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PubMed1987

Central nervous system toxicity of some common environmental residues in the mouse.

To ascertain changes in the level of general central nervous system (CNS) excitability and, therefore, postulated neurotoxicity of some common environmental residues, a bioassay was developed that used a known general CNS stimulant, pentylenetetrazol (PTZ, Metrazol). As a positive control, dieldrin was compared to PTZ and nine other compounds (caffeine, 1,2,3-trichloropropane, ethylene dibromide, Arochlor 1254, pentachlorophenol, heptachlor epoxide, DDT, lindane, and chlordecone) for CNS stimulatory effects, both acutely and subchronically. All doses were administered on an equimole per kilogram basis, rather than milligram per kilogram or %LD50 comparisons. The general level of CNS excitability elicited by each compound relative to the others was assessed. Of the 10 compounds examined, dieldrin showed the most activity in decreasing metrazol-challenge ED50, while chlordecone was most potent in increasing the ED50. Dieldrin, heptachlor epoxide, and chlordecone were shown to potently inhibit PTZ-induced kindling. Of all compounds examined, dieldrin is concluded to have the greatest potential for causing an increase in general CNS excitability, which may relate to persistent behavioral stimulation.

Animals↗

PubMed1980

Flash-evoked afterdischarge in rat as a model of the absence seizure: dose-response studies with therapeutic drugs.

The flash-evoked afterdischarge (FEAD) is a self-sustained burst of wave-and-spike complexes recorded from occipital cortex in the rat and other animals in response to a single light flash. On the basis of behavioral experiments and studies employing single doses of antiepileptic drugs, FEAD has been proposed as a model of the absence seizure. In order to test the validity of FEAD as an absence seizure model, the present experiments determined dose-response relationships for the suppression of FEAD by six antiepileptic drugs with established clinical profiles. It was found that phenobarbital, ethosuximide, and trimethadione suppressed FEAD in a dose-related manner, and that ethosuximide was approximately three times as potent as trimethadione. Mephenytoin produced a maximal reduction of FEAD of only 30 to 40%, which was not dose-related. Neither phenytoin nor acetazolamide suppressed FEAD. The results obtained with ethosuximide, trimethadione, and phenytoin are qualitatively similar to their therapeutic effects in absence epilepsy. The FEAD model failed, however, to unequivocally predict the therapeutic efficacy of mephenytoin or acetazolamide. In this respect, it is similar to the metrazol seizure model. It is concluded that FEAD is a valid absence seizure model with a pharmacological predictive value that is at least as good as the metrazol model.

Acetazolamide↗

PubMed1982

Comparative anticonvulsant activity and neurotoxicity of clobazam, diazepam, phenobarbital, and valproate in mice and rats.

The 1.5-benzodiazepine (clobazam), the 1,4-benzodiazepine (diazepam), and two nonbenzodiazepine antiepileptic drugs (phenobarbital and valproate) were evaluated in mice and rats with a battery of well-standardized anticonvulsant test procedures. The results obtained indicate that clobazam and valproate exhibit a wider range of experimental anticonvulsant activity than either diazepam or phenobarbital. Except for clobazam by the maximal electroshock seizure (MES) test in rats, clobazam and valproate are effective in nontoxic doses against MES and all four chemically induced seizures (Metrazol, bicuculline, picrotoxin, and strychnine). Clobazam is effective by the MES test in rats only in doses that exceed the median minimal toxic dose. Phenobarbital is effective against all of the above tests, but minimal toxic doses must be employed to prevent strychnine seizures. Diazepam, on the other hand, is effective in nontoxic doses against seizures induced by Metrazol, bicuculline, and picrotoxin, but protects animals from maximal electroshock and strychnine seizures only when given in toxic doses. When compared on the basis of protective indices (PI = TD50/ED50) calculated from intraperitoneal data, the PIs for clobazam were 1.6 to 13 times higher than those for diazepam. Overall, except for the MES test in rats, the PIs for clobazam were from 1.5 to 44 times higher than those for any of the other three substances. With respect to the MES test in rats, the PI for clobazam was 10.8 times higher than that for diazepam; however, the PIs for phenobarbital and valproate were 3.5 and 4.4 times higher, respectively, than that for clobazam. These data suggest that the spectrum of anticonvulsant activity for the 1,5-benzodiazepine (clobazam) is superior to that for the 1,4-benzodiazepine (diazepam). Also, the broad experimental profile of anticonvulsant activity of clobazam agrees well with its reported broad clinical efficacy.

