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At least 361 records · Page 20Linked to original sources
PubMed1997

Search for New Anticonvulsant Compounds, Part 2. Structure-activity relationship studies of new N-substituted amides of alpha-piperazine-gamma-hydroxybutyric acid as active anticonvulsants.

In a search for new anticonvulsants, two series of compounds, viz. derivatives of N-benzylamides of alpha-(4-phenylpiperazine)-gamma-hydroxybutyric acid (A) and derivatives of N-benzylamides of alpha-(4-benzylpiperazine)-gamma-hydroxybutyric acid (B), were investigated. These amides were obtained by aminolysis of 3-(4-phenyl-, or 4-benzylpiperazine)-tetrahydrofuran-2-one with primary arylalkylamines (i.e. 2-phenylethylamine and 2,3,4-substituted derivatives of benzylamine). Preliminary pharmacological tests, a maximal electroshock (MES) and a subcutaneous metrazole (scMet), and a rotorod toxicity assay were employed. All compounds displayed anticonvulsant activity at range of doses 100-300 mg/kg in the MES screens. In order to point to some structural features correlating with the MES anticonvulsant activity crystal structure analysis followed by conformational analysis was carried out on two representative compounds of series A and B.

Animals↗
PubMed2004

Synthesis and evaluation of anticonvulsant and antimicrobial activities of 3-hydroxy-6-methyl-2-substituted 4h-pyran-4-one derivatives.

In this study, thirteen 3-hydroxy-6-methyl-2-substituted 4H-pyran-4-one derivatives were synthesized for the evaluation of their potential anticonvulsant activity. Mannich bases were prepared by the reaction of substituted piperazine derivatives with allomaltol and formaline. The structures of the synthesized compounds were confirmed by IR, (1)H-NMR and elemental analysis. Their anticonvulsant activities were determined in vivo by maximal electroshock (MES), sub-cutaneous Metrazol (scMet), and rotorod toxicity tests for neurological deficits. The antimicrobial activities of the synthesized compounds were investigated in vitro against some bacteria and fungi using the microdilution broth method. Ac-cording to the activity studies, 3-hydroxy-6-methyl-2-[4-(2-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-4H-pyran-4-one (3i) was the compound determined to be most active in the scMet test for all doses at four hours and for the 300 mg/kg dose at half an hour. 2-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-3-hydroxy-6-methyl-4H-pyran-4-one (3f) was found to be protective against MES whereas 2-chlorophenyl derivative (3e) was not. Looking at the antifungal activity results, compounds 3b, 3h, and 3i were determined to have activity against all fungi.

Animals↗
PubMed2006

Synthesis of some oxime ether derivatives of 1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone and their anticonvulsant and antimicrobial activities.

In this study, oxime and oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone] were prepared as potential anticonvulsant and antimicrobial compounds. The oxime was synthesized by the reaction of ketone and hydroxylamine hydrochloride. O-Alkylation of the oxime by various alkyl halides gave the oxime ether derivatives. Anticonvulsant activity of the compounds was determined by maximal electroshock and subcutaneous metrazole tests in mice and rats according to procedures of the Anticonvulsant Screening Program of National Institutes of Health. Neurotoxicity was determined by the rotorod test in mice and the positional sense test, gait and stance test in rats. In addition to anticonvulsant tests, all compounds were also evaluated against the following microorganisms: S. aureus, E. coli, P. aeruginosa, E. faecalis, C. albicans, C. parapsilosis, and C. krusei using microdilution broth method for possible antibacterial and antifungal activities. Although most of the O-alkyl substituted oxime ethers exhibited both anticonvulsant and antimicrobial activities, the O-arylalkyl substituted compounds were found to be inactive in both screening paradigms.

Animals↗
PubMed2001

Bretazenil, a benzodiazepine receptor partial agonist, as an adjunct in the prophylactic treatment of OP poisoning.

