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PubMedDate not supplied

Effects of glutaurine treatment on electroshock-induced amnesia. Antiamnesic action of glutaurine.

The effects of oral glutaurine (gamma-L-glutamyl-taurine, LitoralonR Chinoin, Budapest) treatment on electroconvulsive shock-induced amnesia were studied. Oral treatment with glutaurine in a dose of 1-20 micrograms was ineffective on electroshock-induced amnesia if the treatment was applied before the electroconvulsive shock. Fifty micrograms given in the same experimental paradigm could attenuate the amnesia considerably. When the treatment with glutaurine was applied immediately after the electroconvulsive shock, even 1 and 10 micrograms doses were effective in attenuating the amnesia in both the 24h and 48h retestings. However when glutaurine was given one hour before the 24h and 48h retestings, it proved to be ineffective. The data indicate that glutaurine is able to prevent electroconvulsive shock-induced amnesia by counteracting the effect of the electroconvulsive shock on the memory consolidation phase, but it is less effective on learning or it is ineffective on retrieval processes.

Amnesia↗
PubMed1989

Computer-assisted predictive mathematical relationship among electroshock voltage and duration and occurrence of convulsion in mice.

A microcomputer program in BASIC for predicting percentage of occurrence of electroshock-induced convulsion in mice was designed. A formula published by the author to express the mathematical relationship among the drug dose, the time, and the biological response was used in this program. Analysis of the actual, and the computer-assisted predicted percentages of occurrence of convulsion has shown that the program is fairly accurate in expressing convulsion response of mice as a function of the voltage and the duration.

Animals↗
PubMed1985

Pharmacological evidence for a protective role of the endogenous opioid system on electroshock-induced seizures in the mouse.

Acute administration of morphine produced a protective effect on electroshock (ECS)-induced seizures in mice, while naloxone and naltrexone decreased ECS seizure threshold. Chronic morphine administration in mice resulted in a decrease of ECS-induced seizure threshold evident within 24 h following the end of drug treatment. This effect disappeared 5 days after the end of chronic morphine treatment. Moreover, tolerance to the anticonvulsant effect of morphine was evident in mice chronically treated with morphine and subjected to ECS 30 min after the last injection of the drug, as well as in mice subjected to ECS 24 h after the end of chronic treatment.

Animals↗
PubMed1987

Maximal electroshock increases the density of [3H]Ro 5-4864 binding to mouse cerebral cortex.

The effects of chemically and electrically-induced convulsions on the binding of [3H]Ro 5-4864 to peripheral benzodiazepine receptors (PBR) was studied in both peripheral tissues and the central nervous system (CNS). Acute, maximal electroshock (MES) increased the density of PBR in mouse cerebral cortex as evidenced by a 30% increase in the Bmax of this archetypic ligand. These values returned to control levels by 60 minutes after MES treatment. In contrast, thirty and sixty minutes after convulsions induced by Ro 5-4864, strychnine, or pentylenetetrazol, neither the Bmax nor Kd of [3H]Ro 5-4864 binding to mouse cerebral cortical membranes was altered. The increase in [3H]Ro 5-4864 binding to cortex observed 30 minutes after MES was blocked by anticonvulsant doses of phenobarbital, phenytoin and clonazepam. No changes in the characteristics of [3H]Ro 5-4864 binding was observed in cerebellar or hippocampal membranes 30 minutes following acute MES. Further, after long-term MES administration (1 treatment/day, 5 days), no change in PBR density could be detected 30 minutes after the last MES. Finally, while no change in PBR density was noted in the kidneys 30 minutes after the MES, a significant increase in PBR density was seen in the cardiac ventricles. These results demonstrate a selective modulation of PBR density by MES, suggesting that the PBR could be involved in either the generation of seizures or in postictal compensatory processes.

Animals↗
PubMed1987

Brain metabolism after electroshock seizure in the neonatal dog: a [31P]NMR study.

