Action Of Sodium Valproate Research Articles

SGLT-2 inhibitors as potential anticonvulsants: empagliflozin, but not dapagliflozin, renders a pronounced effect and potentiates the sodium valproate activity in pentylenetetrazole-induced seizures

On the way to the search for effective adjuvant medicines for epilepsy treatment, antidiabetic medicines such as sodium-glucose cotransporter-2 inhibitors, which are expressed not only in the kidneys but also in the brain, attract attention. From previous studies, it is known that dapagliflozin improves electroencephalographic parameters in rats on the model of pentylenetetrazole-induced seizures. However, the anticonvulsant potential of other medicines from this group needs to be clarified.
 The aim of the study is to estimate the effect of empagliflozin, dapagliflozin per se and their combinations with sodium valproate on pentylenetetrazole-induced seizures, as well as on muscle tone and motor coordination in mice.
 Material and methods. 42 random-bred male albino mice weighing 24-28 g were used in the experiments. Empagliflozin (20 mg/kg) and dapagliflozin (50 mg/kg) were administered intragastrically for 3 days. The classic anticonvulsant sodium valproate (150 mg/kg) per se, in combination with the medicines mentioned above, was administered in a similar regimen. On the second day, 30 minutes after administering all medicines, their effect on muscle tone and coordination of movements was determined in the rotarod test. On the third day, 30 minutes after the last administration of the medicines, their effect on pentylenetetrazole-induced (80 mg/kg subcutaneously) seizures was studied.
 Results. For the first time, a pronounced anticonvulsant effect of empagliflozin was established both when used alone (a significant increase in latency of the convulsions and a decrease in lethality by 43 %) and especially in combination with sodium valproate (a significant increase in latency of the convulsions, a decrease in the number and severity of seizures and a decrease in lethality by 83 %), as well as the absence of a muscle relaxant effect in both cases. Dapagliflozin has neither its anticonvulsant properties nor its effect on the action of sodium valproate. However, this medicine caused muscle relaxation, especially when combined with sodium valproate.
 Conclusions. The results suggest that empagliflozin, unlike dapagliflozin, has a high potential as an adjuvant medicine in treating epilepsy, as it enhances the efficacy of the classic anticonvulsant sodium valproate without muscle relaxant side effects

Safranal carried by nanostructured lipid vehicles inhibits generalized epilepsy in mice.

Safranal, a main component of Crocus sativus, is suggested to have neuroprotective effects. The aim of this study was to investigate the effect of safranal and nanostructured lipid vehicle (NLV) carried safranal in acute and chronic experimental mice models of epilepsy. In PILO acute seizure model, safranal dose-dependently extended latency to generalized seizure, decreased the highest seizure stages and the number of generalized seizures. Moreover, NLV carried safranal further enhanced the anti-seizure effect, which is comparable to the action of sodium valproate. Meanwhile, NLV carried safranal reduced and delayed the electroencephalogram spectra power after pilocarpine injection. In histological aspect, safranal dose-dependently reduced the loss of neurons induced by seizure and NLV system further improved this protection at the same dose. In MES acute model, safranal markedly increased the electroconvulsive threshold, where NLV further improved its effect. In PTZ chronic seizure model, NLV carried safranal significantly delayed the kindling rate of progress and the time it took to reach generalized seizures as compared to NLV control group. In conclusion, this study indicates that safranal inhibits generalized seizure in acute and chronic epilepsy models in mice and NLV can enhance this effect. So, NLV carried safranal may have potential value in treatment of generalized epilepsy.

Parachlorophenylalanine-induced 5-HT depletion alters behavioral and brain neurotransmitters levels in 6-Hz psychomotor seizure model in mice.

The present study was designed to investigate the role of serotonin and other neurotransmitters namely dopamine (DA), histamine, nor-epinephrine (NE), glutamate, and γ-aminobutyric acid (GABA) in the 6-Hz-induced psychomotor seizures in Swiss albino mice. Parachlorophenylalanine (PCPA, 300 mg/kg/day, i.p for 3 days)-treated mice were given 6-Hz stimulation. Sodium valproate (SVP) (200 mg/kg/day, p.o for 3 days) was used as a reference antiepileptic drug. The behavioral changes induced by 6 Hz including increased rearing and grooming, Straub's tail, behavioral arrest, stun position were amplified by PCPA. The 6-Hz-induced seizures were accompanied by reduced brain 5-HT, DA, NE, histamine, GABA, and enhanced glutamate levels. PCPA facilitated further reduction of endogenous 5-HT and DA levels but not NE, histamine, GABA, and glutamate levels. Pre- and post-treatment with SVP protected the mice from 6-Hz seizures and attenuated PCPA-induced changes in the levels of 5-HT and DA in the mice brain suggesting the protective effect of SVP in the pharmacoresistant model of epilepsy involving mainly serotonergic mechanism. However, the study also suggests modulation of other neurotransmitters both in 6-Hz psychomotor seizures and in the action of SVP against such seizures.