Animals↗

PubMed1982

Effect of epileptogenic agents on the incorporation of 3H-glycine into proteins in the cat's cerebral cortex.

Filter paper strips soaked in 3H-glycine solution were applied to acoustic cortex of cats, anaesthetized with Nembutal and pretreated with epileptogenic agents (Metrazol, G-penicillin, and 3-amino-pyridine) and cycloheximide. The untreated contralateral hemisphere served as control. After 1 h incubation, both cortical samples were excised simultaneously and fixed in Bouin solution for autoradiography. Incorporation was blocked by cycloheximide. There was no glycine incorporation on the penicillin-treated side, while pyramidal cells were intensively labelled in layers II-V of the mirror focus. 3-Aminopyridine produced the same result. Metrazol as convulsant proved to be far weaker than the previous two. The intensity of incorporation was significantly more intensive in the mirror focus than in the primary one. Penicillin and 3-aminopyridine, while provoking cortical seizures, seem to inhibit glycine incorporation into a neuron-specific, function-dependent protein contained by the labelled cells in the autoradiogram.

Acoustic Stimulation↗

PubMed1975

Epileptiform seizures in domestic fowl. V. The anticonvulsant activity of delta9-tetrahydrocannabinol.

The anticonvulsant activity of delta9-tetrahydrocannabinol (delta9-THC) has been determined against seizures induced in epileptic chickens by intermittent photic stimulation (IPS) and in epileptic and nonepileptic chickens by Metrazol. Intravenous administration of the drug reduced both the severity and incidence of seizures evoked by IPS in epileptic chickens. This anticonvulsant action was accompanied by a reduction in frequency of inter-ictal slow-wave high-voltage electroencephalographic activity and by the absence of spiking during IPS. delta9-THC did not affect the incidence of Metrazol-induced seizures in epileptic or nonepileptic chickens.

Animals↗

PubMed1983

Primidone, phenobarbital, and PEMA: II. Seizure protection, neurotoxicity, and therapeutic index of varying combinations in mice.

Neurotoxicity and protection against maximal electroshock (MES) and pentylenetrazol (Metrazol) seizures were determined in mice for various combinations of primidone (PRM), phenobarbital (PB), and phenylethylmalonamide (PEMA). The results suggest that PRM and PB together are superior to either one alone in terms of spectrum of activity and relative toxicity. The protection against Metrazol and the toxicity of PB are both potentiated by PEMA at low concentrations. PEMA also potentiates the toxicity of combined PRM plus PB, without altering their protection against MES, thus lowering their therapeutic index. We conclude that PRM and PB together have an advantage over PB alone, especially when their brain concentration ratio is at or above 1 and PEMA concentrations are low. These conditions are usually not present at steady state in patients treated with PRM.

Animals↗

PubMed1999

[Regeneration and transplantation of nerve tissue].

Initial experimental transplantations and attempts to induce regeneration in the nerve tissue were done during the last decades of the 19th century. Though experiments were partly successful, the Cajal's doctrine about the unchanging adult nervous system overbalanced those promising findings for long period thereafter. Only during the last thirty years requirements of clinicians moved neuroscientists to study the problems of regeneration and transplantation in the CNS again. The possibility of transferring nerve cells from a donor to the host CNS, their survival, and formation of functional contacts has been fully established. Recent findings has shown that techniques of molecular biology can overcome some of the essential problems of transplantation, e.g. the glial scar. It is evident that the key role in plastic processes accompanying integration of the transplanted cells have neurotrophic factors produced both by the host and the graft. The entire microenvironment within the transplanted tissue is altered. Some specific features of the graft may be also significant. As the implant is mostly an embryonic tissue, processes of differentiation have to be considered. Accordingly, transplantation can be used as a model in the studies of neuroontogeny. In our experiments structural association of neurones transplanted as a suspension of embryonic cells into the dorsal blade of the dentate gyrus where granule cells were eliminated was described. Differentiation and signs of synapse formation were observed. Using Timm staining method, changes in the distribution of mossy fibres were identified. In thirty-day-old grafts, high number of NADPH-d positive neurones was found. Some nitric oxide producing neurones formed long processes extending into the host tissue. Such long fibres also produced nitric oxide synthase. In order to influence the process of the graft integration we induced extreme hyperfunction by a metrazol kindling. In kindled animals, more neurones survived, however, the density of apoptotic cells was similar to control animals. Our findings may be related to the hyperfunction or to the effect of metrazol on the nerve cells of both the host and the graft. They may result from microenvironmental changes or from the activation of genes participating on the mechanism of priming.

