Atorvastatin prevents development of kindling by modulating hippocampal levels of dopamine, glutamate, and GABA in mice.

Atorvastatin (ATV) is widely used for the treatment of dyslipidemias. Recent evidence has shown that ATV has protection effects against seizures. However, the effect of ATV on certain neurotransmitter and oxidative stress markers associated with seizures had not been reported. Therefore, the present study aimed to evaluate the effects of ATV on oxidative stress markers on whole brain and GABA, glutamate, and dopamine levels in the hippocampus of PTZ-kindled mice. Additionally, effects of ATV on animal models of seizures, anxiety, and depression were also assessed. Swiss albino mice were given ATV (20, 40, and 80mg/kg/p.o.) in an acute study. On the seventh day, animals were subjected to various neurological and neurobehavioral tests, viz, increasing current electroshock (ICES) test, pentylenetetrazole (PTZ)-induced seizures, Elevated Plus Maze (EPM), and Forced Swim Test (FST). For the development of kindling, a subconvulsant dose of PTZ, i.e., 25mg/kg, i.p., was administered every other day, and ATV in all the three doses was administered daily. Seizure score was continuously monitored until the development of kindling. Thiobarbituric acid reacting species (TBARS), glutathione, dopamine, GABA, and glutamate levels were also assessed in the brain tissues of mice. The results showed that in the ICES test, ATV 80mg/kg increased the seizure threshold to hind limb extension (HLE), and a complete protection against HLE was observed when ATV 80mg/kg was combined with a subanticonvulsant dose of phenytoin. Atorvastatin in all the tested doses suppressed the development of kindling, reduced lipid peroxidation, and increased glutathione levels. All doses of ATV maintained the normal levels of glutamate, GABA, and dopamine in kindled mice. Atorvastatin possesses anticonvulsant activity against electroconvulsions. It was found to suppress the development of PTZ kindling, presumably altering the redox status and hippocampal levels of dopamine, glutamate, and GABA.

Sehar N ，Agarwal NB ，Vohora D ，Raisuddin S ... -  《-》

Resveratrol suppressed seizures by attenuating IL-1β, IL1-Ra, IL-6, and TNF-α in the hippocampus and cortex of kindled mice.

Hoda U ，Agarwal NB ，Vohora D ，Parvez S ，Raisuddin S ... -  《-》

Anticonvulsant activity of an active fraction extracted from Crinum jagus L. (Amaryllidaceae), and its possible effects on fully kindled seizures, depression-like behaviour and oxidative stress in experimental rodent models.

The leaf extract of Crinum jagus L. (Amaryllidaceae) is widely used in traditional Cameroonian medicine as antiepileptic remedy and for the treatment of convulsion, depression and mood disorders associated with epilepsy. Hence, this study was conducted to evaluate the effects of an active fraction extracted from the leaves of Crinum jagus against seizures, depression-like behaviour and oxidative stress in pentylenetetrazole (PTZ)-induced kindling in mice. Bioactive-guided fractionation of the leaf extract of Crinum jagus by using 70mg/kg PTZ-induced convulsions in mice, afforded a potent anticonvulsant fraction (flavonol kaempferol; C4.4). The effects of C4.4 on 30mg/kg PTZ-induced kindling, kindling-induced depression like-behaviour and oxidative stress was evaluated. Mice were injected PTZ (30mg/kg, i.p.) once every alternate day (48±1h) until the development of kindling. Depression was assessed using tail suspension test and forced swim test while the oxidative stress parameters were estimated in the whole brain at the end of experiments. Mice were submitted to the rota-rod task and open-field test in order to assess any non-specific muscle-relaxant or sedative effects of C4.4. Acute toxicity of C4.4 was also assessed in mice. Convulsions-induced by 70mg/kg PTZ were strongly antagonized by C4.4. Oral administration of C4.4 significantly increased the latency to myoclonic jerks, clonic seizures as well as generalized tonic-clonic seizures, improved the seizure mean stage and decreased the number of myoclonic jerks in PTZ-kindled mice. The data indicated also that C4.4 significantly reduced the immobility times in the tail suspension test and the forced swim test. This active fraction has also antioxidant properties by decreasing the lipid peroxidation, and augmenting endogenous antioxidant enzymes in brain. C4.4 administered (12.5-50mg/kg) did not alter the locomotion of animals in the open-field or rotarod tests, which suggest a lack of a central depressant effect. The animals did not exhibit any acute toxicity to C4.4 at the therapeutic doses. These results suggest that pretreatment with C4.4 ameliorates convulsions-induced by PTZ, protects mice against kindling development, depression-like behaviour and oxidative stress in PTZ-kindled mice. These finding provides scientific rationale for the use of Crinum jagus extracts for the amelioration of epilepsy observed in traditional medicine in Cameroon.

Taiwe GS ，Tchoya TB ，Menanga JR ，Dabole B ，De Waard M ... -  《-》

Embelin ameliorates cognitive dysfunction and progression of kindling in pentylenetetrazol-induced kindling in mice by attenuating brain inflammation.

