Protective effect of FK506 (Tacrolimus) in pentylenetetrazol-induced kindling in mice

Abstract

The repeated administration of otherwise subconvulsant dose of pentylenetetrazol (PTZ) is known to produce chemical kindling in animals. In our study, chronic administration of subconvulsant dose of PTZ (40 mg/kg) produced chemical kindling in mice. Pretreatment with l-arginine (50–100 mg/kg ip) potentiated the PTZ-induced kindling, whereas N ω-nitro- l-arginine methyl ester ( l-NAME) (10–20 mg/kg ip) showed a protective effect. FK506, a potent neuroprotective agent, dose dependently (0.5–1 mg/kg po) decreased the kindling score. When given in combination, l-NAME potentiated the protective effect of lower dose of FK506 (0.5 mg/kg) on PTZ-induced kindling. l-Arginine (50–100 mg/kg) reversed the protective effect of FK506 (1 mg/kg) and l-NAME (20 mg/kg). Biochemical studies showed the potential role of free radical toxicity in the kindled mice, as there was an increased lipid peroxidation as indicated by elevated malondialdehyde (MDA) and nitrite levels and decrease in GSH and superoxide dismutase (SOD) levels. FK506 pretreatment significantly reversed the elevated MDA and nitrite levels, GSH and SOD depletion induced by PTZ treatment. In conclusion, the results of the present study suggest the possible neuroprotective action of FK506 against PTZ-induced kindling.