Animals↗

PubMed1992

Antimetrazol action of two potential anticonvulsants, CM 40907 and SR 41378, in immature rats.

The action of two potential anticonvulsants, CM 40907 (10-50 mg/kg i.p.) and SR 41378 (1.25-20 mg/kg i.p.) against metrazol-induced seizures was studied in rats 7, 12, 18 and 25 days old. Two types of motor seizures--minimal, clonic and major, generalized tonic-clonic--were elicited by a 100-mg/kg dose of metrazol (s.c.) and their incidence and latency were evaluated. The severity of seizures was expressed as a score on a 5-point scale. Dimethylsulfoxide, an organic solvent, exhibited anticonvulsant action only in doses far exceeding those used for dissolving the two anticonvulsants. Both drugs suppressed minimal as well as major seizures in all age groups studied in a dose-dependent manner, SR 41378 being approximately four times more potent than CM 40907. The latencies could be measured only in animals given low doses of anticonvulsants. CM 40907 did not change the latencies whereas SR 41378 prolonged them. The severity of seizures was decreased again in a dose-dependent manner. There were only minor changes in the efficacy of CM 40907 among the four age groups. On the contrary, SR 41378 exhibited an extreme efficacy in 7-day-old rat pups, where even the 1.25 mg/kg dose significantly decreased the incidence and severity of seizures. The efficacy in the remaining three age groups was approximately at the same level as in adult rats.

Animals↗

PubMed1976

[Role of the striatum in the influence of serotoninergic substances on the course of corazole seizures in rats].

The effect of 5-oxytryptophane (5-OT) and of parachlor-phenylalanine (pCPA) on the behaviouristic EEG manifestations of metrazol convulsions in electrostimulation and destruction of the striatum was studied. The effect of the preparations on the myoclonia and the spike-wave rhythm caused by metrazol did not largely depend on the functional condition of the corpus striatum. The capacity of 5-OT to facilitate, and of pCPA to aggravate the course of generalized convulsions and of the postconvulsive state became enhanced in stimulation and was eliminated after the destruction of the striatum.

5-Hydroxytryptophan↗

PubMed1975

Toxicological and pharmacological investigations of pinazepam (7-chloro-1-propargyl-5-phenyl-3H-1,4-benzodiazepin-2-one): a new psychotherapeutic agent.

The pharmacological and toxicological properties of 7-chloro-1-propargyl-5-phenyl-3H-1,4-benzodiazepin-2-one (pinazepam) were investigated and compared with those of diazepam. In mouse and rat acute toxicity, in rat motor coordination and in rat metrazol convulsion tests pinazepam was compared with oxazepam too. Pinazepam, which is characterized by the presence of a propargylic side chain, showed a lower toxicity, hypnotic activity and muscular-relaxant activity than diazepam. Pinazepam and diazepam showed, however, similar activity in reducing aggressive behaviour in mice, stimulating the exploratory behaviour in rats and in potentiating hexobarbital narcosis. No clear-cut differences were observed in the anticonvulsant properties of the two drugs when tested against metrazol, strychnine and electroshock induced seizures. Pinazepam differs from diazepam for its longer duration of action. The main metabolic product found in the urine of rats and dogs treated with pinazepam was oxazepam.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Intrauterine diazepam exposure: effects on physical and neurobehavioral development in the rat.