Benzodiazepines, mainly diazepam, are commonly used as anticonvulsants in the treatment of organophosphate casualties. Although very effective, diazepam usually is not used in prophylactic treatments because of its adverse effects on task performance and its abuse liability. Benzodiazepine (BZ) partial agonists are unique in that they are able to occupy all the population of a given receptor without eliciting the maximal physiological response. The BZ receptor agonistic occupancy was found to differ among the various physiological responses in the following order: antipanic > anticonvulsion > sedation > muscle relaxation. Thus, partial agonists, by the use of which controlled levels of agonistic activity can be achieved, might serve as effective anticonvulsants, with fewer side-effects. Bretazenil, a partial agonist, was found to counteract metrazol-induced convulsions in rats. At the anticonvulsive doses (125-250 microg x kg(-1), i.p.) bretazenil, in combination with pyridostigmine (100 microg x kg(-1), i.m.) and aprophen (4 mg x kg(-1), i.m.), conferred prophylactic protection against sarin and soman poisoning (protective ratios 2.6 and 2.1, respectively). Relevant doses of bretazenil (50-400 microg x kg(-1), i.p.) also were tested for general behavioural effects in the open field and for its anti-anxiety properties in the plus maze. The incapacitation was much lower compared with diazepam. Bretazenil should be considered as a candidate for incorporating into a prophylactic mixture as a central nervous system protectant, with significant advantages concerning incapacitation.

Animals↗
PubMed1975

In vivo measurement of 32P in the brain of a freely moving rat.

A new method for measuring the uptake of materials labeled with radioactive phosphorus (32P) in the brain of a freely moving rat is described. The rate of uptake in the brain of a single animal of 32P-labeled phosphate was compared to the uptake rate in the animal's blood or liver. A comparison was made between the uptake following an intravenous (IV) or an intraperitoneal (IP) injection. The effect of convulsions caused by injections of metrazol on the kinetics of 32P uptake in the brain is described.

Animals↗
PubMed2006

Singing, but not seizure, induces synaptotagmin IV in zebra finch song circuit nuclei.

Synaptotagmins are a family of proteins that function in membrane fusion events, including synaptic vesicle exocytosis. Within this family, synaptotagmin IV (Syt IV) is unique in being a depolarization-induced immediate early gene (IEG). Experimental perturbation of Syt IV modulates neurotransmitter release in mice, flies, and PC12 cells, and modulates learning in mice. Despite these features, induction of Syt IV expression by a natural behavior has not been previously reported. We used the zebra finch, a songbird species, to investigate Syt IV because song is a naturally learned behavior whose neuroanatomical basis is largely identified. We observed that, similar to rodents, Syt IV is inducible in songbirds. This induction was selective and depended on the nature of neuronal depolarization. Generalized seizures caused by the GABA(A) receptor antagonist, metrazole, induced the IEG, ZENK, in zebra finch brain. However, these same seizures failed to induce Syt IV in song control areas. In contrast, when nontreated birds sang, three song control areas showed striking Syt IV induction. Further, this induction appeared sensitive to the social context in which song was sung. Together, these data suggest that neural activity during singing can drive Syt IV expression within song circuitry whereas generalized seizure activity fails to do so even though song control areas are depolarized. Our findings indicate that, within this neural circuit for a procedurally learned sensorimotor behavior, Syt IV is selective and requires precisely patterned neural activity and/or neuromodulation associated with singing.

Animals↗
PubMed1992

Pentylenetetrazol-induced seizures in rats: an ontogenetic study.

A quantitative description of motor seizures induced by pentylenetetrazol (PTZ, metrazol) was performed. Seizures were induced by PTZ in doses from 40 to 120 mg/kg s.c. in 477 male albino rats of the Wistar strain 7 to 90 days old. Two patterns of seizures were elicited: minimal, i.e. predominantly clonic seizures of facial and forelimb muscles with preserved righting ability, and major, i.e. generalized tonic-clonic seizures with a loss of righting reflex. Minimal seizures could be reliably elicited since the age of 18 days; the CD50 for these seizures did not significantly differ with age. Major seizures were elicited regularly at all developmental stages studied. Their CD50 did not significantly differ among 7-, 12- and 25-day-old rat pups but the value for 18-day-old rats was smaller and for adult animals larger than these three age groups.

Aging↗
PubMed1982

Anticonvulsant and proconvulsant properties of viloxazine hydrochloride: pharmacological and pharmacokinetic studies in rodents and the epileptic baboon.