In vivo [31P] nuclear magnetic resonance (NMR) spectroscopy disclosed that a 10 second electroshock seizure in oxygenated neonatal dogs produced prolonged alteration of brain phosphocreatine (PCr), inorganic phosphate (Pi), and lactate. The slow return of these metabolites to baseline may be related to lower endogenous stores of high energy phosphates, or less developed pathways for their regeneration.

Adenosine Triphosphate↗
PubMedDate not supplied

Preclinical profile of remacemide: a novel anticonvulsant effective against maximal electroshock seizures in mice.

Anticonvulsant tests in mice revealed specific, potent actions of remacemide for protection of mice against maximal electroshock seizures (MES). Comparisons of oral efficacy to reference compounds yielded the following ED50 values (expressed as mg/kg): remacemide = 33, phenytoin = 11, phenobarbital = 20, carbamazepine = 13 and valproate = 631. The duration for protection by remacemide was longer than carbamazepine or valproate, but shorter than phenytoin or phenobarbital. In neural impairment tests (inverted screen or rotorod) to determine the oral toxic dose 50 (TD50) the following therapeutic indices (TD50/ED50) were obtained: (1) inverted screen--remacemide = 17.6, phenytoin = 57.4, phenobarbital = 5.1, carbamazepine = 10.2, and valproate = greater than 3; and (2) rotorod--remacemide = 5.6, phenytoin = 9.6, phenobarbital 4.8, and valproate = 1.9. Remacemide was devoid of sedative actions and possessed a favorable 28.1 margin of safety value (median estimated lethal dose/ED50 for MES). An intermediate potency against either audiogenic- or N-methyl-D-aspartate-induced seizures was exhibited by remacemide. Tolerance to MES was not apparent after 5 days of oral daily dosing of remacemide. Remacemide was inactive in vitro against gamma-aminobutyrate or benzodiazepine receptors and adenosine uptake mechanisms. Therapeutic utility for generalized tonic/clonic seizures is predicted for remacemide.

Acetamides↗
PubMed1993

Anticonvulsant activity of AMPA/kainate antagonists: comparison of GYKI 52466 and NBOX in maximal electroshock and chemoconvulsant seizure models.

The anticonvulsant activities of a noncompetitive (GYKI 52466) and a competitive (NBQX) AMPA/kainate antagonist were compared in the maximal electroshock (MES) seizure test and various chemoconvulsant models. Both antagonists were protective in the MES and pentylenetetrazol tests. GYKI 52466 was also protective against seizures and lethality induced by 4-aminopyridine, kainate and AMPA, but not by NMDA, whereas NBQX was ineffective in these chemoconvulsant tests. Both GYKI 52466 and NBQX produced motor impairment at doses similar to those that were protective in the MES test. Under some circumstances, noncompetitive AMPA/kainate antagonists could offer advantages over competitive antagonists in seizure therapy. However, neurological toxicity is an obstacle to the potential clinical use of both classes of agents.

4-Aminopyridine↗
PubMed2004

Involvement of prolactin, vasopressin and opioids in post-ictal antinociception induced by electroshock in rats.

