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)

Cats were subjected to a 3.5-atm fluid percussion impact administered to the cerebral cortex. Near-infrared spectrophotometry (NIRS) was used to measure the quantity of oxyhemoglobin and total hemoglobin in the illuminated tissue as well as the cytochrome a, a3 redox state. Corroborative data were obtained by freezing brains with liquid nitrogen and measuring cortical concentrations of ATP, creatine phosphate (CP), and lactate. Immediately postimpact there was a rise in mean arterial pressure with a 38% increase of highly oxygenated blood and a shift toward oxidation in the cytochrome a, a3 redox state. By 4 hours postimpact, cytochrome a, a3 was becoming progressively reduced despite the persistence of hyperemia. This was associated with a significant (p less than 0.01) decrease in ATP and CP concentration. Additional studies in which a 0.5-sec, 100-v electrical seizure was induced before and after fluid percussion demonstrated significant differences in seizure response, indicating a failure of autoregulation.
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PMID:Failure of autoregulation after closed head injury: an experimental model. 283 18

Effects of atropine or diazepam pretreatment on soman-induced convulsions and brain phosphoinositide (PI) metabolism, as assessed by brain regional inositol-1-phosphate (IP1) levels, were studied in saline and LiCl-pretreated rats. IP1, an intermediate in PI turnover, was measured in cortex, caudate, thalamus, hippocampus, and cerebellum. Soman (100 micrograms/kg; sc) produced convulsions in 63% of the saline-pretreated rats, whereas with LiCl pretreatment all rats exposed to 100 micrograms/kg of soman had tonic-clonic convulsions. Thus, LiCl pretreatment potentiated soman-induced convulsions. Tissue IP1 increased severalfold in soman-exposed convulsing rats with the highest increases being in frontal cortex and caudate. In contrast, no marked increases of IP1 occurred in similarly treated nonconvulsing rats. LiCl treatment itself increased IP1 levels without causing convulsions. In LiCl-pretreated rats, soman again markedly elevated IP1 levels above LiCl alone in convulsing rats, whereas no such effect occurred in nonconvulsing rats. In LiCl-pretreated rats, the increased IP1 levels associated with soman-induced convulsions were greatest in hippocampus and piriform cortex. Thus, LiCl appears to lower the threshold for the spread of seizure activity through limbic structures, thereby potentiating cholinergic-induced convulsions. Diazepam and atropine both blocked soman-induced convulsions, and brain regional IP1 elevations were concomitantly abolished as well. These results indicate that soman-induced convulsions involve the inositol lipid signaling system. This involvement is potentiated by lithium but attenuated by atropine and diazepam.
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PMID:Soman-induced convulsions affect the inositol lipid signaling system: potentiation by lithium; attenuation by atropine and diazepam. 284 36

In mice, the diethylglycineamide analogue of LY201116, DEGA (N-(2,6-dimethylphenyl)-4-[[(diethylamino)acetyl]amino]benzamide), is metabolized by consecutive N-deethylations for form MEGA and GA; the monoethylglycineamide and glycineamide analogues of LY201116, respectively. All of these compounds are in turn hydrolyzed to form LY201116 [4-amino-N-(2,6-dimethylphenyl)benzamide]. LY201116 is N-acetylated to form the N-acetyl metabolite, NAC. NAC is also deacetylated to reform LY201116. All of the above compounds inhibit maximal electroshock-induced seizures (MES) in mice. After oral administration, the potencies of these compounds were similar at their time of peak anticonvulsant effect. However, the MES ED50 values for the above compounds 5 min after iv dosing were 43, 13, 2, and 0.5 mg/kg for DEGA, MEGA, GA, and LY201116, respectively. Similar plasma levels of LY201116 were produced in mice 5 min after iv dosing with the respective ED50 values of the above compounds, which suggested that all of the compounds produced their anticonvulsant effects via LY201116. The in vivo metabolism of DEGA and MEGA but not GA to LY201116 was inhibited by the acylamidase inhibitor bis-(p-nitrophenyl) phosphate (BNPP). Mice predosed with BNPP were not protected by DEGA and MEGA from MES-induced seizures and the plasma samples contained little or no LY201116. The metabolism of GA to LY201116 was not inhibited by BNPP, and GA was an active anticonvulsant in BNPP-pretreated mice. The apparent iv potency of DEGA increased dramatically with time after dosing, again suggesting time-dependent, metabolically mediated liberation of the more potent anticonvulsant LY201116.
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PMID:Metabolism of the prodrug DEGA (N-(2,6-dimethylphenyl)-4-[[(diethylamino)acetyl]amino]benzamide) to the potent anticonvulsant LY201116 in mice. Effect of bis-(p-nitrophenyl)phosphate. 290 94