Primiparous timed-pregnant Wistar dams were administered a single daily SC injection of diazepam (1.0 or 5.0 mg/kg) or vehicle, over gestation days 14-20. The offspring were assessed on a number of developmental parameters. Pups exposed to the lower dose exhibited a decrease in birth weight and a delay in hair growth. Although these parameters were apparently not affected in the higher dose group, a significant dose-dependent decrease in pup viability was observed, both at birth and at one week of age. No differences were manifested for incisor eruption, pinna uncurling, eye opening, righting, geotaxis, acoustic startle, swimming, or forward locomotion. Rotarod performance was affected in the prenatal DZP animals and body weight at 60 days of age was depressed in the males of the 1.0 mg/kg group. The high dose of diazepam produced an increased susceptibility to minor metrazol-induced seizures in a kindling paradigm, but these altered seizure thresholds were not evidenced in an acute metrazol dose-response study. The NE and DA contents of hypothalamus, brainstem, hippocampus, and cortex of adult brains were assessed in each group. DA was not altered in any brain region while a single significant effect on NE was found. In the 1.0 mg/kg exposed rats only males, but not females, showed higher brainstem levels than controls. These results indicate that in the rat, prenatal exposure to clinically relevant doses of diazepam causes both fetal toxicity and long-term neurobehavioral alterations.

Animals↗

PubMed1981

Behavioural, electroencephalographic and histological study of the protective effect of etomidate against histotoxic dysoxia produced by cyanide.

The acute toxicity of cyanide is largely due to the inhibition of cytochrome oxidase, and the subsequent breakdown of cellular metabolism. Breakdown in cellular metabolism, leading to a disruption of cellular integrity lies at the heart of the permanent neurological damage resulting from ischemic/hypoxic brain insult. In 200 g male Wistar rats treated with 5 mg/kg KCN i.v. and ventilated until spontaneous breathing restarted, the cornea reflex, tail-pinch reaction and righting reflex disappeared for about 20 min. In curarized and artificially ventilated rats the EEG remained flat for a similar period before slowly returning. Saline treated animals which survive the KCN injection die significantly earlier than non-KCN treated animals when injected with 120 mg/kg metrazol s.c. one week later. Histological examination of KCN treated animals revealed swollen mitochondria at 20 min, and microvacuolization and ischemic cell changes at 1 week. In rats pretreated with etomidate 10 mg/kg s.c. 30 min before cyanide the cornea, tail-pinch and righting reflex were absent for the same time as in controls. The EEG was similar to that seen in saline/KCN animals, however, the time to EEG was similar to that seen in saline/KCN animals, however, the time to EEG silence was doubled. One week after the cyanide injection their reaction to the metrazol injection was similar to animals treated one week earlier with saline. Although there was evidence of swollen mitochondria 20 min after KCN, one week after KCN there was no evidence of ischemic hypoxic brain damage. These results demonstrate that under similar conditions of dysoxia, etomidate treated animals appear to be protected from the behavioural and histological sequelae of those conditions.

Animals↗

PubMed1997

Two models of epileptic spike-and-wave rhythm in rats are differently influenced by ethosuximide.

Epileptic afterdischarges induced by electrical stimulation of the sensorimotor cortex as well as minimal metrazol seizures are characterized by EEG spike-and-wave rhythm and nearly the same motor pattern of clonic seizures. The action of ethosuximide on these two models was tested in adult rats with implanted electrodes. Cortical afterdischarges remained practically uninfluenced by ethosuximide (62.5 or 125 mg/kg i.p.) whereas minimal metrazol seizures were suppressed in a dose-dependent manner (doses of 31.25, 62.5 and 125 mg/kg i.p. were used). Present results in connection with recent data on the abolition of spike-and-wave rhythm elicited by low systemic doses of pentylenetetrazol suggest that spike-and-wave rhythm does not represent a single entity.

Animals↗

PubMed1998

Neocortex in the hippocampus: an anatomical and functional study of CA1 heterotopias after prenatal treatment with methylazoxymethanol in rats.

