Combination treatment with rapamycin and glucocorticoid protects the death of mesostriatal dopaminergic neurons in animal model of Parkinson's disease

Abstract

Glucocorticoids have been used to treat inflammatory diseases because of their potent anti-inflammatory and immunosuppressive actions. However, chronic use of high levels of glucocorticoids causes several adverse effects, limiting their clinical utility. Here, we explored the therapeutic potential of a combination treatment involving reduced concentrations of rapamycin, an autophagy activator and immunosuppressant, and glucocorticoids in an animal model of Parkinson's disease (PD). In vitro experiments with the SH-SY5Y cell line revealed that 10 μM rapamycin significantly increased the survival rate of cells treated with 6-hydroxydopamine to induce cell death, while both dexamethasone and prednisone at 50 μM exhibited an evident increase in survival rates. The combination treatment with reduced concentrations (rapamycin: 5 μM, dexamethasone: 25 μM) showed a more effective recovery in survival than singular treatments with high concentrations of rapamycin, prednisone, or dexamethasone. Propidium iodide–staining confirmed the efficacy of the combination treatment. This treatment did not significantly alter forkhead box O3a (FOXO3a)–triggered apoptosis and autophagic flux but upregulated the expression of the anti-apoptotic protein B-cell lymphoma 2, while B-cell lymphoma–extra-large showed no significant change. In vivo experiments using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced PD animal model revealed that the combination treatment effectively mitigated defects in motor function. The combination treatment completely blocked the loss of tyrosine hydroxylase (TH)–positive neurons in the substantia nigra pars compacta and partially prevented the reduction of TH-positive fibers in the striatum caused by the MPTP treatment. It also reduced the microglial levels caused by the MPTP treatment. Although not significant, it demonstrated an increase in survival rates of MPTP-induced PD model mice. In conclusion, the combination treatment with reduced concentrations of rapamycin and glucocorticoids may serve as potential therapy for PD, albeit further research and clinical trials are warranted to validate its efficacy and safety.