Viloxazine HCl is evaluated as an anticonvulsant in a wide range of rodent seizure models and in the epileptic baboon (Papio papio). In the maximal electroshock test, the oral ED50 for abolition of tonic extension was 9 mg/kg-1 after 30-min pretreatment (mouse) rising to 30 mg/kg-1 after 60 min (mouse and rat). Comparable ED50 values were also found for protection against tonic extension in the mouse induced by the administration of the chemical convulsants metrazole or 3-mercaptopropionic acid. In DBA/2 mice the ED50 for abolition of tonic extension during sound-induced seizures was 6.8 mg/kg-1 IP (30-min pretreatment). Pharmacokinetic studies in the mouse showed peak plasma levels to occur 30 min following oral doses, with a mean half-life of 58 min. The anticonvulsant plasma concentration was within 0.5 -- 1 microgram/ml-1. In the baboon, significant protection against photomyoclonic responses is observed 1 -- 2h after viloxazine (2.6 mg/kg-1 IV), during which period the plasma concentration was again 0.5-1 microgram/ml-1. After administration of approximately ten-times this latter dose level, i.e. 24 mg/kg-1 IV, a syndrome characterised by an abnormal EEG and, in some instances, seizure activity was observed.

Acoustic Stimulation↗
PubMed1984

Long term effects of chronic chlordiazepoxide (CDP) administration.

Three experiments were carried out to test the long-term behavioral effects of 12 days administration of CDP (5 mg/kg/day) in rats. In the first two experiments, 4 weeks after the end of drug administration (CDP or placebo), and after 2 weeks of training to run a straight alley for food reward, animals were tested in extinction, i.e., following omission of reward (Expt. 1) or with punishment, i.e., 0.3 mA electric shock in addition to the food reward (Expt. 2). Drug-treated animals showed significantly increased resistance to extinction and to punishment compared with controls. In the third experiment, 10 weeks after drug administration, animals were exposed to 60 s of intense noise to induce audiogenic seizures. The convulsant metrazol was injected 5 min prior to successive sessions (10 min apart) with doses starting at 10 mg/kg an increased by 10 mg/kg each session up to 40 mg/kg. Drug-treated animals were significantly less susceptible to seizures than their placebo controls. These results suggest that chronic benzodiazepine treatment causes long-term neurochemical changes which are responsible for the observed behavioral effects.

Animals↗
PubMed1980

Anticonvulsant activity of cyclopentano amino acids.

The hypothesis that certain amino acid analogues possessing a five-membered ring structure or amino acid analogues that can be viewed as fragments derived from such a ring would have anticonvulsant activity was proposed and tested. The compounds 1-aminocyclopentane carboxylic acid, 1-amino-3-methylcyclopentane carboxylic acid, 3-aminotetrahydrothiophene carboxylic acid, and alpha-aminoisobutyric acid were found to protect rats against seizures in the maximal electroshock test but offered no protection against metrazol- (pentylenetetrazol) induced seizures in mice. The structural feature of this class of anticonvulsants that allows for hydrophobic interactions at the receptor site is considered to be a major physical factor necessary in promoting the activity of this class of anticonvulsants.

Amino Acids↗
PubMed1983

Anticonvulsant effects of some inhibitory neurotransmitter amino acids.

The anticonvulsive effects of GABA, taurine, and glycine were investigated on several chemically-induced and genetic seizure models. Intravenous injections of either GABA, taurine, or glycine provided protection against 3-mercaptopropionic acid (MPA)-induced convulsions in adult Swiss mice. GABA was partially effective against isonicotinic acid hydrazide and was without effect against bicuculline-induced convulsions. Prolonged administration of glycine prevented MPA-induced convulsions but not electrically induced seizures or seizures induced by strychnine or metrazol. Intragastric glycine protected young audiogenic seizure-susceptible DBA/2 mice against all three phases of sound-induced convulsions (wild running, clonic and tonic seizure), but GABA and taurine provided little or no protection. With increase of glycine, the cerebral levels of glutamine and serine also increased, but that of glutamic acid decreased. The endogenous glutamic and glycine levels were slightly higher in the brains of the audiogenic seizure-susceptible DBA/2 mice than in that of the resistant BALB/Cy strain.

Acoustic Stimulation↗
PubMed1991

A review of evidence for GABergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: more support for a continuum hypothesis of "functional" psychosis.

