"Pharmacological Study on the Neuroprotective Effect of Selegiline in 3Nitropropionic Acid-Induced Experimental Animal Model of Huntington's Disease Phenotype"

Abstract

3-Nitropropionic acid (3-NP), a mitochondrial toxin, is considered a reliable agent for inducing HD-like phenotype in experimental animals. Reduction of prepulse inhibition (PPI) of acoustic startle response, locomotor hypoactivity, increased oxidative stress, activation of apoptotic cascade and bilateral striatal lesions are the major manifestations of 3-NP-induced neurotoxicity. Selegiline is a non-competitive monoamine oxidase-B (MAO-B) inhibitor with previously reported antioxidant and antiapoptotic effects. The present study was designed to investigate neuroprotective effect of selegiline on 3-NP induced neurotoxicity. Rats administered 3-NP (20 mg/kg, i.p.) for four consecutive days exhibited PPI deficits, locomotor hypoactivity, increased striatal and cortical malondialdehyde (MDA) and reduced respective glutathione (GSH) level, catalase and superoxide dismutase (SOD) activities. Changes in the level of apoptotic regulatory gene expressions were demonstrated as increased striatal and cortical caspase-3 and Bax expression and decreased respective Bcl2 expression. Selegiline was given by i.p. injection at doses 2.5, 5 and10 mg/kg, 3 days prior to- and continued daily, 30 minutes before 3-NP administration. The high dose levels of selegiline (5 and 10 mg/kg), significantly increased locomotor activity, improved PPI, reduced striatal and cortical MDA, caspase-3 and Bax and increased respective GSH level, catalase and superoxide dismutase activities and Bcl2 expression. Selegiline at dose 2.5 mg/kg could only reverse some of the manifestations of 3-NP-induced neurotoxicity. It could significantly improve PPI, reduce striatal MDA level and Bax expression, and increase striatal GSH level, catalase and superoxide dismutase activities. It could also significantly increase cortical superoxide dismutase level and decreased cortical Bax expression. Histological examination further affirmed the neuroprotective effect of high dose levels of selegiline against 3-NP toxicity. Taken together, these results suggest that selegiline attenuate 3-NP-induced neurotoxicity. This neuroprotective effect may be related to antioxidant properties and antiapoptotic effects.