Evaluation of the effect of volatile oil extract of Nigella sativa seeds on maximal electroshock-induced seizures in albino rats

Background: Epilepsy is one of the most common serious neurological disorders, responsible for substantial morbidity and mortality due to the seizures and the available medications. Natural products from folk remedies have contributed significantly in the discovery of modern drugs with novel structures and better safety and efficacy profiles. In this regard, one such plant is Nigella sativa. Aims and Objectives: (i) To evaluate the anticonvulsant activity of volatile oil extract of N. sativa seeds by maximal electroshock (MES)-induced seizure model of epilepsy in albino rats; (ii) To evaluate the influence of volatile oil extract of N. sativa seeds on the anticonvulsant activity of sodium valproate in albino rats. Materials and Methods: Male Albino rats (150-200 g) were randomly selected, from Central Animal Facility, Mysore Medical College and Research Institute, Mysore. The anticonvulsant activity was screened using MES-induced seizure model. Albino rats were divided into six groups of six rats each. Six groups were treated with gum acacia 0.5 ml (control group), sodium valproate 300 mg/kg (standard group), Groups 3, 4, and 5 were administered the test drug, volatile oil extract of N. sativa seeds at doses of 200, 400, and 600 mg/kg, respectively, and Group 6 was treated with the combination of test drug, volatile oil extract of N. sativa seeds 200 mg/kg and sodium valproate 150 mg/kg. All the drugs were dissolved in gum acacia and administered intraperitoneally 30 min prior to induction of seizures. Results: The volatile oil extract of N. sativa seeds showed the anticonvulsant activity in electroshock-induced seizure model at the dose of 400 and 600 mg/kg body weight and the potentiation of anticonvulsant activity of sodium valproate. The anticonvulsant activity of volatile oil of N. sativa seeds was less when compared to sodium valproate. Conclusions: The N. sativa seeds showed the anticonvulsant activity in MES-induced seizure model of epilepsy. This study showed that volatile oil of N. sativa seeds potentiated the effect of sodium valproate.

Stimulation of Gastric Mucosal Afferents with Mesaton Potentiates the Anticonvulsant and Eliminates the Sedative Actions of Sodium Valproate in Rats with Corasol Kindling

Chronic oral sodium valproate given at high doses (100–200 mg/kg) suppressed the development of generalized clonic-tonic corasol (pentylenetetrazole) kindled convulsions in 100% of rats but prevented local clonic kindled convulsions in only 33–57%. At these doses, sodium valproate induced strong sedation. Combined chronic oral administration of Mesaton at the threshold dose of 0.2 mg/kg, inactive when give alone, and sodium valproate at the high doses of 100 and 200 mg/kg potentiated the anticonvulsant action of sodium valproate and prevented not only clonic-tonic kindled convulsions in 100% of rats, but also clonic kindled convulsions in 86–100% of rats, and also increased the anticonvulsant activity of valproate by factors of 1.7–1.9. These combinations of sodium valproate with Mesaton did not induce any sedative side effect. The mechanism of potentiation of the anticonvulsant effect and elimination of the sedative side effect of high-dose sodium valproate is based on stimulation of gastric mucosal afferents by Mesaton.

Dose-finding study with nicotine as a proconvulsant agent in PTZ-induced seizure model in mice

The present study was conducted to investigate the possible interaction between low doses of nicotine and pentylenetetrazole (PTZ) in vivo and also to evaluate the influence of nicotine on the antiseizure efficacy of topiramate and sodium valproate in the PTZ-induced seizure model in mice. Graded dose-response study with nicotine showed the CD50 value for nicotine at 6.76 mg/kg. i.p. Subtheshold dose of nicotine (4 mg/kg, i.p.) pretreatment significantly decreased the CD50 value for PTZ from 47.86 mg/kg, i.p. (of PTZ per se) to 31.62 mg/kg, i.p. Sodium valproate but not topiramate, significantly inhibited PTZ-induced seizures in mice with an ED50 value of 177.83 mg/kg, i.p. Nonconvulsive dose of nicotine (1 mg/kg, i.p.) significantly antagonized the protective efficacy of sodium valproate against PTZ-induced seizures and increased the ED50 value to 338.84 mg/kg, i.p. PTZ-induced seizures significantly increased the mouse brain levels of MDA and reduced the level of GSH while sodium valproate reversed such changes. Nicotine pretreatment reversed the anti-lipid peroxidative action of sodium valproate in the PTZ-induced seizure model in mice. The study highlighted the convulsant as well as proconvulsant role of nicotine and established dose discrimination for nicotine as a proconvulsant agent and an anti-antiseizure agent. The study bears significant clinical relevance particularly amongst epileptic smokers who may show failure of efficacy of antiepileptic agents and present with breakthrough seizure attacks on exposure to nicotine.

Anticonvulsive activity of sodium valproate and some calcium antagonists used in combination in mice

Anticonvulsive activity of sodium valproate and some calcium antagonists used in combination in mice

Blockade of "antiabsence" activity of sodium valproate by THIP in rats with petit mal-like seizures. Comparison with ethosuximide.

Wistar rats from our laboratory spontaneously present frequent epileptic seizures whose clinical semeiology, EEG signs and pharmacological reactivity resemble absence seizures in humans. In these rats, GABAmimetics such as THIP enhance the duration of seizures in a dose-dependent fashion. In contrast to the action of these drugs, valproate sodium (VPA), which potentiates GABAergic transmission, abolishes the seizures. VPA injected in association with THIP completely loses its therapeutic effects; moreover, VPA potentiates the aggravating effects of THIP. Ethosuximide which does not interact with GABA, was still effective when given in association with THIP. These findings raise questions as to 1. the role of GABAergic neurotransmission in the occurrence of spontaneous petit-mal-like seizures in the rat, and 2. the mode of action of antiepileptics against these seizures.