טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentBadinter Felix
SubjectNeuroprotective Effects of the Anti-Parkinsonian Drug
Rasagiline and its Major Metabolite 1-(R)-
Aminoindan in Animal Models of Aging
DepartmentDepartment of Biotechnology
Supervisors Professor Emeritus Moussa Youdim
Dr. Orly Weinreb
Full Thesis textFull thesis text - English Version


Abstract

Aging is often characterized by changes in the brain volume, accompanied by a decline in motor and cognitive performances that resulted from oxidative stress, mitochondrial dysfunction, reduced neurotransmitters levels and changes in molecular/functional mechanisms of neuronal plasticity. The current study aimed to investigate the protective effects of the brain selective, irreversible monoamine oxidase (MAO)-B inhibitor/ novel anti-Parkinsonian drug, rasagiline (RAS; Azilect?) and its major metabolite,  1-(R)-aminoindan (AI), in aging animals (24 months old).

Our findings from behavioral experiments demonstrated that chronic treatment of aged mice with RAS (0.2 mg/kg, daily, for 3 months) exerted significant beneficial effects on mood-related dysfunction and spatial learning and memory. At this dose of RAS, chronic drug administration completely blocked MAO-B activity and caused a significant increase in striatal dopamine (DA) and serotonin levels, while decreasing their metabolism. In addition, RAS elevated striatal mRNA expression levels of DA receptors D1 and D2. Furthermore, we found that RAS up-regulated expression levels of brain derived neurotrophic factor (BDNF), tyrosine kinase (TrK)-B receptor and the synaptic plasticity marker synapsin-1 and increased Bcl-2/Bax anti-apoptotic ratio in the hippocampus and striatum of aged mice. RAS also antagonized the age-dependent decreases in the activity of the antioxidant enzyme, catalase. Similar findings obtained in the hippocampus and striatum of aged mice-treated with chronic systemic treatment of AI (5 mg/kg, daily, for 3 months ): exertion of significant positive impact on neuropsychiatric functions and cognitive behavior deficits; elevation of mRNA expression levels of neurotrophins (such as, BDNF and NGF), Trk-B receptor, synapsin-1, growth-associated protein-43 (GAP-43) and the pro-survival Bcl-2; increase in the anti-apoptotic index Bcl-2/Bax and enhancement of the activity of the antioxidant enzyme catalase. These neuroprotective effects of RAS and AI were also confirmed in aged rats.

Altogether, the regulatory effects of RAS on neuronal synaptic, cell survival and neurotrophic factors' genes may account for the antidepressant-like and cognition-enhancing activities observed in drug-treated aged animals. In addition, the current study indicated that AI possessed neuroprotective effects similar to RAS in aged animals, suggesting that AI may contribute to the overall beneficial effects of its parent compound.