The neurochemical mechanisms involved in post-ictal antinociception remain to be elucidated. Application of electroconvulsive shock (ECS) to rats results in post-ictal antinociception. The objective of this study was to identify endogenous substances that could participate in antinociception during post-ictal depression induced by ECS (70 mA, 60 Hz, 1 s). Antinociception was measured by the rat paw-pressure test, in which increased sensitivity is induced by intraplantar injection of carrageenan. This test proved to be efficient in detecting the electroshock-induced antinociception. Intense post-ictal antinociception was observed over a period of 30 min after the end of the seizure. It was used nonspecific opioid and specific vasopressin antagonists and the prolactin (PRL) release inhibitor to test the reversal of antinociception. Administration of naloxone (5, 7.5 and 10 mg/kg) blocked the post-ictal antinociception. The V(1) (125 microg/kg) and V(2) (250 microg/kg) vasopressin receptor antagonists ([beta-mercapto-beta,beta-cyclopentamethylenepropionyl(1),O-Et-Tyr(2),Val(4),Arg(8)]-vasopressin and [adamantaneacetyl(1),O-Et-d-Tyr(2),Val(4),Abu(6),Arg(8,9)]-vasopressin) also inhibited the nociceptive response. The antinociception blockade was more intense after administration of the V(1) receptor antagonist. Bromocriptine (4, 8 and 12 mg/kg) was able to reverse antinociception behavior during the post-ictal period. Morphine (1, 2 and 4 mg/kg), vasopressin (12.5, 100 and 400 microg/kg) and prolactin (100, 200 and 400 microg/kg) administration promoted a higher nociceptive threshold. It was administered the three substances with their respective antagonists to verify the opioidergic pathway and vasopressin and prolactin release interactions, and as a positive control. We observed that the tested mediators were released in an independent manner, indicating no interference in which other.

Animals↗
PubMed2005

Synergistic interaction of gabapentin and oxcarbazepine in the mouse maximal electroshock seizure model--an isobolographic analysis.

The anticonvulsant effects produced by mixtures of oxcarbazepine and gabapentin (two second-generation antiepileptic drugs) in numerous fixed-ratio combinations of 1:1, 1:2, 1:5, 1:10, 1:15, and 1:20 were examined isobolographically in the mouse maximal electroshock seizure model. Results displayed that mixtures of both drugs at the fixed-ratios of 1:2, 1:5, 1:10, 1:15, and 1:20 exerted supra-additive (synergistic) interactions against electroconvulsions. Only a fixed-ratio of 1:1 was indifferent with isobolography, although the combination displayed the trend towards supra-additivity. Furthermore, the combinations of oxcarbazepine with gabapentin, administered at their median effective doses (ED(50 mix)s), did not alter motor performance of animals challenged with the chimney test. Additionally, neither gabapentin nor oxcarbazepine affected total brain concentrations of co-administered drug, indicating a pharmacodynamic nature of interaction between these antiepileptics. Finally, based on preclinical data presented here the combination of oxcarbazepine and gabapentin is of particular importance for further therapy in patients with refractory partial seizures.

Amines↗
PubMed2003

Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electroshock seizure models.

Glutamatergic ionotropic and metabotropic receptor modulators have been shown to produce anticonvulsant activity in a number of animal seizure models, e.g. maximal electroshock (MES) and DBA/2 sensory-induced seizures. The 6 Hz model of partial seizures is an alternative low frequency, long duration stimulation paradigm resulting in a seizure characterized by jaw and forelimb clonus, immobility, and an elevated tail (Straub-tail). A unique aspect of this model is that it is the only acute electrically-induced seizure model in which levetiracetam has displayed anticonvulsant activity, suggesting that the 6 Hz seizure model may be useful in identifying compounds with unique anticonvulsant profiles. The purpose of the present study was to examine the role of glutamate receptors in the MES and 6 Hz seizure models using a number of NMDA, AMPA/KA, and mGlu receptor modulators. The pharmacological profile of the 6 Hz seizure model was compared to that of the MES model using eight ionotropic glutamate receptor antagonists and eight mGlu receptor modulators. The ionotropic receptor antagonists MK-801, LY235959, NBQX, LY293558, GYKI 52466, LY300168, and LY377770 produced complete protection from tonic extension in the MES model. Furthermore, the noncompetitive mGlu1 (LY456236) and mGlu5 (MPEP) metabotropic receptor antagonists and the mGlu8 metabotropic receptor agonist (PPG) were also effective in the MES model whereas the competitive mGlu1 (LY367385) receptor antagonist, the mGlu2/3 (LY379268 and LY389795) and Group III (L-AP4) metabotropic receptor agonists were ineffective. In contrast, all of the compounds tested, produced dose-dependent protection in the 6 Hz model with an increase in potency as compared to the MES model. The largest protective indices (P.I.=TD50/ED50) observed were associated with the iGlu5 antagonist LY382884 and the mGlu2/3 receptor agonists LY379268 and LY389795 (P.I.=>14, 14, and 4.9, respectively) in the 6 Hz model. The results from the present study support the continued search for glutamate receptor modulators as potential antiepileptic agents. Furthermore these results illustrate the importance of using several different animal seizure models in the search for novel AEDs and the potential utility of the 6 Hz seizure model in identifying novel AEDs.

