A binding site for selegiline was found on the GAPDH molecule by Tatton and coworkers,54 but the existence of a similar site for rasagiline has not yet been established. At the whole animal level, rasagiline has been observed to reverse MPTP-induced reduction of tyrosine hydroxylase-positive neurons in the substantia nigra in mice as well as the neurological deficit caused by the MPTP administration.53 Since neurogenesis does not occur in mouse substantia nigra, rasagiline must therefore enhance the expression of tyrosine hydroxylase which has been down-regulated

by the neurotoxin. Inhibitors,research,lifescience,medical The important aspect of this study is that rasagiline administration was commenced 2 weeks after MPTP had been given and tyrosine Inhibitors,research,lifescience,medical hydroxylase levels had already been depleted. CLINICAL STUDIES WITH RASAGILINE Clinical anti-Parkinsonian

effect of rasagiline was described in two major clinical trials. The first (TEMPO)6 compared rasagiline with entacapone (peripherally-acting COMT inhibitor). Both drugs were found to cause significant anti-Parkinsonian Inhibitors,research,lifescience,medical effect as shown by reduction of about 2 points in the UPDRS clinical rating scale. The second (LARGO)7 was designed to establish the efficacy of rasagiline in combination with L-dopa. In this study rasagiline was effective both in increasing “on” time and reducing the severity of “off”. Building on the experience with DATATOP and other studies, rasagiline was chosen by the Parkinson’s Inhibitors,research,lifescience,medical Study Group for a new trial (ADAGIO)8,9 designed to detect whether the drug can reduce disease progression. Since the estimation of disease protection is made on the basis of clinical neurological score (UPDS), any symptomatic drug will give a false positive result. The test selleck chemical format INCB-018424 adopted in ADAGIO was to Inhibitors,research,lifescience,medical compare drug and placebo groups of recent onset patients for a period of time judged to be sufficient for detectable disease progression

(9 months) and then put all patients on the active drug therapy for an additional period of 9 months. At the end of this period, patients were compared for clinical status. Since all patients received active drug therapy at conclusion of the trial, AV-951 the symptomatic effect of the drug was balanced out. It was found that patients who received the drug at 1 mg daily for 18 months finished the trial period in a significantly better clinical status than those who received it for only 9 months, although this effect was not significant at a dose of 2 mg. SUMMARY Rasagiline is a selective MAO-B inhibitor which is devoid of the amphetamine-like actions of its predecessor, selegiline. The drug has two distinct actions: selective irreversible inhibition of MAO-B, and neuroprotective effect not dependent on MAO inhibition.