This study was conducted to evaluate the effect of embelin (EMB) on various epileptic models and related brain inflammation. Male Swiss albino mice were administered EMB (5, 10, and 20 mg/kg/p.o.) in acute and chronic study for 7 days and 35 days, respectively. Acute study included increasing current electroshock (ICES) and pentylenetetrazol (PTZ)-induced seizure test. Step-down latency (SDL) and forced swim test (FST) were performed to evaluate cognitive functions and depression-like behavior, respectively. Chronic study included PTZ-induced kindling. Levels of inflammatory biomarkers, namely interleukin-1 beta (IL-1β), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), were estimated in the hippocampus and cortex of the kindled brains by ELISA technique. Further, neurotransmitters (NTs), namely gamma aminobutyric acid (GABA), glutamate, and dopamine, were estimated by using validated liquid chromatography-mass spectrometry (LC-MS) method followed by ultra-high-performance liquid chromatography (UHPLC). Embelin (EMB) treatment increased the seizure threshold to hind limb extension (HLE) in the ICES test and decreased the seizure scores in the kindling experiment. Significantly low levels of IL-1β, IL-1Ra, IL-6, and TNF-α were observed in the hippocampus of PTZ + EMB (10 and 20 mg/kg)-treated groups compared with PTZ+ vehicle-treated group. Significantly lower levels of IL-1Ra, IL-6, and TNF-α compared with PTZ+ vehicle-treated group were observed in the cortex of PTZ + EMB (10 and 20 mg/kg)-treated groups, while IL-1β levels were found to be significantly lower only in the cortex of PTZ + EMB (20 mg/kg)-treated group. Increased levels of dopamine and GABA and decreased levels of glutamate in both hippocampus and cortex were observed in EMB + PTZ-treated groups compared with vehicle + PTZ-treated group. Latency of step down was found to be increased and immobility time in FST was decreased in EMB + PTZ groups compared with vehicle + PTZ group. Embelin suppressed epileptogenesis in the kindled mice via neurochemical modulation of neurotransmitters and inhibiting the inflammatory pathway. Further, EMB was also observed to be protecting the kindled animals from cognition and depression-like behavior.

Hoda U ，Jain S ，Samim M ，Jain GK ，Agarwal NB ... -  《-》

Pergularia daemia hydro-ethanolic extract protects against pentylenetetrazole kindling-induced seizures, oxidative stress, and neuroinflammation in mice.

Current antiepileptic drugs fail to control approximately 30% of epilepsies. Therefore, there is a need to develop more effective antiepileptic drugs, and medicinal plants provide an attractive source for new compounds. Pergularia daemia (Asclepiadaceae) is used in Cameroon traditional medicine to treat stroke, anemia, inflammation, and epilepsy. Recently, traditional healers claim that an hydro-ethanolic extract of the roots of P. daemia is more effective than an aqueous extract on refractory seizures. The antiepileptic effect of P. daemia hydro-ethanolic extract was investigated on the pentylenetetrazole kindling model of temporal lobe epilepsy in mice and possible mechanisms of action. Mice were divided into 8 groups treated as follows: normal group received distilled water (10 ml/kg, p.o.), control group received distilled water (10 ml/kg, p.o.), ethanol group received ethanol (5%, p.o.), positive control received sodium valproate (300 mg/kg, p.o.), and test groups received P. daemia hydro-ethanolic (HE) extract (1.6, 4, 8 and 16 mg/kg, p.o.). All groups were kindled by 11 injections of pentylenetetrazole (PTZ) (35 mg/kg, i.p.), once every alternate day (48 ± 2 h), until the development of kindling, i.e., the occurrence of stage 5 seizures for two consecutive trials. One week later, i.e., 29th day, mice were challenged with a single and lower dose of PTZ (25 mg/kg, i.p.) that does not induce seizures in normal mice but causes seizures in mice prone to seizures and behavioral alterations. After completion of the kindling procedure, Morris water maze, passive avoidance, and open field tests were performed. Afterward, animals were euthanized, and hippocampi were removed for the estimation of the levels of GABA-transaminase (GABA-T), L-glutamate decarboxylase (L-GAD), and γ-aminobutyric acid (GABA). Oxidative stress and neuroinflammation markers also were quantified. Finally, histological analysis of the hippocampus was carried out. PTZ-kindling induced myoclonic jerks and generalized tonic-clonic seizures in control mice. However, the HE extract of P. daemia (4-16 mg/kg), compared to sodium valproate, significantly protected mice against myoclonic jerks and generalized tonic-clonic seizures. Also, the HE extract (1.6-16 mg/kg) significantly increased the seizure score. Furthermore, the HE extract of P. daemia significantly reduced seizure-induced cognitive impairments. PTZ-kindling induced significant alterations in GABA, GABA-T, and L-GAD contents as well as oxidative stress, and neuroinflammation, and the HE extract significantly reversed these effects, suggesting possible mechanisms. All these activities of the HE extract were confirmed by its protective effect against neuronal loss in the hippocampus. The HE extract of P. daemia protected mice against kindled seizures and cognitive impairments, and these effects were greater than those of sodium valproate, a widely used antiepileptic drug. These effects may be mediated by neuromodulatory, anti-oxidant, and anti-inflammatory activities, thus suggesting a neuroprotective effect. These findings help to explain the beneficial use of these HE extracts of P.daemia in traditional medicine to treat epilepsy in Cameroon.

Kavaye Kandeda A ，Okomolo Moto FC ，Mbomo Ayissi RE ，Omam Omam JP ，Ojong L ，Ngo Bum E ... -  《-》