It is assumed that when anticonvulsants arrest seizure, there is rapid return of brain high energy phosphates and brain lactate to control values. To test this hypothesis, diazepam was administered to neonatal dogs during flurothyl-induced seizure. In vivo 31P nuclear magnetic resonance spectroscopy disclosed that diazepam quickly arrested electrographic seizure and restored brain phosphocreatine and inorganic phosphate to baseline values. In contrast, in vivo 1H nuclear magnetic resonance spectroscopic measurements showed that arrest of seizure with diazepam did not return brain lactate to control values. The sustained increase in cerebral blood flow and prolonged elevation of brain lactate, acetate, valine, and succinate in the postictal period indicate that metabolic recovery of the brain occurs over an extended period of time after the normalization of EEG, phosphocreatine, and brain pH.
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PMID:The effect of diazepam on neonatal seizure: in vivo 31P and 1H NMR study. 291 13

The anticonvulsive action of diazepam, carbamazepine, sodium valproate and their combinations with pyridoxal-5-phosphate, nicotinamide, and alpha-tocopherol were investigated in acute experiments on mice with corazole-induced seizures. Diazepam (0.5 mg/kg), carbamazepine (50 mg/kg) and sodium valproate (200 mg/kg) were shown to reduce convulsive intensity and lethality. Vitamins nicotinamide (250 mg/kg), pyridoxal-5-phosphate (10 mg/kg) and alpha-tocopherol (100 mg/kg) potentiated anticonvulsive action of the above antiepileptic drugs. The results of the investigation suggest the efficacy of pathogenetic therapy and give new evidence of the advisability of using vitamins in combination with synthetic anticonvulsive drugs.
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PMID:[Effect of diazepam, carbamazepine, sodium valproate and their combinations with vitamin preparations on epileptic activity]. 293 95

The present study was undertaken to compare the effectiveness of a new water-soluble benzodiazepine, midazolam, to diazepam, both administered im for protection against diethyl-p-nitrophenyl phosphate (paraoxon) toxicity. Adult male Sprague-Dawley rats were pretreated with midazolam or diazepam (0.32-32.0 mg/kg) alone or in combination with atropine (10.0 mg/kg). Twenty minutes later 2 X LD50 of paraoxon was injected sc and the incidence of seizures and death were recorded for 24 hr. In another series of experiments, the LD50 of paraoxon was evaluated in the rats pretreated im with atropine (10.0 mg/kg) and midazolam or diazepam (10.0 mg/kg). Pretreatment with atropine alone did not prevent paraoxon-induced seizures but did reduce mortality. Both benzodiazepines were very effective alone or when combined with atropine in reducing the incidence of paraoxon-induced seizures. When given alone, neither benzodiazepine protected against paraoxon-induced mortality. However, when combined with atropine both benzodiazepines dramatically decreased the lethality of 2 X LD50 of paraoxon. In equal doses given im, midazolam proved to be more potent than diazepam.
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PMID:Comparative effects of diazepam and midazolam on paraoxon toxicity in rats. 293 66

[3H]Kainic acid binding sites with a slow dissociation rate in the rat limbic system were investigated in detail. Extensively washed membranes prepared from the hippocampal formation and from the region comprising the amygdala and the piriform cortex yielded non-linear Scatchard plots. Microdissection showed that the high-affinity component (affinity constant around 1 nM) was present in the hippocampal CA3 region (4.2 fmol/mg wet tissue) and the amygdaloid complex (4.6 fmol/mg wet tissue), whereas the remaining part of the hippocampal formation and the piriform lobe contained the low-affinity component (affinity constant 5-20 nM; 11.6 and 11.3 fmol/mg wet tissue, respectively). In the lateral + medial septum we detected only the low-affinity component. Severe limbic seizures, induced by unilateral injection of 0.7 or 0.8 microgram kainic acid in 0.3 microliter of phosphate-buffered saline into the amygdala, reduced kainic acid binding sites in the ipsilateral amygdala and CA3 region. The decline of kainic acid binding sites in the injected amygdala was followed by a similar effect in the contralateral amygdala ("mirror focus") and later by a moderate loss also in the contralateral CA3 region. Kainic acid receptor autoradiography demonstrated that binding sites were lost from the stratum lucidum in hippocampus. Septal lesion had no effect on kainic acid binding sites in the hippocampus. Comparison with previous results on the histopathological changes after this lesion shows that high-affinity kainic acid binding sites are preferentially located on neurons that undergo selective degenerations after severe kainic acid-induced seizures.
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PMID:Effect of seizures induced by intra-amygdaloid kainic acid on kainic acid binding sites in rat hippocampus and amygdala. 301 84

