Controlled release of rasagiline mesylate promotes neuroprotection in a rotenone-induced advanced model of Parkinson's disease

Microencapsulation of rasagiline mesylate (RM) into PLGA microspheres was performed by method A (O/W emulsion) and method B (W/O/W double emulsion). The best formulation regarding process yield, encapsulation efficiency and in vitro drug release was that prepared with method A, which exhibited constant drug release for two weeks (K0 = 62.3 μg/day/20 mg microspheres). Exposure of SKN-AS cells to peroxide-induced oxidative stress (1 mM) resulted in cell apoptosis which was significantly reduced by RM (40.7-102.5 μM) as determined by cell viability, ROS production and DNA fragmentation. Daily doses of rotenone (2 mg/kg) given i.p. to rats for 45 days induced neuronal and behavioral changes similar to those occurring in PD. Once an advanced stage of PD was achieved, animals received RM in saline (1 mg/kg/day) or encapsulated within PLGA microspheres (amount of microspheres equivalent to 15 mg/kg RM given on days 15 and 30). After 45 days RM showed a robust effect on all analytical outcomes evaluated with non-statistically significant differences found between its administration in solution or within microparticles however; with this controlled release system administration of RM could be performed every two weeks thereby making this new therapeutic system an interesting approach for the treatment of PD.

FE-SEM microphotographs of RM-loaded PLGA microspheres, in vitro release profiles of RM from PLGA microspheres, confocal images of mitochondrial staining (red fluorescence) of SKN-AS control cells, cells treated with H2O2 (1 mM) and co-treated with RM (87.6 μM). Catalepsy (bar and grid) and akinesia results obtained in the rotenone-induced rat model of PD. Group G1: control group; G2: rotenone-treated control group; and rotenone-treated animals also receiving: G3: PLGA-blank microspheres; G4: RM in saline (1 mg/kg/day for 45 days, starting on day 15th of the study) and, G5: RM-loaded PLGA microspheres (amount of microspheres equivalent to 15 mg/kg RM injected on days 15 and 30 of the study). RM: rasagiline mesylate.131