significantly longer latencies to myoclonic jerk (MJ) and generalized clonic-tonic (CT) seizures than Dbh +/- mice fed normal chow. In contrast, Dbh -/- mice fed the KD had seizure latencies to both MJ and CT comparable to Dbh -/- mice fed normal chow. These results suggest that an intact, functional noradrenergic nervous system is required for the KD to exert an anticonvulsant effect.
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PMID:Norepinephrine is required for the anticonvulsant effect of the ketogenic diet. 1150 65

Epilepsy is a disease of neuronal hyperexcitability, and pharmacological and genetic studies have identified norepinephrine (NE) and neuropeptide Y (NPY) as important endogenous regulators of neuronal excitability. Both transmitters signal through G-protein-coupled receptors, are expressed either together or separately, and are abundant in brain regions implicated in seizure generation. NPY knock-out (NPY KO) and dopamine beta-hydroxylase knock-out (DBH KO) mice that lack NE are susceptible to seizures, and agonists of NE and NPY receptors protect against seizures. To examine the relative contributions of NE and NPY to neuronal excitability, we tested Dbh;Npy double knock-out (DKO) mice for seizure sensitivity. In general, DBH KO mice were much more seizure-sensitive than NPY KO mice and had normal NPY expression, demonstrating that an NPY deficiency did not contribute to the DBH KO seizure phenotype. DKO mice were only slightly more sensitive than DBH KO mice to seizures induced by kainic acid, pentylenetetrazole, or flurothyl, although DKO mice were uniquely prone to handling-induced seizures. NPY contributed to the seizure phenotype of DKO mice at high doses of convulsant agents and advanced stages of seizures. These data suggest that NE is a more potent endogenous anticonvulsant than NPY, and that NPY has the greatest contribution under conditions of extreme neuronal excitability.
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PMID:Genetic comparison of seizure control by norepinephrine and neuropeptide Y. 1156 66

The alpha2-adrenoreceptor (AR) is the most investigated noradrenergic receptor with regard to modulation of seizure activity. However, because of the complexity of multiple alpha2-AR subtypes and their distribution, the exact role of this receptor in modulating seizure activity is not clear. alpha2A- and alpha2C-ARs function as both autoreceptors (presynaptic) on noradrenergic neurons, where they regulate norepinephrine (NE) release, and as postsynaptic receptors on neurons that receive noradrenergic innervation, where they regulate the release of other neurotransmitters (heteroreceptor). The nonselective alpha2-AR agonist clonidine produced a proconvulsant effect on seizure susceptibility, while the selective alpha2A-AR agonist guanfacine was anticonvulsant. The effects of both alpha2-AR agonists were absent in alpha2a knockout mice, suggesting that the alpha2A-AR mediates the proconvulsant and anticonvulsant effect of alpha2-AR agonists on seizure susceptibility. To determine whether the alpha2-AR agonists were acting on inhibitory presynaptic autoreceptors to decrease NE release or on postsynaptic receptors on NE target neurons, the effects of clonidine and guanfacine were determined in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack NE. The anticonvulsant effect of guanfacine persisted in Dbh -/- mice, suggesting that guanfacine may act preferentially on alpha2A-postsynaptic receptors that regulate the action of NE on target neurons. In contrast, the proconvulsant effect of clonidine was lost in Dbh -/- mice, suggesting that clonidine may act on presynaptic autoreceptors to decrease NE release. We hypothesize that the alpha2A-presynaptic autoreceptor is responsible for the proconvulsant effect of alpha2-AR agonists, while the alpha2A-postsynaptic receptor is responsible for the anticonvulsant effect of alpha2-AR agonists. These data help to clarify the inconsistent effects of alpha2-AR agonists on seizure activity.
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PMID:The anticonvulsant and proconvulsant effects of alpha2-adrenoreceptor agonists are mediated by distinct populations of alpha2A-adrenoreceptors. 1518 27

Valproic acid (VPA) is a widely used treatment for both epilepsy and bipolar disorders, although its therapeutic mechanism of action is not fully understood. Because norepinephrine (NE) is implicated in seizure susceptibility and affective disorders, and given previous findings indicating that VPA can act on the NE system, it is possible that NE may mediate some of the therapeutic actions of VPA. To test this hypothesis, we measured flurothyl-induced seizure susceptibility and severity parameters after both acute and chronic VPA treatments in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack NE. We found that the protective effects of acute VPA on seizure susceptibility, as measured by latency to first myoclonic jerk, were attenuated in Dbh -/- mice. Further, while acute VPA reduced the number of control mice that progressed to tonic extension, VPA did not reduce seizure severity in Dbh -/- mice. The carryover anticonvulsant effects following cessation of chronic VPA treatment were similar in both genotypes. Therefore, we conclude that NE is involved in some of the anticonvulsant effects of VPA, especially the effect of acute VPA on seizure severity.
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PMID:Reduced anticonvulsant efficacy of valproic acid in dopamine beta-hydroxylase knockout mice. 1595 69

The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine beta-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). We previously showed that DBH knockout (Dbh -/-) mice, which lack NE, are susceptible to seizures and are hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, suggesting that disulfiram might exacerbate cocaine-induced seizures (CIS) by inhibiting DBH. To test this, we examined CIS in wild-type and Dbh -/- mice following administration of disulfiram or the selective DBH inhibitor nepicastat. We found that Dbh genotype had no effect on CIS probability or frequency, whereas disulfiram, but not nepicastat, increased the probability of having CIS in both wild-type and Dbh -/- mice. Both disulfiram and nepicastat increased CIS frequency in wild-type but not Dbh -/- mice. There were no genotype or treatment effects on serum cocaine levels, except for an increase in disulfiram-treated Dbh -/- mice at the highest dose of cocaine. These results suggest that disulfiram enhances CIS via two distinct mechanisms: it both increases CIS frequency by inhibiting DBH and increases CIS frequency in a DBH-independent manner.
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PMID:Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures. 1832 1


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