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

Both organophosphate (OP) and carbamate pesticides may produce seizures and death commonly attributed to the inhibition of acetylcholinesterase (AChE) and subsequent excess of acetylcholine (ACh). The anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) receptor antagonists in animals encouraged us to investigate their effects on the toxic and convulsant properties of OP and carbamate pesticides. Adult Swiss mice were systemically injected with the OP pesticide, chlorfenvinphos (CVP), or the carbamate pesticide, methomyl (MET). Both CVP and MET induced dose-dependent seizure activity and death in mice. Pretreatment with the muscarinic antagonist, atropine (ATR), at a dose of 1.8 mg/kg did not prevent seizures but decreased the lethal effects of CVP and MET. Pretreatment with the NMDA antagonists, dizocilpine (MK-801) at a dose of 1 mg/kg or 3-((R,S)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) at a dose of 10 mg/kg, influenced neither MET-induced seizures nor CVP- or MET-induced death. However, both MK-801 and CPP blocked CVP-induced seizures. Concurrent administration of ATR and the NMDA antagonists prevented seizures produced by CVP, but not those produced by MET. Nevertheless, both MK801 and CPP coadministered with ATR markedly enhanced its antilethal effects in CVP- and MET-intoxicated mice. The antidotes had no influence upon brain AChE activities in mice treated with saline or CVP or MET. It seems that combined treatment with ATR and NMDA receptor antagonists might be of clinical relevance.
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PMID:On the interactions between antimuscarinic atropine and NMDA receptor antagonists in anticholinesterase-treated mice. 1121 47

Huperzine A (HUP), an alkaloid isolated from the Chinese club moss, Huperzia serrata is a reversible inhibitor of cholinesterases which crosses the blood-brain barrier and shows high specificity for acetylcholinesterase (AChE) and a prolonged biological half-life. We tested, in vivo, its efficiency in protecting cortical AChE from soman inhibition and preventing subsequent seizures. The release of acetylcholine (ACh) was also followed in the cortex of freely moving rats using microdialysis techniques. We previously found that soman-induced seizures occurred in rodents only when the cortical AChE inhibition was over 65% and when the increase of ACh level was over 200 times the baseline level. This was verified in the present study in control animals intoxicated by 1 LD50 of soman (90 microg/kg). Using the same dose of soman in rats pre-treated with 500 microg/kg of HUP, we observed that 93% of the animals survived and none of them had seizures. This dose of HUP reduced AChE inhibition to 54% and increase of ACh level to 230 times baseline value. HUP thus appears as a promising compound to protect subjects against organophosphorus intoxication.
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PMID:Effects of Huperzine used as pre-treatment against soman-induced seizures. 1130 48

OP nerve agents, such as soman, are potent irreversible inhibitors of central and peripheral acetylcholinesterases. Pretreatment of OP poisoning relies on the subchronic administration of a reversible acetylcholinesterase inhibitor. In the present study, the protective effects against soman toxicity of such compounds i.e. pyridostigmine, physostigmine (alone or associated with scopolamine) or huperzine are compared in guinea-pigs instrumented for EEG recording. Each medication is given via a subcutaneous mini-osmotic pump for 6 days at a delivery rate providing about 30% maximal inhibition of red cell acetylcholinesterase activity. The animals then receive iterative injections of soman (1/3 LD50) every 10 min. With pyridostigmine, reflecting a decreased overall tolerance to the poisoning, the cumulative doses of soman producing either tremors and convulsions or seizures are lower than those found in non-pretreated intoxicated controls. On the other hand, physostigmine does not afford satisfactory protection against the early mortality after intoxication. On this specific point, physostigmine + scopolamine and huperzine, although they do not prevent the appearance of seizures, give best results. The effects of each pretreatment on acetylcholinesterase, butyrylcholinesterase and carboxylesterase (these two latter enzymes may act as endogenous scavengers of OP compounds) are also examined in vitro and in the blood of each animal during subchronic administration. Huperzine appears as a selective inhibitor of red cell acetylcholinesterase activity while pyridostigmine or physostigmine additionally inhibit plasmatic butyrylcholinesterase. Considerations about huperzine or physostigmine + scopolamine as the most appropriate candidate for the pretreatment of OP poisoning are given.
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PMID:Subchronic administration of various pretreatments of nerve agent poisoning. II. Compared efficacy against soman toxicity. 1136 Apr 33