Animals↗
PubMed2004

Influence of antazoline and ketotifen on the anticonvulsant activity of conventional antiepileptics against maximal electroshock in mice.

Experimental studies have indicated that the central histaminergic system plays an important role in the inhibition of seizures through the stimulation of histamine H1 receptors. H1 receptor antagonists, including classical antiallergic drugs, occasionally may induce convulsions in healthy children and patients with epilepsy. The purpose of this study was to investigate the effects of antazoline and ketotifen (two H1 receptor antagonists) on the anticonvulsant activity of antiepileptic drugs against maximal electroshock (MES)-induced convulsions in mice. The following antiepileptic drugs were used: valproate, carbamazepine, diphenylhydantoin and phenobarbital. In addition, the effects of antiepileptic drugs alone or in combination with antazoline or ketotifen were studied on long-term memory (tested in the passive avoidance task) and motor performance (evaluated in the chimney test), acutely and after 7-day treatment with these H1 receptor antagonists. The influence of antazoline and ketotifen on the free plasma and brain levels of the antiepileptics was also evaluated. Antazoline (at 0.5 mg/kg), given acutely and after 7-day treatment, significantly diminished the electroconvulsive threshold. Similarly, ketotifen, after acute and chronic doses of 8 mg/kg markedly reduced the threshold for electroconvulsions. In both cases, antazoline and ketotifen were without effect upon this parameter at lower doses. Antazoline (0.25 mg/kg) significantly raised the ED50 value of carbamazepine against MES (both, acutely and after 7-day treatment). Furthermore antazoline (0.25 mg/kg) also reduced the anticonvulsant activity of diphenylhydantoin, but only after repeated administration, without modifying the brain and free plasma level of this drug. Moreover, valproate and phenobarbital did not change their protective activity when combined with antazoline. Ketotifen (4 mg/kg) possessed a biphasic action, acutely it enhanced the anticonvulsant action of carbamazepine and phenobarbital while, following 7-day treatment, reduced the antiseizure activity of carbamazepine. Ketotifen did not affect the free plasma or brain levels of antiepileptics tested. Only acute antazoline (0.25 mg/kg) applied with valproate impaired the performance of mice evaluated in the chimney test. Ketotifen (4 mg/kg) co-administered with conventional antiepileptic drugs impaired motor coordination in mice treated with valproate, phenobarbital or diphenylhydantoin. Acute and chronic antazoline (0.25 mg/kg) alone or in combination with antiepileptic drugs did not disturb long-term memory, tested in the passive avoidance task. Similarly, ketotifen (4 mg/kg) did not impair long-term memory, acutely and after 7-day treatment. However, valproate alone or in combination with chronic ketotifen (4 mg/kg) worsened long-term memory. The results of this study indicate that H1 receptor antagonists, crossing the blood brain barrier, should be used with caution in epileptic patients. This is because antazoline reduced the protective potential of diphenylhydantoin and carbamazepine. Also, ketotifen reduced the protection offered by carbamazepine and elevated the adverse activity of diphenylhydantoin, phenobarbital and valproate.

Animals↗
PubMed2005

Interaction between lamotrigine and felbamate in the maximal electroshock-induced seizures in mice: an isobolographic analysis.