Seizure-experienced Genetically Epilepsy-prone Rats (GEPRs) have increased acetylcholine content and choline acetyltransferase activity in the thalamus and striatum. These cholinergic differences are accompanied by a slight but statistically significant reduction in acetylcholinesterase activity in the midbrain. In addition, no abnormalities were found in the numbers of specific 3H-QNB binding sites in the striatum, hippocampus, inferior colliculi or cortex. Other work has shown no difference in muscarinic receptor function as measured by carbachol-stimulated inositol-1-phosphate formation. These data suggest a possible presynaptic defect in the striatal and thalamic cholinergic system which may play some role in the seizure-prone state of the GEPR. However, caution must be used in interpreting these cholinergic derangements since more recent findings show no differences in thalamic acetylcholine content in seizure-naive GEPRs. Thus, the original cholinergic abnormalities detected in the seizure-experienced GEPR may be an enduring response to seizure activity.
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PMID:Abnormalities in the central cholinergic transmitter system of the genetically epilepsy-prone rat. 301 14

All of the known pathways for metabolizing the phospholipase C (EC 3.1.4.10) products of phosphoinositide metabolism eventually lead to myo-inositol monophosphates and products that are hydrolyzed by myo-inositol 1-phosphatase (EC 3.1.3.25). That enzyme is inhibited by lithium (Ki about 1 mM). In animals treated with LiCl, elevations of myo-inositol 1-phosphate (1-IP) occur in brain that appear to result from endogenous neural activity for they are diminished by the anesthetics halothane and pentobarbital. Lithium is thus a useful tool for assessing endogenous in vivo cerebral phosphoinositide metabolism. The 1-IP elevation is also useful for revealing in vivo central nervous system (CNS) receptor activity that is stimulated by endogenous or exogenous processes such as the effects of centrally acting drugs and of seizures. Stimulation of the CNS in the presence of lithium causes myo-inositol to be sequestered in 1-IP in proportion to the amount of stimulation. Thus if the inositol level falls sufficiently resynthesis of the phosphoinositides may be compromised and receptor response to stimuli may be reduced. Evidence for such an occurrence would support the theory that this is one mechanism by which lithium acts in the therapy of manic illness. We extended our efforts to identify such a lowering of phosphoinositide levels to mice where cerebral metabolism can be halted more rapidly than in rats. However, the only change detected was a small elevation in phosphatidylinositol 4-phosphate. We were successful, however, in causing all of the phosphoinositides to be reduced in rat cerebral cortex by pilocarpine stimulation after lithium treatment, a procedure that causes seizures. The same procedure causes the largest reduction in cortical myo-inositol levels that we have observed, and thus may represent the point where the inositol decrement is sufficient to interfere with resynthesis of the lipids.
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PMID:Effects of lithium on phosphoinositide metabolism in vivo. 301 84

In ventilated rats, levels of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bisphosphate (PIP2), diacylglycerol (DAG), triacylglycerol (TAG), free fatty acids (FFA) and phosphatidic acid, as well as their fatty acid contents, were measured in forebrain tissue after 1, 20 and 60 min of seizures induced by bicuculline. Cerebral energy state was also measured. PI decreased progressively throughout 60 min of seizures, whereas the levels of PIP and PIP2 did not change. DAG increased modestly and persistently. FFA increased markedly during the early seizure period, but decreased later. Following an initial drop, TAG rose above control. Phosphatidic acid did not change. The levels of ATP and energy charge potential decreased slightly and lactate accumulated. Stearic acid (18:0) and arachidonic acid (20:4) primarily accounted for the changes in the levels of the lipids. At the onset of seizures, the decrease of 18.0 and 20:4 in PI occurred in parallel with an enrichment of these fatty acids in FFA and DAG. Despite the fact that the losses of 18:0 and 20:4 from PI were quantitatively similar to each other at all times examined, the increase in free 18:0 was much larger than the increase in free 20:4 at 20 min of seizures. Concurrently there was a rise of 20:4 in TAG. As the FFA levels declined thereafter, 20:4 and docosahexaenoate (22:6) in TAG continued to increase. The results are consistent with the view that seizure activity stimulates the hydrolytic breakdown of brain phosphoinositides--the pathway catalyzed by phosphodiesterase of the phospholipase C type followed by lipases, and probably the pathway catabolized by phospholipases A as well. Preferential incorporation of polyunsaturated fatty acids into TAG-acyl residues may represent a mechanism to reduce the level of their free forms when the latter are produced in large amounts.
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PMID:Cerebral phosphoinositide, triacylglycerol and energy metabolism during sustained seizures induced by bicuculline. 303 62


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