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This peptide produced in the gut not only crosses the blood\u2013brain barrier but is also synthesized in the brain and acts on<jats:styled-content style=\"fixed-case\">GLP<\/jats:styled-content>\u20101R exerting central anti\u2010inflammatory and antiapoptotic effects, thus impeding neuronal damage. This study investigated the antiparkinsonian effect of vildagliptin, a dipeptidyl peptidase (<jats:styled-content style=\"fixed-case\">DPP<\/jats:styled-content>)\u20104 inhibitor in a rat rotenone model targeting mainly the<jats:styled-content style=\"fixed-case\">RAGE<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u03baB\/Nrf2\u2010signaling pathways, to judge the potential anti\u2010inflammatory\/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 (<jats:styled-content style=\"fixed-case\">ADP<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>) associated with partial antagonism of body weight reduction. This incretin enhancer suppressed nuclear factor (<jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>)\u03baB and, consequently, the downstream inflammatory mediator tumor necrosis factor\u2010\u03b1. Normalization of receptor for advanced glycated end product (<jats:styled-content style=\"fixed-case\">RAGE<\/jats:styled-content>) is a main finding which justifies the anti\u2010inflammatory effects of vildagliptin, together with hampering striatal inducible nitric oxide synthase, intracellular adhesion molecule\u20101 as well as myeloperoxidase. The antioxidant potential of vildagliptin was depicted as entailing reduction in thiobarbituric acid\u2010reactive substances and the transcriptional factor Nrf\u20102 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\u20103. In conclusion, vildagliptin is endowed with various neuroprotective effects and thus can be a promising candidate for the management of Parkinson's disease.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13087-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><jats:p>In the rat rotenone model of Parkinson's disease (PD), striatal RAGE\/NF\u03baB signaling was up\u2010regulated 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)\u20104 inhibitor, blocked the RAGE\/NF\u03baB cascade exerting a potential antiparkinsonian effect. RAGE, receptor for advanced glycation end product; NF\u03baB, nuclear factor \u03baB; TNF\u03b1, tumor necrosis factor alpha; ICAM, intracellular adhesion molecule; iNOS, inducible nitric oxide synthase; MPO, myeloperoxidase.<\/jats:p>","DOI":"10.1111\/jnc.13087","type":"journal-article","created":{"date-parts":[[2015,3,5]],"date-time":"2015-03-05T12:18:57Z","timestamp":1425557937000},"page":"700-707","source":"Crossref","is-referenced-by-count":209,"title":["Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of<scp>RAGE<\/scp>\u2010<scp>NF<\/scp>\u03baB and Nrf2\u2010antioxidant signaling pathways"],"prefix":"10.1111","volume":"133","author":[{"given":"Rania M.","family":"Abdelsalam","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy Department of Pharmacology and Toxicology Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa M.","family":"Safar","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Department of Pharmacology and Toxicology Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,3,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2011.11.016"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(96)00249-7"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1999.0731127.x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21483"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2008.05.017"},{"key":"e_1_2_7_7_1","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/S0022-3565(25)24140-4","article-title":"Differential effects of dopaminergic drugs on open\u2010field behavior of spontaneously hypertensive rats and normotensive Wistar\u2010Kyoto rats","volume":"248","author":"van den Buuse M.","year":"1989","journal-title":"J. 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