Anxiolytic-like effect of etazolate, a type 4 phosphodiesterase inhibitor in experimental models of anxiety.

Etazolate is a selective inhibitor of type 4 phosphodiesterase (PDE4) class enzyme. Antidepressant-like effect of etazolate has been previously demonstrated in the rodent models of depression. The present study was designed to investigate the anxiolytic-like activity of etazolate in experimental mouse models of anxiety. The putative anxiolytic effect of etazolate (0.25-1 mg/kg, ip) was studied in mice by using a battery of behavioural tests of anxiety such as elevated plus maze (EPM), light/dark (L/D) aversion, hole board (HB) and open field (OFT) with diazepam (2 mg/kg, ip) as reference anxiolytic. Like diazepam (2 mg/kg, ip), etazolate (0.5 and 1 mg/kg, ip) significantly increased the percentage of both time spent and entries into open arms in the EPM test. In the L/D test etazolate (0.5 and 1 mg/kg, ip) increased the both total time spent in and latency time to leave the light compartment. Etazolate (0.5 and 1 mg/kg, ip) also significantly increased head dipping scores and time spent in head dipping, whereas significantly decreased the head dipping latency in HB test. In addition, etazolate (0.5 and 1 mg/kg, ip) significantly increased the ambulation scores (square crossed) and number of rearing in OFT. In conclusion, these findings indicated that etazolate exhibited an anxiolytic-like effect in experimental models of anxiety and may be considered an alternative approach for the management of anxiety disorder.

Investigation of seizure activity after cyclic nucleotide phosphodiesterase inhibition with second messenger and calcium ion channel inhibition in mice.

The role of PDE-4 inhibitor etazolate, was evaluated in the presence of PDE-7 inhibitor, BRL-50481, in animal models of epilepsy. Seizures were induced in the animals by subjecting them to injection of chemical convulsants, Pilocarpine, Kainic acid (KA) and maximal electroshock (MES). The combination of etazolate and BRL50481 treated mice showed a significant (P<0.001) quick onset of action, jerky movements and convulsion when compared to gabapentin. The combination of etazolate and sGC inhibitor, methylene blue (MB) treated mice showed a significant (P<0.001) delay in onset of action, jerky movements and convulsion when compare to gabapentin as well as against the combination of etazolate with BRL 50481.The present study mainly highlights the individual effects of etazolate and combination with BRL-50481 potentiates (P<0.001) the onset of seizure activity against all models of convulsion. The study mainly comprises the onset of seizures, mortality/recovery, percentage of prevention of seizures (anticonvulsant) and total duration of convulsive time. The total convulsive time was prolonged significantly (P<0.05 and P<0.01) in combination of methylene blue with etazolate treated (28.59% and 35.15 %) groups, compared to DMSO received group (100%) in the MES model. In the same way, the combination of calcium channel modulator (CCM) and calcium channel blocker (CCB) amiodarone and nifedipine respectively, with etazolate showed a significant (P<0.001) delay in onset of seizures, compared to DMSO and etazolate treated groups in all models of epilepsy. This confirms that both CCM and CCB possess anticonvulsant activity. Finally, the study reveals that identification of new cAMP mediated phosphodiesterases family members offers a potential new therapy for epilepsy management in future.