Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

L-dopa is still considered as the gold standard therapy for parkinson's disease (PD) however, L-dopa-induced dyskinesia (LID) is a serious complication of long-term L-dopa treatment. The present study investigated the therapeutic potential of sitagliptin and liraglutide in comparisons with L-dopa against PD induced inflammatory, trophic and apoptotic pathways. In addition, their capacity to modulate L-dopa dose and/or side effects was investigated, too. Rats were injected with rotenone (3 mg/kg/day, s.c) for ten consecutive days to induce the experimental PD. The rotenone-treated rats were administered sitagliptin (30 mg/kg/day, p.o.) and liraglutide (50 og/kg, s.c.) for 16 days either alone or together with L-dopa/carbidopa (50/25 mg/kg/day, i.p). Scoring of LID was done on days 2, 4, 8, 12 and 16 in all L-dopa-treated groups. Twenty-four hours after the last administered dose of tested drugs, the behavior of rats in each group was screened by using cylinder and catalepsy tests. Sitagliptin and liraglutide revealed marked attenuation of LID scores; in addition, they markedly increased animals' motor performance. Moreover, they preserved substantia nigra pars compacta (SNpc) tyrosine hydroxylase (TH) and vesicular monoamine transporter2-positive (VMAT2) cells with prominent increase of the striatal dopamine (DA) content. On the other hand, they significantly decreased nigral neuromelanin-positive cells, activated microglia, gliosis and other pathological changes. Interestingly, they significantly decreased the pro-inflammatory cytokines: interleukin (IL)-1Ý, IL-6, transforming growth factor (TGF)-Ý1, together with a significant increase of the nigral glial cell line-derived neurotrophic factor (GDNF). In addition, they exhibited a significant decrease of Bax/Bcl2 ratio

Issued also as CD