Status epilepticus (SE)-induced neuronal injury may involve excitotoxicity, energy impairment and increased generation of reactive oxygen species (ROS). Potential treatment therefore should consider agents that protect mitochondrial function and ROS scavengers. In the present study, we examined whether the spin trapping agent N-tertbutyl-alpha-phenylnitrone (PBN) and the antioxidant vitamin E (DL-alpha-tocopherol) protect levels of high-energy phosphates during SE. In rats, SE was induced by either of two inhibitors of acetylcholinesterase (AChE), the organophosphate diisopropylphosphorofluoridate (DFP, 1.25 mg/kg, sc)- or the carbamate carbofuran (1.25 mg/kg, sc). Rats were sacrificed 1 h or 3 days after onset of seizures by head-focused microwave (power, 10 kW; duration 1.7 s) and levels of the energy-rich phosphates adenosine triphosphate (ATP) and phosphocreatine (PCr) and their metabolites adenosine diphosphate (ADP) and adenosine monophosphate (AMP), and creatine (Cr), respectively, were determined in the cortex, amygdala and hippocampus. Within 1 h of seizure activity, marked declines were seen in ATP (34-60%) and PCr (25-52%). Total adenine nucleotides (TAN = ATP + ADP + AMP) and total creatine compounds (TCC = PCr + Cr) were also reduced (TAN 38-60% and TCC 25-47%). No changes in ATP/AMP ratio were seen. Three days after the onset of seizures, recovery of ATP and PCr was significant in the amygdala and hippocampus, but not in the cortex. Pretreatment of rats with PBN (200 mg/kg, ip, in a single dose), 30 min before DFP or carbofuran administration, prevented induced seizures and partially prevented depletion of high-energy phosphates. Pretreatment with the natural antioxidant vitamin E (100 mg/kg, ip/day for 3 days), partially prevented loss of high energy phosphates without affecting seizures. In controls, citrulline, a product of nitric oxide synthesis, was found to be highest in the amygdala, followed by hippocampus, and lowest in the cortex. DFP- or carbofuran-induced seizures caused elevation of citrulline levels seven- to eight-fold in the cortex and three- to four-fold in the amygdala and hippocampus. These results suggest a close relationship between SE, excitotoxicity and energy metabolism. The involvement of oxidative stress is supported by the findings that DFP and carbofuran trigger an excessive nitric oxide (NO) production in the seizure relevant regions of the brain.
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PMID:Depletion of energy metabolites following acetylcholinesterase inhibitor-induced status epilepticus: protection by antioxidants. 1140 58

Acute effects of seizure-inducing doses of the organophosphate compound diisopropylphosphorofluoridate (DFP, 1.25 mg/kg s.c.) or the carbamate insecticide carbofuran (CF, 1.25 mg/kg s.c.) on nitric oxide (NO) were studied in the brain of rats. Brain regions (pyriform cortex, amygdala, and hippocampus) were assayed for citrulline as the determinant of NO and for high-energy phosphates (ATP and phosphocreatine) as well as their major metabolites (ADP, AMP, and creatine). Rats, anesthetized with sodium pentobarbital (50 mg/kg i.p.), were killed using a head-focused microwave (power, 10 kW; duration, 1.7 s). Analyses of brain regions of controls revealed significantly higher levels of citrulline in the amygdala (289.8+/-7.0 nmol/g), followed by the hippocampus (253.8+/-5.5 nmol/g), and cortex (121.7+/-4.3 nmol/g). Levels of energy metabolites were significantly higher in cortex than in amygdala or hippocampus. Within 5 min of CF injection, the citrulline levels were markedly elevated in all three brain regions examined, while with DFP treatment, only the cortex levels were elevated at this time. With either acetylcholinesterase (AChE) inhibitor, the maximum increase in citrulline levels was noted 30 min post-injection (> 6- to 7-fold in the cortex, and > 3- to 4-fold in the amygdala or hippocampus). Within 1 h following DFP or CF injection, marked declines in ATP (36-60%) and phosphocreatine (28-53%) were seen. Total adenine nucleotides and total creatine compounds were reduced (36 58% and 28-48%, respectively). The inverse relationship between the increase in NO and the decease in high-energy phosphates, could partly be due to NO-induced impaired mitochondrial respiration leading to depletion of energy metabolites. Pretreatment of rats with an antioxidant, the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN, 200 mg/kg i.p.), prevented DFP- or CF-induced seizures, while the antioxidant vitamin E (100 mg/kg i.p. per day for 3 days) had no anticonvulsant effect. Both antioxidants, however, significantly prevented the increase of citrulline and the depletion of high-energy phosphates. It is concluded that seizures induced by DFP and CF produce oxidative stress due to a marked increase in NO, causing mitochondrial dysfunction, and thereby depleting neuronal energy metabolites. PBN pretreatment provides protection against AChE inhibitor-induced oxidative stress mainly by preventing seizures. Additional antioxidant actions of PBN may contribute to its protective effects. Vitamin E has direct antioxidant effects by preventing excessive NO production.
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PMID:Nitric oxide modulates high-energy phosphates in brain regions of rats intoxicated with diisopropylphosphorofluoridate or carbofuran: prevention by N-tert-butyl-alpha-phenylnitrone or vitamin E. 1157 Jun 92

