Sitagliptin does not protect against MPTP-induced dopaminergic striatal toxicity

C. A. Fontes Ribeiro, A. M. Silva, S. D. Viana, F. C. Pereira. Faculty of Medicine, Pharmacology and Experimental Therapeutics, Portugal

Background and objectives. Parkinson\'s disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) accompanied by depletion of dopamine (DA) in the striatum. These neuropathological findings translate into motor symptoms such as resting tremor, rigidity, bradykinesia and postural instability. It has been recently demonstrated that GLP-1 receptor stimulation preserves dopaminergic neurons in cellular and rodent models of Parkinson’s disease (PD).

The aim of this study is to verify a possible neuroprotective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on nigrostriatal dopaminergic system from the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.

Methods. Adult C57BL/6 mice were injected with sitagliptin (40 mg/Kg, i.p.) 30 minutes prior to MPTP (20 mg/Kg every 2 hours, 4 times, i.p.) and sacrificed 7 days post-treatment, following a locomotor function assessment (Rotarod test) (acute treatment). In another group of mice sitagliptin was administered daily (20 mg/Kg, i.p.) for 9 days, being MPTP injected in the second day (4 x 20 mg/Kg, i.p.); the Rotarod test was performed in the 3rd day of sitagliptin treatment (subchronic treatment). Striatal levels of DA, as well as TH (tyrosine hydroxylase) were evaluated to assess loss of dopaminergic neurons. Striatal GFAP (Glial Fibrillary Acidic Protein - a marker of astrogliosis) was also determined. Catecholamines were measured by HPLC (High Performance Liquid Chromatography) with electrochemical detection. Protein levels were determined by Western Blot methodology. Statistical differences were evaluated by ANOVA followed by post test Bonferroni´s multiple comparison test. Significant effects were set at p<0.05 and data were presented as mean SEM.

Results and conclusions. Our data clearly showed that sitagliptin did not prevent MPTP-induced striatal dopaminergic degeneration since it did not hamper the severe DA and TH depletion induced by this toxin. Moreover, the increase in DA turnover as well as astrogliosis, further suggestive of dopaminergic denervation, were not counteracted by sitagliptin. Intriguingly this dopaminergic toxicity did not translate into abnormal motor coordination. Whether other sitagliptin dosing regimens (eg. higher doses or prolonged treatments) could be protective warrant further investigation.

Keywords: Parkinson’s disease, neurotoxicity, MPTP, dopamine, astrocytes, sitagliptin.