Nefopam enhances the protective activity of antiepileptics against maximal electroshock-induced convulsions in mice.

Nefopam is a centrally acting non-opioid analgesic with a mechanism of action that is not completely understood. Adverse effects associated with the therapeutic use and overdose of nefopam are mainly associated with the central nervous system, such as hallucinations, cerebral edema and convulsions. The aim of this study was to assess the effect of nefopam on the electrical threshold and its influence on the protective activity of antiepileptic drugs in the maximal electroshock test in mice. A 5 mg/kg dose of nefopam significantly elevated the electric seizure threshold, while a dose of 1 mg/kg failed to protect mice against electroconvulsion. At a subthreshold dose of 1 mg/kg, nefopam significantly enhanced the anticonvulsant activity of valproate against electroconvulsions. The protective activity of phenobarbital and phenytoin was significantly enhanced by co-administration of nefopam at the 5 mg/kg dose, but this same dose of nefopam failed to affect the protective activity of carbamazepine. In conclusion, nefopam exerts an anticonvulsive effect when given alone and significantly enhances the protective activity of certain antiepileptic agents against electroconvulsions induced in mice.

Influence of orphenadrine upon the protective activity of various antiepileptics in the maximal electroshock-induced convulsions in mice.

Orphenadrine is an anticholinergic drug used in the treatment of Parkinson's disease, and is also known to exert nonspecific antagonistic activity at the phencyclidine binding site of the N-methyl-D-aspartate (NMDA) receptor. The aim of this study was to assess the anticonvulsant properties of orphenadrine and to evaluate its effect on the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced seizures in mice. Orphenadrine given at a dose of 5.65 mg/kg elevated the electrical seizure threshold from 5.7 (5.4-6.1) to 6.8 (6.3-7.3) mA, while a dose of 2.8 mg/kg was ineffective. The ED(50) values of orphenadrine administered 10, 30 and 120 min before maximal electroshock-induced convulsions were 16.8 (11.3-25.1), 17.8 (15.7-20.0) and 25.6 (23.3-28.3) mg/kg, respectively. Orphenadrine at a sub-threshold dose of 2.8 mg/kg significantly enhanced the anticonvulsant activity of valproate by reducing its ED(50) value from 315.8 (270.0-369.4) to 245.9 (207.1-292.0) mg/kg without affecting the free plasma levels of valproate. However, orphenadrine failed to enhance the protective activity of carbamazepine, phenytoin, phenobarbital, lamotrigine, topiramate, or oxcarbazepine against maximal electroshock-induced seizures.

Influence of NG-nitro-L-arginine on the anticonvulsant and acute adverse effects of some newer antiepileptic drugs in the maximal electroshock-induced seizures and chimney test in mice.

Overwhelming evidence indicates that nitric oxide (NO) plays an important role in epileptogenesis and seizure activity in the brain. The results of experimental studies on animals provide, however, discrepant information reporting that NO has both anti- and pro-convulsant action in the brain. The objective of this study was to determine the effect of N(G)-nitro-L-arginine (L-NA--a non-specific NO synthase inhibitor) on the anticonvulsant and acute adverse-effect profiles of four second-generation antiepileptic drugs (felbamate [FBM], lamotrigine [LTG], oxcarbazepine [OXC] and topiramate [TPM]) in the maximal electroshock (MES)-induced seizure model and the chimney test in mice. Results indicated that L-NA(at 40 mg/kg, ip) did not affect significantly the antiseizure activity of all examined drugs. However, the antielectroshock action of FBM and LTG after co-administration of L-NA was attenuated by 36% and 28%. In contrast, the anticonvulsant effects of TPM and OXC were almost unchanged after L-NA administration. Moreover, the NO synthase inhibitor (40 mg/kg, ip) did not enhance the acute adverse-effect profiles of the studied antiepileptic drugs in the chimney test. In conclusion, the observed reduction of the anticonvulsant effects of FBM and LTG after co-administration of L-NA may suggest a pro-convulsant activity of L-NA and the cooperation of NO with the antiseizure properties of FBM and LTG in the MES test in mice.

[Neuroprotective activity of antiepileptic drugs]. / Neuroprotekcyjne dzialanie leków przeciwpadaczkowych.

Clinical and experimental data indicate that epilepsy may lead to neuronal death and lesions placed in diverse brain regions. Also, the anticonvulsant activity of some antiepileptic drugs can be impaired in case of neurodegeneration in the brain. The main aim of this review is making a reader familiar with a patomechanism of neurodegeneration as well as the current data concerning the neuro-protective potential of antiepileptic drugs. It is noteworthy that a great number of papers devoted to this problem concern animal models of neurodegeneration produced by either seizure activity or ischemia. Interestingly, there are apparent differences in the direct central effects of antiepileptic drugs in adult and young animals. Majority of antiepileptics at anticonvulsant doses produce massive apoptosis in brains of young rodents, this effect being not present in adult animals. Only topiramate required higher than anticonvulsant doses to induce apoptotic response. Neuroprotective activity in models of ischemia and epilepsy was evident for benzodiazepines (diazepam), lamotrigine, tiagabine, topiramate, and vigabatrin. Recently, topiramate has been documented to exert potent neuroprotective action in human oligodendrocytes exposed to hypoxic-ischemic damage.