Experiments on male rats examined the effect of a basic antidotal therapy consisting of various types of anticholinergic substances and reactivators of acetylcholinesterase on the lethal effects of the highly toxic organophosphorous compound soman by means of determination of the medium lethal dose of soman in 24-hour survival of experimental animals. The efficacy of the basic antidotal therapy of acute intoxications by soman evaluated in this way was compared with the effect of an antidotal therapy enriched with diazepam, a drug with anticonvulsive action. The obtained results show that addition of diazepam to the basic antidotal therapy increases the ability of the antidotal therapy to eliminate acute lethal effects of soman if it includes atropine as an anticholinergic agent regardless of the employed type of acetylcholinesterase reactivator. In the case of employment of anticholinergic agents with prevailing central effects, such as benactyzine, biperiden, or scopolamine, the addition of diazepam will not significantly influence the therapeutic efficacy of the antidotal therapy regardless of the selected aetylcholinesterase reactivator. At the same time, the addition of diazepam to the antidotal therapy does not change the difference in the efficacy of the antidotal therapy in dependence on the selected anticholinergic agent or acetylcholinesterase reactivator. At present the most common combination of antidotes against soman, consisting of obidoxime and atropine, as well as a prospective combination containing oxime HI-6 and atropine should be supplemented with diazepam not only to prevent centrally induced seizures and tonic-clonic convulsions but also to increase the ability of such antidotal therapy to eliminate acute lethal toxicity of soman.
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PMID:[Effect of diazepam on antidote therapy of lethal toxic effects of soman in rats]. 1157 93

Patients and experimental models of temporal lobe epilepsy display loss of somatostatinergic neurons in the dentate gyrus. To determine if loss of the peptide somatostatin contributes to epileptic seizures we examined kainate-evoked seizures and kindling in somatostatin knockout mice. Somatostatin knockout mice were not observed to experience spontaneous seizures. Timm staining, acetylcholinesterase histochemistry, and immunocytochemistry for NPY, calbindin, calretinin, and parvalbumin revealed no compensatory changes or developmental abnormalities in the dentate gyrus of somatostatin knockout mice. Optical fractionator counting of Nissl-stained hilar neurons showed similar numbers of neurons in wild type and somatostatin knockout mice. Mice were treated systemically with kainic acid to evoke limbic seizures. Somatostatin knockout mice tended to have a shorter average latency to stage 5 seizures, their average maximal behavioral seizure score was higher, and they tended to be more likely to die than controls. In response to kindling by daily electrical stimulation of the perforant path, to more specifically challenge the dentate gyrus, mean afterdischarge duration in somatostatin knockout mice was slightly longer, but the number of treatments to five stage 4-5 seizures was similar to controls. Although we cannot exclude the possibility of undetected compensatory mechanisms in somatostatin knockout mice, these findings suggest that somatostatin may be mildly anticonvulsant, but its loss alone is unlikely to account for seizures in temporal lobe epilepsy.
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PMID:Heightened seizure severity in somatostatin knockout mice. 1182 9

