Promising Outcomes of Original Grant:
Dipeptidyl protease-4 (DPP-4) inhibitors are widely used in the effective treatment of type 2 diabetes to safely regulate blood glucose levels. DPP-4 is the key enzyme responsible for the metabolism of the endogenous incretins GLP-1 and GIP, whose elevated levels in brain, we hypothesized, would provide neurotrophic/neuroprotective actions in cellular and pre-clinical models of Parkinson’s disease (PD). On evaluating several DPP-4 inhibitors, brain and plasma incretin levels were, indeed, substantially elevated and this resulted in amelioration of parkinsonism and elevations in brain dopamine levels in a well-characterized PD model.
Objectives for Supplemental Investigation:
The proposed studies will extend the evaluation of DPP-4 inhibitors as a new treatment strategy for Parkinson’s disease by assessing one DPP-4 inhibitor (sitagliptin) in larger models. Focused studies will, first, determine whether clinically translatable doses of sitagliptin will elevate plasma and spinal fluid levels of GLP-1 and GIP levels by a minimum of two-fold, considered to be within their protective sphere of activity. Second, studies will correlate spinal fluid GLP-1/GIP levels with (i) plasma levels, (ii) DPP-4 inhibition and (iii) sitagliptin concentrations to define a potential marker of elevated incretin levels for translational studies in humans. Finally, the targets for incretin therapy — the receptors for GLP-1 and GIP — will be quantified in human post-mortem PD and control age-matched brains to evaluate whether they are maintained in human disease state.
Importance of This Research for the Development of a New PD Therapy:
Our initial DPP-4 inhibitor studies defined this drug class as beneficial in well-characterized cellular and pre-clinical PD models. Our aim is to evaluate whether the beneficial actions of DPP-4 inhibitors will translate to larger models as a key step to de-risk clinical translation. If successful, our proposed studies will lay the essential groundwork for a clinical trial of the DPP-4 inhibitor sitagliptin in PD by defining a drug dose and a systemic biomarker of central incretin actions. Sitagliptin is a well-tolerated and widely used type 2 diabetes drug that could be rapidly repositioned for clinical assessment in PD.
Sitagliptin is a fully approved drug and well-‐tolerated in the effective treatment of type 2 diabetes mellitus, and is not associated with hypoglycemia (allowing its use in normoglycemic non-‐diabetics). Its proven pharmacological action is to inhibit the activity of DPP-‐4 and, thereby, elevate the levels of the endogenous incretins GLP-‐1 and GIP. Sitagliptin’s beneficial neuroprotective and neuroregenerative actions at a translational dose and route of administration in our former 6-‐OHDA pre-clinical models, together with the current studies demonstrating that similar elevations in GLP-‐1 and GIP can be achieved at an equivalent dose in nonhuman primates studies strongly support the further evaluation of sitagliptin as a new treatment strategy for PD.