Influence of nebivolol on anticonvulsant effect of lamotrigine.

OBJECTIVE: The present study describes the effect of nebivolol (NBV) either alone or in combination with lamotrigine (LTG) using increasing current electroshock seizures (ICES) model in mice. MATERIALS AND METHODS: Male albino mice of Swiss strain each weighing 18-30 g were used. Lamotrigine (Lamitor tablets, Torrent; 1.5 and 3.0 mg/kg) and NBV (Nebicard tablets, Torrent; 0.25 and 0.5 mg/kg) were suspended in 0.25% of carboxy methyl cellulose (CMC) in 0.9% saline and administered orally in volumes of 10 mg/kg. Control animals received an equivalent volume of 0.25% CMC in 0.9% saline suspension. The anticonvulsant effects of the drugs were measured using ICES model whereas cognitive behavior was measured by the spontaneous alternation behavior and grip-strength test. The biochemical estimation was done by measuring the lipid peroxidation and reduced glutathione (GSH). RESULTS: Both NBV and LTG produced significantly enhanced seizure threshold (ST), decreased grip strength, inhibited lipid peroxidation, and increased brain GSH levels in acute and chronic dosages likened to control group, whereas there was no significant effect on alternation scores. The combination of NBV with LTG significantly potentiated the ST when compared to LTG. CONCLUSION: Nebivolol showed antiepileptic effects in addition to its reported antihypertensive effect, which could be attributed to action of the two drugs through different mechanisms or due to drug interaction that may be pharmacodynamic or pharmacokinetic needing elucidation.

Seizures, antiepileptics, antioxidants and oxidative stress: an insight for researchers.

BACKGROUND: Neuronal hyperexcitability and excessive production of free radicals have been implicated in the pathogenesis of a considerable range of neurological disorders, including epilepsy. The high rate of oxidative metabolism, coupled with the low antioxidant defenses and the richness in polyunsaturated fatty acids, makes the brain highly vulnerable to free radical damage. The increased susceptibility of the brain to oxidative damage highlights the importance of understanding the role of oxidative stress in the pathophysiology of seizures. OBJECTIVES: The present review aims not only to address the link between mitochondrial dysfunction, oxidative stress and seizures, but also the modulation of the pro-oxidant/antioxidant balance following seizures and treatment with antioxidants and antiepileptic drugs. METHODS: A literature review revealed that there are articles that address the role of oxidative stress and mitochondrial dysfunction in neurological disorders, including those involving different seizure models where the modulation of the pro-oxidant/antioxidant balance by seizures per se and by antioxidant agents is discussed. However, the critical role of oxidative stress in all seizure models is not uniform. Therefore, there is a need for a review article that will address all these issues together. RESULTS/CONCLUSIONS: The experimental and clinical data suggest a putative role of oxidative stress in the pathophysiology of certain seizure types. The pro-oxidant/antioxidant balance is not only modulated by seizures per se, but also by antiepileptic drugs. The ability of antioxidants for reducing the seizure manifestations and the accompanying biochemical changes (i.e., markers of oxidative stress) further supports a role of free radicals in seizures and highlights a possible role of antioxidants as adjuncts to antiepileptic drugs for better seizure control.

On the mechanism of anticonvulsant effect of tramadol in mice.

