linagliptin and Parkinson-Disease

While all current therapies' main focus is enhancing dopaminergic effects and remission of symptoms, delaying Parkinson's disease (PD) progression remains a challenging mission. Linagliptin, a Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, exhibited neuroprotection in various neurodegenerative diseases. This study aims to evaluate the neuroprotective effects of Linagliptin in a rotenone-induced rat model of PD and investigate the possible underlying mechanisms of Linagliptin's actions. The effects of two doses of Linagliptin (5 and 10 mg/kg) on spontaneous locomotion, catalepsy, coordination and balance, and histology were assessed. Then, after Linagliptin showed promising results, it was further tested for its potential anti-inflammatory, antiapoptotic effects, and different pathways for oxidative stress. Linagliptin prevented rotenone-induced motor deficits and histological damage. Besides, it significantly inhibited the rotenone-induced increase in pro-inflammatory cytokines: Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6) and decrease in caspase 3 levels. These effects were associated with induction in the levels of Protein deglycase also known as DJ-1, Hypoxia-inducible factor 1-alpha (HIF-1α), potentiation in the Sirtuin 1 (SIRT-1)/Nuclear factor erythroid-2-related factor 2 (Nrf-2)/Heme oxygenase-1 (HO-1) pathway, and an increase in the antioxidant activity of catalase which provided neuroprotection to the neurons from rotenone-induced PD. Collectively, these results suggest that Linagliptin might be a suitable candidate for the management of PD.

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Linagliptin; Neuroprotection; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Protein Deglycase DJ-1; Rats; Rotenone; Sirtuin 1

The nigrostriatal dopaminergic system (NDS) controls motor activity, and its impairment during type 2 diabetes (T2D) progression could increase Parkinson's disease risk in diabetics. If so, whether glycemia regulation prevents this impairment needs to be addressed. We investigated whether T2D impairs the NDS and whether dipeptidyl peptidase-4 inhibition (DPP-4i; a clinical strategy against T2D but also neuroprotective in animal models) prevents this effect, in middle-aged mice. Neither T2D (induced by 12 months of high-fat diet) nor aging (14 months) changed striatal dopamine content assessed by high-performance liquid chromatography. However, T2D reduced basal and amphetamine-stimulated striatal extracellular dopamine, assessed by microdialysis. Both the DPP-4i linagliptin and the sulfonylurea glimepiride (an antidiabetic comparator unrelated to DPP-4i) counteracted these effects. The functional T2D-induced effects did not correlate with NDS neuronal/glial alterations. However, aging itself affected striatal neurons/glia, and the glia effects were counteracted mainly by DPP-4i. These findings show NDS functional pathophysiology in T2D and suggest the preventive use of two unrelated anti-T2D drugs. Moreover, DPP-4i counteracted striatal age-related glial alterations suggesting striatal rejuvenation properties.

Topics: Aging; Animals; Corpus Striatum; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Dopamine; Linagliptin; Male; Mice; Mice, Inbred C57BL; Models, Animal; Parkinson Disease; Risk; Substantia Nigra; Sulfonylurea Compounds