Comparison of neuroprotective and neurorestorative capabilities of rasagiline and selegiline against lactacystin-induced nigrostriatal dopaminergic degeneration

• Published in: Journal of neurochemistry 2008-06, Vol.105 (5), p.1970-1978
• Main Authors: Zhu, Wen, Xie, Wenjie, Pan, Tianhong, Jankovic, Joseph, Li, Jun, Youdim, Moussa B.H, Le, Weidong
• Format: Article
• Language: English
• Subjects: Acetylcysteine - analogs & derivatives; Acetylcysteine - antagonists & inhibitors; Acetylcysteine - toxicity; Animals; Biochemistry; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine - physiology; Indans - therapeutic use; Inhibitor drugs; lactacystin; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nerve Degeneration - prevention & control; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; neuroprotection; Neuroprotective Agents - therapeutic use; neurorestoration; Parkinson's disease; Pharmacology; rasagiline; selegiline; Selegiline - therapeutic use; ubiquitin-proteasome system
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05330.x

Nigrostriatal neurodegeneration in Parkinson's disease (PD) has been postulated to be caused by various pathological conditions, such as mitochondrial defects, oxidative stress, and ubiquitin-proteasome system (UPS) dysfunction. Pharmacological strategies designed to interfere with these pathological pathways may effectively counteract the degeneration. Rasagiline and selegiline are selective and irreversible monoamine oxidase-B inhibitors that possess significant protective properties on dopamine neurons in various pre-clinical models of PD. In the present study, the neuroprotective and neurorestorative effects of rasagiline and selegiline were compared in an animal model of PD produced by inhibition of the UPS. C57BL/6 male mice were microinjected bilaterally with UPS inhibitor lactacystin (1.25 μg/side), into the medial forebrain bundle. Administration of rasagiline (0.2 mg/kg, i.p. once per day) or selegiline (1 mg/kg, i.p. once per day), started 7 days before or after (up to 28 days) after lactacystin microinjection. We found that both rasagiline and selegiline exerted a significant neuroprotective effect against lactacystin-induced neurodegeneration; but only rasagiline managed to restore the nigrostriatal degeneration. Furthermore, rasagiline showed a modest protection against lactacystin-induced inhibition of proteasomal activity. Our study indicates that compared with selegiline, rasagiline is more potent in protecting neurodegeneration induced by UPS impairment and may, therefore, exert disease-modifying effects in PD.