The present study was conducted to examine the effects of tramadol, an atypical opioid on convulsive behaviour in maximal electroshock (MES) seizure test on mice. Moreover, an attempt was also made to investigate the role of possible receptor mechanisms involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 sec). Seizure severity was determined by (1) the duration of tonic hindlimb extensor (THE) phase and by (2) mortality due to electroconvulsions. Intraperitoneal (i.p.) administration of tramadol dose-dependently (10-50 mg/kg) decreased the duration of THE phase of MES. The anticonvulsant effect of tramadol was antagonized by the opioid antagonists, naloxone in high dose, and MR2266, a selective kappa antagonist but not by naltrindole, a delta opioid antagonist. Coadministration of either gamma-aminobutyric acid (GABA)-ergic drugs (diazepam, GABA, muscimol and baclofen) or N-methyl-D-aspartate (NMDA) receptor antagonist, MK801 with tramadol augmented the anticonvulsant effect of the latter drug. By contrast, flumazenil, a central benzodiazepine (BZD) receptor antagonist, counteracted the diazepam-induced facilitation of anti-MES effect of tramadol. Similarly, delta-aminovaleric acid (DAVA), a GABAB receptor antagonist, abolished the facilitatory effect of baclofen, a GABAB agonist on anti-MES action of tramadol. These BZD-GABAergic antagonists, flumazenil or DAVA, on their own also antagonized the anti-MES effect of tramadol administered alone. No significant effect on mortality was observed in any of the studied groups. Taken together, the current results have demonstrated a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), GABAA-BZD receptors system, GABAB receptors and NMDA channel involvement in the antielectroshock effect of tramadol in mice.

Studies on the anticonvulsant effect of U50488H on maximal electroshock seizure in mice.

The present study was designed to investigate the effect of U50488H, a prototype non-peptide kappa opioid agonist on convulsive behaviour using a maximal electroshock (MES) seizure test in mice. An attempt was also made to explore the role of possible receptors involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 s). Seizure severity was evaluated by means of two parameters, i.e., (1). duration of tonic hindlimb extensor phase and (2). mortality due to convulsions. Intraperitoneal (i.p.) administration of U50488H dose dependently (5-20 mg/kg) decreased the hindlimb extensor phase of MES. The anticonvulsant effect of U50488H was attenuated by the general opioid antagonist, naloxone at a high dose, and by MR2266, a selective kappa antagonist, but not by naltrindole, a delta antagonist. Coadministration of gamma-aminobutyric acid (GABA)ergic drugs (diazepam, GABA, muscimol, and baclofen) and the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with U50488H augmented the anticonvulsant effect of the latter drug in mice. On the other hand, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the protective effect of diazepam and similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, blocked the protective effect of baclofen, a GABA(B) agonist on the anti-MES action of U50488H. These BZD-GABAergic antagonists, namely, flumazenil or DAVA, on their own also counteracted the anti-electroshock seizure effect of U50488H given alone. However, mortality was not significantly altered in any of the above animal groups. Taken together, the findings have shown a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), NMDA channel, GABA(A)-BZD-chloride channel complex, and GABA(B) receptors in the anticonvulsant action of U50488H.

Possible mechanism involved in the anticonvulsant action of butorphanol in mice.

The study was designed to examine the effect of butorphanol, a classical opioid on convulsive behaviour using maximal electroshock (MES) test. An attempt was also made to investigate the role of possible receptor mechanisms involved. MES seizures were induced in mice via transauricular electrodes (60 mA, 0.2 s). Seizure severity was assessed by the duration of tonic hindlimb extensor phase and mortality due to convulsions. Intraperitoneal administration of butorphanol produced a dose-dependent (0.25-2 mg/kg) protection against hindlimb extensor phase. The anticonvulsant effect of butorphanol was antagonized by all the three opioid receptor antagonists (i.e., naloxone [mu], MR2266 [kappa], and naltrindole [delta], respectively). Coadministration of gamma-aminobutyric acid (GABA)-ergic drugs (diazepam, GABA, muscimol, and baclofen) and N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with butorphanol augmented the anticonvulsant action of the latter drug. In contrast, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the facilitatory effect of diazepam on the anti-MES effect of butorphanol. Similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, antagonized the facilitatory effect of baclofen, a GABA(B) agonist on anti-MES action of butorphanol. These BZD-GABAergic antagonists, flumazenil or DAVA, per se also counteracted the anti-MES effect of butorphanol given alone. These data exemplify the benefits of using the MES test, which is sensitive to opioidergic compounds and distinguished convulsive behavioural changes associated with GABAergic and NMDAergic effects. Taken together, the results implicate a role for multitude of neurotransmitter systems, i.e., opioid (mu, kappa, delta), NMDA channel, BZD-GABA(A) chloride channel complex, and GABA(B) receptors in the anti-MES action of butorphanol.