Impact of cyclic nucleotides on the antiseizure activity of acute and chronic diazepam administration in isoniazid-induced seizures and pentylenetetrazole kindling in rats

Abstract

BackgroundIt is estimated that ~10% of the population suffers a single convulsive episode during their lifetime. Epilepsy is the second most common chronic neurological disorder after stroke, affecting ~0.5% of the population in developed countries and 1.5-2% in developing countries. Diazepam (DZ) is among the benzodiazepines used most widely in status epilepticus as well as resistant and refractory seizures. However, tolerance to its antiseizure activity is among the obstacles facing it use on a wider basis. Exploration of the role of cyclic nucleotides in seizures might enable finding ways to combat tolerance as well as discover new treatment modalities.Materials and methodsSeizure severity, electroencephalography, and levels of γ-aminobutyric acid (GABA), glutamate, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) in brain homogenate were assessed upon single administration of isoniazid and repeated pentylenetetrazole injections, whether untreated or treated with DZ, either acutely or on a chronic basis, respectively.ResultsA single DZ injection, 10 min after single isoniazid, could significantly improve seizure severity, associated with increased power of the fast β wave, implying ameliorated cognitive functions, together with an equal GABA/glutamate ratio versus significant reduction in the cAMP/cGMP ratio. Repeated DZ injections, 10 min after each pentylenetetrazole injection, on alternate days for 1 month and every 2 days for another month produced a significant improvement in seizure severity, accompanied by reduced power of the fast β and the slow δ waves, associated with an increased GABA/glutamate ratio and an unchanged cAMP/cGMP ratio.ConclusionThe current study assumes that a certain interplay exists between GABA/glutamate on the one hand and cAMP/cGMP on the other so that DZ could exert an anticonvulsant effect on an acute basis despite an unchanged GABA/glutamate ratio as well as upon chronic administration in the presence of an unchanged cAMP/cGMP ratio. In addition, the unchanged cAMP/cGMP ratio associated with chronic DZ administration suggests that cyclic nucleotides might lead to loss of some of the effects of DZ, as shown by reduced β wave power, indicating a reduction in cognitive abilities, concentration, and learning abilities, in contrast to higher β power after single use.