NEUROSCIENCE RESEARCH COMMUNICATIONS, VOL. 26, NO. 2 87 THE ROLE OF NITRIC OXIDE IN THE PROTECTIVE EFFECT OF INSULiN AGAINST PENTYLENETETRAZOLE-INDUCED SEIZURES IN MICE Ahmet Ulugol’ V *, Ender Arikan *, Turban Dost ‘, Dikmen Dokmeci ’ , Hakan C. Karadag I, Ismet Dokmeci ’ ’ Department of Pharmacology, Faculty of Medicine, Trakya University, 22030-Edirne, TURKEY * Department of Internal Medicine, Faculty of Medicine, Tmkya University, 22030-Edirne, TURKEY * Corresponding Author (Accepted December 28, 1999) SUMMARY Both insulin, depending on the glycemic state, and nitric oxide (NO), depending on the experimental conditions, have been suggested to have either proconvulsant or anticonvulsant effects. It is also known that NO plays an important role in some of the peripheral effects of insulin. The aim of the present study was to investigate the effects of NO and insulin against convulsions produced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) in mice and whether NO plays a role in the effect of insulin. Nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine-methyl ester (L-NAME, l-100 mg/kg, i.p.) shortened the onset of PTZ-induced convulsions and increased the incidence and mortality rate, at the higher doses. Insulin (1 U/kg, i.p.), when given with dextrose (3 g/kg, i.p.) to counteract the hypoglycemic effect of the hormone, prolonged the onset of convulsions and decreased the incidence and mortality rate. L-NAME pretreatment (3 mg/kg, i.p.), at the .dose which it produced no effect on PTZ-induced convulsions, attenuated the protective effect of 1 U/kg insulin + 3 g/kg dextrose combination significantly. Concomitant administration of the NO synthesis precursor, L- arginine (500 mg/kg), completely reversed this facilitatory effect of L-NAME. Our results indicate that NO has a protective effect against PTZ-induced convulsions in mice; insulin has a similar effect when given with dextrose; and, NO production may play an important role in the anticonvulsant effect of insulin. Key words: nitric oxide; insulin; L-NAME; pentylenetetrazole; convulsions INTRODUCTION Although insulin affects central nervous system functions indirectly by producing hypoglycemia (1,3), there are papers indicating that central nervous system can be directly modulated by insulin (6,8,16,22,27). It is known that insulin causes seizures indirectly by producing hypoglycemia (1,23). It has been also shown that insulin inhibits PTZ- induced seizures in normoglycemic mice (3 1,32). NO, a small membrane-diffusible molecule, has been identified recently as a neuronal messenger altering synaptic efficacy in central nervous system (9,13). Moreover, NO has been suggested to be either an anticonvulsive or a proconvulsive endogenous substrate (10,21). In view of the data indicating that the insulin-induced vasodilatation is mediated by the release of endothelium-derived NO (45) and that insulin is an inhibitor of inducible NOS-mediated NO production (7,1.5); the present study was undertaken to explore the possibility that NO may also be involved in the central effects of insulin by investigating the role of NO in the effect of insulin against PTZ-induced convulsions in mice. 0 2000 Wiley-Liss, Inc.