How Rolipram, as a Phosphodiesterase-4 Inhibitor, Affects Acute Isoniazid-Induced Seizures and Pentylenetetrazole Kindling in Rats

Background: It is estimated that 10% of the population suffer 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. Aim: The target of this investigation was to find out the effect of phosphodiesterase-4 inhibitor (PDE4I), rolipram (Rol), on the isoniazid (INH)-induced seizures and the pentylenetetrazole (PTZ) kindled rats, in comparison to the benzodiazepine (BZ) agonist, diazepam (DZ). Methods: Acute seizures were produced by intraperitoneal (i.p.) administration of INH, 250 mg/kg, either alone or 10 minutes before either i.p. 10mg/kg DZ, or i.p. 0.5mg/kg Rol. Kindling model was produced by repeated i.p. administration of 30mg/kg PTZ, every other day, for one month and every two days for another month, either alone or followed, ten minutes later, by i.p. 10mg/kg DZ or 0.5mg/kg Rol. Following drug(s) administration, seizure severity score, electroencephalography, biochemical measurement of gamma-aminobutyric acid (GABA), glutamate, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in brain homogenate were done. Results: In the acute INH-induced seizures, single i.p. 0.5 mg/kg Rol effects were opposite to DZ. These included unchanged seizure severity, significantly reduced power of the fast waves (ß and a), significantly increased brain GABA/glutamate ratio, together with no significant change in cAMP/cGMP ratio. While in kindled rats, i.p. 0.5mg/kg Rol administration on chronic basis, showed similar effects, but less than DZ, in the form of significantly improved seizure severity score, accompanied by reduced power of S wave with unchanged a and 0 waves, significantly increased GABA/ glutamate ratio, together with unchanged cAMP/cGMP ratio. Conclusion: Based on this preclinical study, caution with the use of rolipram in case of INH-induced seizures. In contrast to this preliminary warning, rolipram might be able, on chronic basis, to aid in the management of epilepsy, though less than DZ. These changes did not correspond to cyclic nucleotides changes.