Migration disorders cause neurons to differentiate in an abnormal heterotopic position. Although significant insights have been gained into the etiology of these disorders, very little is known about the anatomy of heterotopias. We have studied heterotopic masses arising in the hippocampal CA1 region after prenatal treatment with methylazoxymethanol (MAM) in rats. Heterotopic cells were phenotypically similar to neocortical supragranular neurons and exhibited the same temporal profile of migration and neurogenesis. However, they did not express molecules characteristic of CA1 neurons such as the limbic-associated membrane protein. Horseradish peroxidase injections in heterotopia demonstrated labeled fibers not only in the neocortex and white matter but also in the CA1 stratum radiatum and stratum lacunosum. To study the pathophysiological consequences of this connectivity, we compared the effects of neocortical and limbic seizures on the expression of Fos protein and on cell death in MAM animals. After metrazol-induced seizures, Fos-positive cells were present in CA1 heterotopias, the only hippocampal region to be activated with the neocortex. By contrast, kainic acid-induced seizures caused a prominent delayed cell death in limbic regions and in CA1 heterotopias. Together, these results suggest that neocortical heterotopias in the CA1 region are integrated in both the hippocampal and neocortical circuitry.

Animals↗

PubMed1999

Synthesis, calcium channel antagonist activity, and anticonvulsant activity of 3-ethyl 5-methyl 1,4-dihydro-2-[(2-hydroxyethoxy) methyl]-6-methyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate coupled to a 1-methyl-1,4-dihydropyridyl-3-carbonyl chemical delivery system.

3-Ethyl 5-methyl 1,4-dihydro-2-[(2-hydroxyethoxy) methyl]-6-methyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (13), a bioisostere of amlodipine, was prepared by the reaction of ethyl 4-(2-hydroxyethoxy)acetoacetate (11) with methyl 2-(2,3-dichlorobenzylidene)acetoacetate (12) and NH4OAc. Compound 13 was elaborated to the target product 3-ethyl 5-methyl 1,4-dihydro-2-[2- [(1-methyl-1,4-dihydropyridyl-3-carbonyloxy)ethoxy]methyl]- 6-methyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (16). The C-2 CH2OCH2CH2OH compound (13, IC50 = 6.56 x 10(-9) M) was about 44-fold more active as a calcium channel antagonist than the reference drug nimodipine (IC50 = 1.49 x 10(-8) M), but 4-fold less potent than felodipine (IC50 = 1.45 x 10(-9) M). Compound 16, possessing the 1-methyl-3-pyridylcarbonyloxy chemical delivery system moiety is a slightly less potent calcium channel antagonist (IC50 = 2.99 x 10(-8) M) than the parent compound 13. Compounds 13, 16, felodipine and nimodipine are highly lipophilic (Kp = 227, 344, 442 and 187, respectively). The C-2 CH2OCH2CH2OH compound (13) exhibited equipotent anticonvulsant activity to nimodipine in the maximal electroshock (MES) anticonvulsant screen. Unlike nimodipine, 13 provided modest protection in the subcutaneous metrazol (scMet) anticonvulsant screen. In contrast, compound 16 was inactive in both the MES and scMet screens.

Animals↗

PubMed1999

Synthesis, physicochemical properties, anticonvulsant activities, and GABA-ergic and voltage-sensitive calcium channel receptor affinities of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid. Part 4: Search for new anticonvulsant compounds.

In a search for new anticonvulsant compounds, two series of N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (series A) and alpha-(2-phenylethylamino)-gamma-hydroxybutyric acid (series B), were investigated in maximal electroshock (MES), subcutaneous metrazole, and rotorod toxicity assays. The most potent anticonvulsant compounds were alpha-(benzylamino)-gamma-hydroxybutyric acid N-benzylamide (3) and N-(2-chlorobenzylamide (4) with median effective (ED50) doses 63.0 mg/kg and 54.0 mg/kg, respectively. alpha-(4-Phenylpiperazinyl)-gamma-hydroxybutyric acid N-(4-methylbenzyl)amide (17) and alpha-(benzylpiperazinyl-gamma-hydroxy-butyric acid N-(4-methylbenzyl)amide (18) were also tested for their ability to potentiate [3H]-muscimol binding and to inhibit [35S]-TBPS binding (as indices of GABA-A receptor potentiation). Amide 17 exhibited activity at the GABA-A complex which may be the mechanism by which the anticonvulsant effect of this compound is mediated. The N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (3-9) were also evaluated for their ability to displace [3H]-nitrendipine from voltage-sensitive calcium channel (VSCC) receptors isolated from rat cortex.