Virtually all antidepressant and antipsychotic drugs, including clozapine, rimcazole and lithium ion, are proconvulsants, and convulsive therapy, using metrazol, a known GABA-A antagonist, as well as electro-convulsive therapy, can be effective in treating both schizophrenia and affective psychoses. Many antidepressant and antipsychotic drugs, including clozapine, as well as some of their metabolites, reverse the inhibitory effect of GABA on 35S-TBPS binding, a reliable predictor of GABA-A receptor blockade. A review of relevant literature suggests that 1) "functional" psychoses constitute a continuum of disorders ranging from schizophrenia to affective psychoses with overlap of symptoms, heredity and treatments, 2) a weakening of GABergic inhibitory activity, or potentiation of counterbalancing glutamatergic neurotransmission, in the brain, may be involved in the therapeutic activities of both antidepressant and antipsychotic drugs, and 3) schizophrenia and the affective psychoses may be different expressions of the same underlying defect: GABergic preponderance/glutamatergic deficit. Schizophrenia and affective psychoses share the following: 1) several treatments are effective in both, 2) similar modes of inheritance, 3) congruent seasonal birth excesses, 4) enlarged cerebral ventricles and cerebellar vermian atrophy, 5) dexamethasone non-suppression. Both genetic and environmental factors are involved in both schizophrenia and affective psychoses, and several lines of evidence suggest that important environmental factors are neurotropic pathogens that selectively destroy glutamatergic neurons. One group of genes associated with psychoses may increase vulnerability to attack and destruction, by neurotropic pathogens, of excitatory glutamatergic neurons that counterbalance inhibitory GABergic neurons. A second group of genes may encode subunits of overactive GABA-A receptors, while a third group of genes may encode subunits of hypo-active glutamate receptors. Improved antipsychotic drugs may be found among selective blockers of GABA-A receptor subtypes and/or enhancers of glutamatergic neurotransmission. A mechanism similar to kindling, leading to long-lasting reduction of GABergic inhibition in the brain, may be involved in several treatments of psychoses.

Affective Disorders, Psychotic↗
PubMed1986

Anticonvulsant properties of spirohydantoins derived from optical isomers of camphor.

Natural camphor exists as the d (+) form but the l (-) form has been synthesized. Replacement of the keto group on carbon 2 of each form with a hydantoin moiety led to only one spirohydantoin derivative. Both d and l derivatives were synthesized. Both forms and their racemic mixture were tested in vivo for toxicity and behavioral effects in mice. A dose of 100 mg/kg of the d form was not toxic: mice showed normal grooming and exploratory behavior; the l form induced hunched posture, body jerks and myoclonic manifestations followed by quiescence. The dl form showed intermediate effects. Challenge with the convulsant pentylenetetrazol (Metrazol) 2 hr after treatment with placebo or the camphor spirohydantoins produced seizure manifestations in all controls, in half of the subjects pretreated with the d-camphor derivative, in none of those pretreated with the l derivative and an intermediate response in those pretreated with racemic mixture. Thus, a spirohydantoin moiety added to camphor conferred strong anticonvulsive properties on the l form and modest ones on the d form; the d form did not seem to antagonize the l form.

Animals↗
PubMed1997

Anxiolytic-like effects of PNU-101017, a partial agonist at the benzodiazepine receptor.

PNU-101017 is a chemically novel ligand at the benzodiazepine recognition site of cloned GABAA receptors. It was reported to potentiate GABA-mediated chloride current in cultured cells with a moderate intrinsic activity and a biphasic dose-response relationship. In this study, we confirmed that PNU-101017 has a partial agonist-like effect in the antagonism of metrazole-induced seizures in mice. It produced no sedation or ataxia, but did antagonize diazepam-induced motor deficit of mice in the rotarod test. PNU-101017 was weakly active in anti-conflict anxiolytic tests, but attenuated the plasma corticosteroid response to mild stress in rats. It also antagonized stress-induced elevation of cerebellar cGMP levels in mice. Like chlordiazepoxide, it increased drinking of saline solution in thirsty rats. PNU-101017 did not potentiate the CNS-depressant effects of ethanol, and produced no evidence of physical dependence when administered repeatedly. Agonists with low intrinsic activity at the benzodiazepine receptor, such as PNU-101017, should be further explored for therapeutic uses.

Animals↗
PubMed1975

Changes in regional blood flow and cardiodynamics associated with electrically and chemically induced epilepsy in cat.

