Abstracts

Rationale: The mechanism by which atorvastatin, a HMG-CoA inhibitor, exert protective effect in different experimental models of epilepsy in not clearly understood. HMG-CoA inhibitors have been reported to modulate adenosinergic pathway via enhanced activity of ecto-5'-nucleotidase (5-NTE), thus increasing extracellular adenosine production. Also, adenosine has been shown to possess anti-convulsant property by acting through A₁ receptors. Correlating the above two, we hypothesized that atorvastatin exerts its anticonvulsant effect via modulation of adenosinergic pathway in pentylenetetrazol (PTZ)-induced seizures in rats. Methods: Pretreatment with vehicle/atorvastatin (10 mg/kg/day, orally) was given daily for 7 days to male Wistar rats. On day 7, different groups were given single dose of (i) 5-NTE inhibitor-Adenosine 5′-(α,β-methylene) diphosphate (AMPCP, 4mg/kg, i.m.); (ii) Adenosine (1000 mg/kg, i.p.); (iii) adenosine A₁ receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1mg/kg, i.p.); and (iv) adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 1mg/kg, i.p.) along with PTZ (60 mg/kg, i.p.). For 30 minutes after single dose of PTZ, the incidence of myoclonic jerks (MJ) and generalized clonic seizures (GCS) with loss of righting reflex along with respective latencies were observed. Results: Atrovastatin significantly decreased the latencies and incidence of MJ (p<0.001) and GCS (p<0.001) as compared to PTZ group alone. AMPCP reversed this protection conferred by atorvastatin as seen by significant decrease in MJ (p<0.001) and GCS (p<0.01) latencies (Table 1). However, this reversal is not complete as evident by increase in the incidence of MJ (83.3% to 100%) and GCS (50.0% to 83.3%) in AMPCP + atorvastatin group as compared to atorvastatin alone. Similarly, significant decrease was observed in MJ and GCS latencies with the addition of DPCPX to atrovastatin. But, DMPX did not block the anticonvulsant effect of atorvastatin. Conclusions: The anti-convulsant effect of atrovastatin in PTZ-induced (single dose) seizures is mediated by adenosinergic pathway via possible enhanced activity of ecto-5'-nucleotidase enzyme. However, incomplete reversal with AMPCP and DPCPX indicates that there are other mechanisms also which are mediating the anti-convulsant action of atorvastatin.