Neuroprotective Effects of Atorvastatin on Animal Models of Seizure and Behaviour Nouroz Sehar #*, Nidhi B. Agarwal #, Md. Ubedul Hoda ¥, S. Raisuddin *, Divya Vohora ¥ # Centre for Translational and Clinical Research; *Department of Medical Elementology and Toxicology; ¥ Department of Pharmacology- Jamia Hamdard, New Delhi Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, widely used for the treatment of dyslipidemias Statins are reported to show pleiotropic effects that are independent of cholesterol lowering Recently, different statins have shown neuroprotective activity against animal models of Alzheimer’s disease, Parkinson’s disease and seizures They can modulate several cellular pathways, including modulation of immune response, and effect on oxidative and nitrosative stress levels In view of its pleiotropic effect, the present study had been designed to investigate the effects of atorvastatin in different doses on animal models of seizures and related behavior  To study the effect of acute administration of atorvastatin on ICES and PTZ seizure  To assess the effect of acute administration of atorvastatin on anxiety  To study the effect of acute administration of atorvastatin on depression ANIMAL Strain : Swiss albino mice Weight : g DRUGS & DOSING SCHEDULE Acute study : 7 days Atorvastatin : 20, 40 and 80 mg/kg body wt Phenytoin : 25 mg/kg Pentylenetetrazole : 50 mg/kg, i.p CMC : 1% NEUROPHARMACOLOGICAL EVALUATION Seizures Increasing current electroshock test (ICES) (Kitano et al 1996, Marwah et al.,1999) Pentylenetetrazole-induced convulsions (Bharal et al.,2006) Anxiety Elevated plus maze (Pellow et al., 1985) Depression Forced swim test ( Porsolt et al.,1978) Statistical analysis –Data is expressed as Mean ± SEM. ANOVA followed by Dunnett’s test Kasra Moazzami, Sahra Emamzadeh-Fard,Mohammad Shabani * Anticonvulsive effect of atorvastatin on pentylenetetrazole-induced seizures in mice: the role of nitric oxide pathway Fundamental and Clinical Pharmacology,Volume 27,issue 4,pages 387–392, August 2013 Kitano Y, Chiharu U, Takasuna K, Hirohashi M.. ICES test, A new method for assessment of anti & proconvulsive activities of drugs in mice. J Pharmacol Toxicol Meth 1996; 35:25-29 Lee J, Won J, Singh AK, Singh I. Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death. Neurosci Lett. 2008; 440: 260–264. Marwah R., Pillai K.K., Pal S. N. Effect of fluoxetine alone and in combination with anticonvulsants on the increasing current electroshock test. M.Pharm. Thesis, Jamia Hamdard, New Delhi, 1998; pp Moezi L, Shafaroodi H, Hassanipour M, Fakhrzad A, Hassanpour S, Dehpour AR. Chronic administration of atorvastatin induced anti- convulsant effects in mice: the role of nitric oxide. Epilepsy Behav Apr;23(4): Pahan K, Sheikh FG, Namboodiri AM, Singh I. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest. 1997; 100:2671–2679. Pellow S, Phillipe C, File S, Briley M. Validation of open: close arm entries in an elevated plus maze as a measure of anxiety in rat. J Neurosci Meth;14: Porsolt RD, Anton G, Blavet N, Jalfre M. Behavioural; 1978.Despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47: Shitara Y, Sugiyama Y;2006. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy 3-methylglutaryl coenzyme a (hmg-coa) reductase inhibitors: Drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther. 112:71–105 Atorvastatin acute administration significantly increased seizure threshold on ICES, suggesting its potential anticonvulsant effect Devoid of effect on anxiety, depression and cognition Atorvastatin can be potential adjunct to prevent seizure. Further studies are required to establish its antiseizure effect. Table 2 : Effect of Atorvastatin on PTZ induced seizure in mice (Mean ± SEM) Table1: Effect of Atorvastatin on ICES (Mean ± SEM) Values are Mean ± SEM a p<0.05 compared to control group (Acute) b p<0.05 compared to control INTRODUCTION AIMS AND OBJECTIVES MATERIALS AND METHODS RESULTS SUMMARY AND CONCLUSIONS REFERENCES GroupDose (mg/kg)STC(mA) Acute study n=6 Control10 ml15.3±0.42 Atorvastatin2016.3±0.95 Atorvastatin4018±0.73 Atorvastatin8022.6±1.838 a Phenytoin2523±1.000 Atorva + phenytoin ±1.333 b GroupDose (mg/kg)MYOCLONIC JERK GENERALISED SEIZURE Acute study n=6 Control10 ml76.5± ±14.2 Atorvastatin20103± ±21.7 Atorvastatin40119± ±13.7 Atorvastatin ± ±18.6 Table 3: Effect of Atorvastatin on EPM (Mean ± SEM) GroupDose (mg/kg) EPM CLOSE ARM ENTRIES EPM OPEN ARM ENTRIES EPM CLOSE ARM TIME SPENT Acute study n=6 Control10 ml6±1.44± ±13.69 Atorvastatin205.3± ± ±9.58 Atorvastatin403.6± ± ±12.2 Atorvastatin804.3± ± ±54.7 Table 4: Effect of Atorvastatin on FST (Mean ± SEM) GroupDose (mg/kg)IMMOBILITY (Sec) Acute study n=6 Control10 ml94.6±9.28 Atorvastatin ±12.3 Atorvastatin ±29.2 Atorvastatin ±23.3 Data is expressed as Mean ± SEM. ANOVA followed by Dunnett’s test