Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE-NFκB and Nrf2-antioxidant signaling pathways.
Gliptins have been recently shown to conquer neuronal degeneration in cell cultures via modulating glucagon-like peptide (GLP)-1. This peptide produced in the gut not only crosses the blood-brain barrier but is also synthesized in the brain and acts on GLP-1R exerting central anti-inflammatory and antiapoptotic effects, thus impeding neuronal damage. This study investigated the antiparkinsonian effect of vildagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor in a rat rotenone model targeting mainly the RAGE-NFκB/Nrf2-signaling pathways, to judge the potential anti-inflammatory/antioxidant effects of the drug. Vildagliptin markedly improved the motor performance in the open field and rotarod tests, effects that were emphasized by the accompanied reduction in striatal dopamine content. It modified the striatal energy level (ADP/ATP) associated with partial antagonism of body weight reduction. This incretin enhancer suppressed nuclear factor (NF)κB and, consequently, the downstream inflammatory mediator tumor necrosis factor-α. Normalization of receptor for advanced glycated end product (RAGE) is a main finding which justifies the anti-inflammatory effects of vildagliptin, together with hampering striatal inducible nitric oxide synthase, intracellular adhesion molecule-1 as well as myeloperoxidase. The antioxidant potential of vildagliptin was depicted as entailing reduction in thiobarbituric acid-reactive substances and the transcriptional factor Nrf-2 level. Vildagliptin guarded against neuronal demise through an antiapoptotic effect as reflected by the reduction in the mitochondrial matrix component cytochrome c and the key downstream executioner caspase-3. In conclusion, vildagliptin is endowed with various neuroprotective effects and thus can be a promising candidate for the management of Parkinson's disease. In the rat rotenone model of Parkinson's disease (PD), striatal RAGE/NFκB signaling was up-regulated associated with elevated levels of inflammatory, oxidative stress, and apoptotic mediators resulting in dopaminergic neurons death and hence motor impairment. Vildagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, blocked the RAGE/NFκB cascade exerting a potential antiparkinsonian effect. RAGE, receptor for advanced glycation end product; NFκB, nuclear factor κB; TNFα, tumor necrosis factor alpha; ICAM, intracellular adhesion molecule; iNOS, inducible nitric oxide synthase; MPO, myeloperoxidase.
Faculty of Pharmacy, Department of Pharmacology and Toxicology, Cairo University, Cairo, Egypt.
Rania M
RM
Abdelsalam
Marwa M
MM
Safar
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000187:drug effects*; D016328:NF-kappa B / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000187:drug effects*; D012402:Rotenone; D015398:Signal Transduction / Q000187:drug effects*; D014475:Uncoupling Agents; D000077597:Vildagliptin
D000975:Antioxidants; D007004:Hypoglycemic Agents; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D009570:Nitriles; D011759:Pyrrolidines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014475:Uncoupling Agents; D012402:Rotenone; D000077597:Vildagliptin; D000218:Adamantane; D004298:Dopamine
RAGE; Vildagliptin; apoptosis; dipeptidyl peptidase-4; neuroinflammation; rotenone