Isobolographic profile of interactions between lamotrigine (LTG) and felbamate (FBM), two second-generation antiepileptic drugs, against maximal electroshock (MES)-induced seizures, and neurotoxic adverse effects in the chimney test in mice were determined. LTG combined with FBM at the fixed ratios of 1:3, 1:1, and 3:1 exerted merely additive interactions against MES-induced seizures. In the chimney test, isobolography revealed that LTG coadministered with FBM at the fixed ratio of 1:1 displayed subadditivity (antagonism), whereas the remaining combinations tested (1:3 and 3:1) exerted additivity in terms of their neurotoxic side effects. LTG (at the dose of 2.3 mg/kg) coadministered with FBM (25.7 mg/kg) at the fixed ratio of 1:1 from the MES test did not impair long-term memory of mice challenged with the passive avoidance task. Furthermore, FBM (25.7 mg/kg) altered neither the free plasma nor brain concentration of LTG, hence pharmacokinetic events, which might affect the observed interactions in the MES test, are unlikely. Considering benefit indices for the respective fixed ratio combinations, it may be concluded that the combination of LTG with FBM at the fixed ratio of 1:1 is advantageous from a preclinical point of view, offering the highest benefit index reaching the value of 1.46. Likewise, the two-drug combination of 1:3 was also beneficial and is worth recommendation with benefit index amounting to 1.36. Only the combination of 3:1 was neutral with a benefit index of 1.08. Protection offered by LTG in combination with FBM against maximal electroconvulsions and its favorable neurotoxic side effect profile might provide the patients with intractable seizures with an efficacious treatment, as the rational polytherapy however, it requires to be clinically confirmed and verified.

Animals↗
PubMed2006

Isobolographic analysis of interactions between losigamone and conventional antiepileptic drugs in the mouse maximal electroshock model.

The aim of this study was the isobolographic evaluation of interactions between losigamone (LSG), valproate (VPA), carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, and tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor coordination) and the passive avoidance task (long-term memory). Brain concentrations of antiepileptic drugs (AEDs) were measured by immunofluorescence or high-performance liquid chromatography. Isobolographic analysis indicated synergistic interactions between LSG and VPA. For example, in the proportion of 1:1 the theoretically calculated 50% effective dose for additivity (ED(50add)) was 138 mg/kg, while the experimentally derived ED(50) for the mixture (ED(50mix)) was 85.2 mg/kg. The difference was significant at p<0.001. LSG combined with CBZ or PHT showed additivity, whereas the combinations of LSG with PB were either additive, for the fixed ratios of 1:3 and 1:1, or antagonistic for the ratio of 3:1 (ED(50add)=18.4 mg/kg versus ED(50mix)=26.7 mg/kg, p<0.05). Impairment of long-term memory was noted only in the case of VPA given at its ED(50), however this AED did not affect motor performance. LSG, CBZ, PHT and PB (applied at their ED(50) values) and co-administration of LSG with conventional AEDs (including VPA) impaired neither motor performance nor long-term memory. LSG did not affect the brain concentration of VPA or PB, but significantly elevated the brain concentrations of CBZ and PHT. In contrast, VPA, CBZ and PHT significantly increased the brain concentration of LSG, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. Although LSG exhibited some favorable pharmacodynamic interactions with various AEDs, these were complicated by pharmacokinetic interactions and emphasize the importance of measuring AED concentrations in studies designed to identify desirable AED combinations.

Animals↗
PubMed2006

Interactions between zonisamide and conventional antiepileptic drugs in the mouse maximal electroshock test model.