Animals↗

PubMed1990

Steroids in relation to epilepsy and anaesthesia.

Increasing numbers of reports indicate direct effects of ovarian steroids on the central nervous system. Effects of progesterone and its metabolites on brain excitability in humans and in experimental animals have been studied. Anti-epileptic effects have been shown in cats and in women with partial epilepsy and well-defined epileptic foci. The reduced progesterone metabolite 5 alpha-pregnan-3 alpha-ol-20-one and its 5 beta analogue also decreased the epileptic activity resulting from a penicillin-induced cortical focus in cats. 5 alpha-Pregnan-3 alpha-ol-20-one protected mice against metrazol-, bicuculline- and picrotoxin-induced seizures but not against electroshock-and strychnine-induced seizures. Progesterone, 5 alpha-pregnan-3 alpha-ol-20-one and 5 beta-pregnan-3 alpha-ol-20-one also induce anaesthesia in humans and animals; in a rat model of anaesthesia 5 alpha-pregnan-3 alpha-ol-20-one was eight times more potent than methohexitone (the most potent anaesthetic barbiturate). Anaesthesia with loss of the eyelash reflex was observed in humans 75-90 seconds after the intravenous injection of 5 beta-pregnan-3 alpha-ol-20-one in lipid emulsion. The in vivo production and brain distribution of centrally active steroids has also been studied in relation to the phases of the ovarian and menstrual cycle. A subset of women with epilepsy show changes in seizure frequency in relation to hormonal variations during the menstrual cycle. In the luteal phase when progesterone levels are high the number of generalized seizures is low. It is possible that progesterone and its metabolites play a role in epileptic seizures and also in the premenstrual syndrome.

Anesthetics↗

PubMedDate not supplied

Syntheses, calcium channel antagonist and anticonvulsant activities of substituted 1,4-dihydro-3,5-pyridinedicarboxylates containing various 3-alkyl ester substituents.

A group of 3-alkyl 5-isopropyl 4-aryl-1,4-dihydro-2,6-dimethyl- 3,5-pyridinedicarboxylates 10-20 containing an amine, quaternary ammonium, aryl (heteroaryl)alkenyl, 4-(4-fluorophenyl)- piperazin-1-yl or methoxy moiety in the C-3 alkyl ester R-substituent in combination with a C-4 phenyl ring bearing a 2,3-Cl2, 3-NO2, 3-NMe2, 4-NMe2 or 3,4,5-(OMe)3 X-substituent were prepared using the Hantzsch 1,4-dihydropyridine reaction. In vitro calcium channel antagonist activity (CCA) was determined using a guinea pig ileum longitudinal smooth muscle assay. In the C-4 3-nitrophenyl series of compounds, the C-3 ester R-substituent was a determinant of CCA activity where the relative potency order was -CH2CH2CH=C-(2-methylphenyl)2 > or = -CH2CH2NMe2.HCI> -CH2CH2CH=C-(3-methyl-2-thienyl)2 > -CH2CH2+NMe3I -. The position and nature of the C-4 phenyl X-substituent, were also determinants of CCA activity where the relative activity order was 3-NMe2 > 4-NMe2 > 3,4.5-(OMe)3. Anticonvulsant activities were determined in mice using the subcutaneous metrazol (scMet) and maximal electroshock (MES) screens. The compounds investigated were generally not effective for protecting against scMet induced seizures, except for 10 (X = 2,3-Cl2, R = 2-[4-(4- fluorophenyl)piperazin-l-yl]ethyl] and 14a (X = 3-NMe2.HCl, R = CH2CH2OMe), which exhibited modest activity. Compound 11a (X = 3-NO2, R = -CH2CH2NMe2.HCl) was the most effective agent in the MES screen. All of the compounds investigated, except for 11b (X = 3-NO2, R = -CH2CH2+NMe3 I-, Kp = 0.15), are lipophilic with n-octanol/aqueous phosphate buffer (pH = 7.4) partition coefficients (Kp) in the 121-424 range relative to the reference drug nimodipine (Kp = 187). The structure-activity relationships acquired reinforce the concept that calcium is only one of several factors that are involved in seizure generation.

Animals↗