Changes in cardiodynamics and regional blood flow were examined in chronically prepared paralyzed cats during seizures induced electrically by transcerebral or direct cortical stimulation or by administration of flurothyl ether (Indoklon) or pentylenetetrazol (Metrazol). Transcerebral and chemical stimuli produced the greatest vascular responses. During seizures there was an abrupt elevation of arterial pressure unassociated with consistent changes in heart rate. Vascular resistance was increased in femoral, renal and mesenteric arteries with variable reductions in blood flow. Resistance was decreased and flow passively increased in the common carotid artery reflecting the loss of cerebral autoregulation. Cardiac output was unchanged. With seizures associated with large elevations of arterial pressure, the central venous and left ventricular end-diastolic pressures were markedly increased indicating incipient congestive failure. The pressor response was blocked by alpha-adrenergic blockade with phentolamine. Increased regional vascular resistance was abolished by regional sympathectomy. While either adrenalectomy or treatment with 6-hydroxydopamine alone failed to abolish the pressor response, combined, they did. Such treatment unmasked an atropine-sensitive bradycardia. The pressor response with seizures is a consequence of increased vascular resistance in viscera and muscles due to widespread activation of sympathetic neurons and release of adrenomedullary catecholamines. Co-activation of cardiovagal and cardiosympathetic neurons may underlie some associated arrhythmias. Cardiovascular events may severe, by redistribution of the cardiac output, to assure increased availability of oxygen and nutrients to brain to meet the metabolic demands of convulsions.

Adrenalectomy↗
PubMed1978

Use of cortical circuits during focal penicillin seizures: an autoradiographic study with [14C]deoxyglucose.

Autoradiography with [14C]deoxyglucose was used to study the architectural pattern of glucose utilization in the motor cortex of rats during focal penicillin seizures. The seizure focus was characterized by a well circumscribed area whose metabolic activity was increased 2-3 times normal. This was tightly surrounded by cortex that was normal or slightly depressed. The posterior third of the focus showed an increase in glucose utilization in a columnar pattern with particular accentuation of activity in lamina V. There was a loss of normal activity in lamina IV within the focus and in somatosensory and occipital cortex far behind the focus. This depression was particularly prominent in the ipsilateral barrel field. Increased metabolic activity was found in a small area in contralateral homotopic cortex, in lamina Vb with columns extending above this from lamina IV to the surface. Glucose utilization was accentuated 1.2-1.8 fold in the ipsilateral secondary somatosensory area, but was normal in the contralateral cortex. The intensity of focal seizures was increased by the intracortical injection of more penicillin or by giving intravenous metrazol. Both of these methods resulted in an increase in the size of the focus as determined with [14C]deoxyglucose. This was most prominent on the lateral border in lamina I-II and V. In addition, there was an accentuation of the columnar pattern in the posterior part of the focus, ipsilateral somatosensory cortex, and contralateral motor cortex. The architectural pattern of glucose utilization in the cortex during focal seizures is discussed with reference to corticocortical, commissural, and corticothalamic circuits that have been identified by others in anatomical studies. Superimposed on this structure are physiological principles of recurrent excitation, lateral spread, and surround inhibition that characterize basic electrophysiological mechanisms of epilepsy, and influence the intensity of activity within the architectural design.

Animals↗
PubMed1979

An analysis of [3H]gamma-aminobutyric acid (GABA) binding in the human brain.

The binding of [3H]GABA to membranes prepared from human brains obtained post morten was examined. This binding was independent of patient sex, age (16--80 years), postmortem interval (4--33 h) or storage time when frozen (0-64 months). In preparations from cerebellar cortex various compounds displaced [3H]GABA binding with the following order of potency: muscimol greater than 3-aminopropanesulfonic acid greater than GABA greater than imidazoleacet acid greater than delta-amino-n-valeric acid greater than 3-hydroxyGABA greater than bicuculline. Other compounds active 'in vitro' included strychnine, homocarnosine and some (e.g. clozapine, thioridazine, pimozide) but not all (chlorpromazine, haloperiodol) neuroleptics. Compounds inactive 'in vitro' included aminooxyacetic acid, baclofen, picrotoxin, anticholinergics, metrazole, anticonvulsants and naloxone. Triton X-100 augmented the [3H]GABA binding (25 nM) by about 10--20-fold in most brain regions. [3H]GABA binding (IC50) was altered in Huntington's chorea and Reye's syndrome, but not in schizophrenics (4-neuroleptic-treated patients) or sudden infant death syndrome. The data presented strongly support the proposal that the measurement of [3H]GABA binding in postmortem human brain offers a reflection of the state of the physiologically relevant GABA receptor.

Adolescent↗