Despite the major advances in antiepileptic drug (AED) therapeutics, about one third of patients with epilepsy still do not have adequate seizure control with currently available AEDs when prescribed as monotherapy. Typically, in this setting polytherapy with two or more AEDs is used. Zonisamide (ZNS) is a new AED effective in the treatment of refractory epilepsy and since it is only prescribed in polytherapy regimens, its interactions with other AEDs is of particular importance. The aim of this study was to isobolographically determine interactions between ZNS and four conventional AEDs: carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA), in the mouse maximal electroshock (MES)-induced seizure model. The total brain concentrations of conventional AEDs and ZNS were measured with immunofluorescence and high-pressure liquid chromatography (HPLC), respectively, in order to determine any pharmacokinetic contribution in any observed interactions. With isobolography, synergistic interactions were observed for the combination of ZNS plus VPA and ZNS plus PHT at the fixed-ratio of 1:1, while additivity was observed for their combinations at the remaining dose ratios of 1:3 and 3:1. In contrast, the interactions between ZNS and PB and between ZNS and CBZ, applied at the fixed-ratios of 1:3, 1:1 and 3:1 proved to be additive. None of these AED combinations were associated with motor and long-term memory impairment. Furthermore, whilst brain AED concentrations were unaffected by ZNS, PHT significantly increased and PB reduced brain ZNS concentrations. Thus, the resultant interactions between ZNS and PHT and between ZNZ and PB were consequent to both pharmacodynamic and pharmacokinetic components. Finally, one can conclude that because of the synergistic pharmacodynamic interaction between ZNS and VPA, this combination might be useful in clinical practice.

Animals↗
PubMed2004

Evidence for augmented brainstem activated forebrain seizures in Wistar Audiogenic Rats subjected to transauricular electroshock.

Previous work from our laboratory has shown that naïve Wistar Audiogenic Rats (WARs), a genetic model of reflex epilepsy in which seizures are induced by high-intensity sound stimulation (120 dB SPL), are seizure-prone to a variety of pro-convulsive stimuli (e.g., transauricular electroshock, pentylenetetrazole and pilocarpine). On the other hand, repetitive acoustic stimulation of WARs causes a slow recruitment of limbic structures, known as audiogenic kindling, changing seizure expression to include behavior characteristic of temporal-lobe epilepsy. Thus, our hypothesis is that WARs have facilitated acoustic-limbic projections when compared to Wistar controls. Wistar controls (n = 9) and WARs (n = 9) underwent EEG electrode implants in the cortex-Cx, amygdaloid complex-AMY and inferior colliculus-IC and received one low current transauricular electrical stimulus (ES) daily, for three consecutive days, with intensities of 10, 20 and 30 mA, respectively. The video-electroencephalographic activity was recorded 1 min before and 4 min after ES. Our results confirm previously described data indicating a greater susceptibility of WARs to seizure. However, low current ES (e.g., 20 mA) triggered epileptiform activity in the AMY only after epileptiform EEG was visible in the Cx and IC electrode leads. The AMY after-discharge continued even though no evident epileptiform activity was present in the Cx. In conclusion, our results add electrophysiological data to previously published behavioral evidence of WAR enhanced susceptibility to ES seizures and, also, support the hypothesis that the acoustic-limbic circuitry is facilitated even in unkindled WARs.

Acoustic Stimulation↗
PubMed2001

beta-Adrenoceptor blockade enhances the anticonvulsant effect of glutamate receptor antagonists against maximal electroshock.

In this study, we evaluated whether beta-adrenoceptor antagonists may modify the protective efficacy of dizocilpine (MK-801), a NMDA receptor antagonist, and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), a non-NMDA (AMPA/kainate) receptor antagonist, against maximal electroshock-induced seizures in mice. Propranolol, acebutolol, metoprolol and atenolol were used in doses that did not alter the electroconvulsive threshold. Propranolol potentiated the anticonvulsant activity of MK-801 and GYKI 52466, significantly lowering their ED(50) values from 0.38 and 15.0 to 0.15 (P<0.001) and 8.4 mg/kg (P<0.001), respectively. Similarly, metoprolol lowered the ED(50) of MK-801 and GYKI 52466 from 0.38 and 15.0 to 0.17 (P<0.05) and 11.2 mg/kg (P<0.05). Acebutolol enhanced the protective action of GYKI 52466, lowering its ED(50) value from 15.0 to 12.2 mg/kg (P<0.05), but not that of MK-801. Atenolol, not penetrating the blood-brain barrier, did not affect the anticonvulsive efficacy of MK-801 and GYKI 52466. In conclusion, beta-adrenoceptor antagonists may act synergistically with excitatory amino acid receptor antagonists to inhibit generalised tonic-clonic seizures.