These studies investigated the effectiveness of combination treatment with a benzodiazepine and an anticholinergic drug against soman-induced seizures. The anticholinergic drugs considered were biperiden, scopolamine, trihexaphenidyl, and procyclidine; the benzodiazepines were diazepam and midazolam. Male guinea pigs were implanted surgically with cortical screw electrodes. Electrocorticograms were displayed continually and recorded on a computerized electroencephalographic system. Pyridostigmine (0.026 mg x kg(-1), i.m.) was injected as a pretreatment to inhibit red blood cell acetylcholinesterase by 30-40%. Thirty minutes after pyridostigmine, 2 x LD50 (56 microg x kg(-1)) of soman was injected s.c., followed 1 min later by i.m. treatment with atropine (2 mg x kg(-1)) + 2-PAM (25 mg x kg(-1)). Electrographic seizures occurred in all animals. Anticonvulsant treatment combinations were administered i.m. at 5 or 40 min after seizure onset. Treatment consisted of diazepam or midazolam plus one of the above-mentioned anticholinergic drugs. All doses of the treatment compounds exhibited little or no antiseizure efficacy when given individually. The combination of a benzodiazepine and an anticholinergic drug was effective in terminating soman-induced seizure, whether given 5 or 40 min after seizure onset. The results suggest a strong synergistic effect of combining benzodiazepines with centrally active anticholinergic drugs and support the concept of using an adjunct to supplement diazepam for the treatment of nerve-agent-induced seizures.
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PMID:Combination anticonvulsant treatment of soman-induced seizures. 1192 Sep 21

Soman, a potent acetylcholinesterase inhibitor, induces status epilepticus in rats followed by conspicuous neuropathology, most prominent in piriform cortex and the CA3 region of the hippocampus. Cholinergic seizures originate in striatal-nigral pathways and with fast-acting agents (soman) rapidly spread to limbic related areas and finally culminate in a full-blown status epilepticus. This leads to neurochemical changes, some of which may be neuroprotective whereas others may cause brain damage. Pretreatment with lithium sensitizes the brain to cholinergic seizures. Likewise, other agents that increase limbic hyperactivity may sensitize the brain to cholinergic agents. The hyperactivity associated with the seizure state leads to an increase in intracellular calcium, cellular edema and metal delocalization producing an oxidative stress. These changes induce the synthesis of stress-related proteins such as heat shock proteins, metallothioneins and heme oxygenases. We show that soman-induced seizures cause a depletion in tissue glutathione and an increase in tissue 'catalytic' iron, metallothioneins and heme oxygenase-1. The oxidative stress induces the synthesis of stress-related proteins, which are indicators of 'stress' and possibly provide neuroprotection. These findings suggest that delocalization of iron may catalyze Fenton-like reactions, causing progressive cellular damage via free radical products.
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PMID:Soman-induced seizures: limbic activity, oxidative stress and neuroprotective proteins. 1192 Sep 27

This study shows that pentoxifylline (ptx), a xanthine derivative, significantly attenuates scopolamine-induced memory impairment in rats, as demonstrated in a passive avoidance task (50 mg/kg intraperitoneally [i.p.]) and in an elevated T-maze (10 and 50 mg/kg i.p.). Ptx (25, 50 and 100 mg/kg i.p.) also potentiates oxotremorine-induced tremors in mice, in a dose-dependent manner, and this effect was completely prevented by atropine. In addition, ptx (50 and 100 mg/kg i.p.) increased the number of animals developing pilocarpine-induced seizures, and potentiated the latency to the first pilocarpine-induced convulsion. Hippocampus homogenates from rats treated with ptx (100 mg/kg) for 1 week and sacrificed 15 min after the last injection showed a significant decrease in the muscarinic receptor numbers, indicative of a downregulation phenomenon. Similar effects were observed when assays were performed 24 h after the last ptx injection (10 and 50 mg/kg i.p.), but not after 72 h. Additionally, in vitro assays showed that ptx inhibits acetylcholinesterase activity in a dose-dependent manner when incubated with homogenates from rat hippocampus. Our data suggest that the muscarinic agonist effect of ptx could possibly depend on factors such as endogenous cholinergic activity.
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PMID:Evidence for the involvement of the muscarinic cholinergic system in the central actions of pentoxifylline. 1198 Dec 27


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