Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE‐NFκB and Nrf2‐antioxidant signaling pathways

Abstract

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-NFjB/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)jB and, consequently, the downstream inflammatory mediator tumor necrosis factor-a. 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.

Parkinson';s Disease, Diabetes and Cognitive Impairment

“…Tau protein is glycated, and able to induce oxidative stress, thus contributing to the formation and toxicity of NFT [44]. In PD, glycation of α-synuclein may be one of the mechanisms underlying the abnormal agglomeration of α-synuclein that leads to the development of Lewy bodies [44]. This phenomenon might also be related to the activation of the receptor for advanced products of glycosylation (RAGE), found ubiquitously on neurons.…”

“…The polymerization of Aβ, a major component of senile plaques, is enhanced by AGE mediated protein cross-linking. Tau protein is glycated, and able to induce oxidative stress, thus contributing to the formation and toxicity of NFT [44]. In PD, glycation of α-synuclein may be one of the mechanisms underlying the abnormal agglomeration of α-synuclein that leads to the development of Lewy bodies [44].…”

“…AGEs can induce protein aggregation and inflammation in the brain through the formation of (ROS) [43]. In AD, Amyloid β (Aβ) and tau protein, which are associated with the development of both senile plaques and neurofibrillary tangles (NFT), are influenced by AGEs [44]. The polymerization of Aβ, a major component of senile plaques, is enhanced by AGE mediated protein cross-linking.…”

Ligands of Receptor for Advanced Glycation End-Products Produced by Activated Microglia are Critical in Neurodegenerative Diseases

“…S100β is found in degenerative cells of AD and PD [59], and it has been reported S100β overexpression ameliorates AD-like pathology and enhances microgliosis and astrogliosis [60]. S100 proteins have also been reported to cause neuronal cell death via TNF-α and NF-κB in PD [61].…”

Rodent Model of Parkinson’s Disease: Unilateral or Bilateral?

“…The pathophysiological process is similar to the human PD. The inflammation response is linked to mitochondrial dysfunction in the progress [32,33].The reproduction of clinical PD features through the intragastric administration of rotenone uncovers a novel view on the gut-brain transmission of PD [34].…”