Adrenergic beta-Antagonists↗
PubMed2003

Effects of seizure severity and seizure repetition on postictal cardiac arrhythmia following maximal electroshock.

Convulsive seizures triggered by maximal electroshock (MES) induce profound abnormalities in neural regulation of cardiac rhythm that are manifested by a period of marked cardiac arrhythmia in the immediate postictal state. It is not known whether seizure severity or seizure experience may influence the duration of cardiac arrhythmia in the postictal state. We varied the duration of MES administered to rats to vary seizure severity, as measured by the extensor to flexion (E/F) ratio. In separate experiments, rats were subjected to daily MES. Finally, we pretreated rats with ketamine prior to MES to block seizures hindlimb extension. In all animals, the R-R interval was plotted on the tachogram, and the duration of the arrhythmia was measured. Increases in MES duration increased significantly the E/F ratio and prolonged significantly the postictal cardiac arrhythmia. Repetition of MES caused a kindling effect with respect to seizure severity resulting in a significant increase of the E/F ratio and significant increases in the duration of postictal arrhythmia. Blocking of the hindlimb extension by ketamine abolished arrhythmia suggesting that the arrhythmia is not caused directly by MES. Severity of tonic convulsive seizures is a determinant of disordered cardiac autonomic regulation and directly influences the duration of cardiac arrhythmia during the immediate postictal state following MES. Seizure repetition also increases abnormalities of postictal neural regulation of the heart, but further studies are needed to determine whether this effect is independent of seizure severity increases.

Animals↗
PubMed2003

New morphinan derivatives with negligible psychotropic effects attenuate convulsions induced by maximal electroshock in mice.

Interest in dextromethorphan (DM) has been renewed because of its anticonvulsant and neuroprotective properties. However, DM at supra-antitussive doses can produce psychotomimetic effects in humans. Recently, we demonstrated that DM exerts psychotropic effects in mice [Neurosci. Lett. 288 (2000) 76, Life Sci. 69 (2001) 615]. We synthesized a series of compounds with a modified morphinan ring system, with the intention of developing compounds that retain the anticonvulsant activity with weak psychotropic effects [Bioorg. Med. Chem. Lett. 11 (2001) 1651]. In order to extend our understanding of the pharmacological intervention of these morphinans, we assessed their behavioral effects, and then examined whether they exert protective effects on maximal electroshock convulsions (MES) in mice. Repeated treatment (20 or 40 mg/kg, i.p./day x 7) with DM or dextrorphan (a major metabolite of DM; DX) significantly enhanced locomotor activity in a dose-related manner. This locomotor stimulation was accentuated more in the animals treated with DX, and might be comparable to that of phencyclidine (PCP). By contrast, treatment with a metabolite of DM [3-methoxymorphinan (3MM) or 3-hydroxymorphinan (3HM)], 3-allyloxy-17-methylmorphinan (CPK-5), or 3-cyclopropylmethoxy-17-methylmorphinan (CPK-6) did not significantly alter locomotor activity or patterns. The behavioral effects mediated by these morphinans and PCP paralleled the effects of conditioned place preference. DM, DX, CPK-5, and CPK-6 had anticonvulsant effects against MES, while 3MM and 3HM did not show any anticonvulsant effects. We found that DM, DX, CPK-5 and CPK-6 were high-affinity ligands at sigma(1) receptors, while they all had low affinity at sigma(2) receptors. DX had relatively higher affinity for the PCP sites than DM. By contrast, CPK-5 and CPK-6 had very low affinities for PCP sites, suggesting that PCP sites are not requisites for their anticonvulsant actions. Our results suggest that the new morphinan analogs are promising anticonvulsants that are devoid of PCP-like behavioral side effects, and their anticonvulsant actions may be, in part, mediated via sigma(1) receptors.

Animals↗