Saxagliptin: A novel antiparkinsonian approach

- Antiparkinsonian role for saxagliptin (SAX) was adopted based on structural activity.
- Rotenone-induced PD was associated by neurobehavioral biochemical changes.
- SAX enhanced striatal dopamine and reduced neurodegeneration.
- Antiparkinsonian actions were linked to SAX dipeptidylpeptidase-4 inhibition.
- SAX also showed antioxidant, antiapoptotic, and neuroprotective mechanisms

The emergence of glucagon-like peptide-1 as a crucial contender in modifying neurodegenerative diseases in the preclinical studies has instigated interest in investigating the antiparkinsonian effect of dipeptidyl peptidase (DPP)-4 inhibition. Notably, saxagliptin (SAX), the DPP-4 inhibitor, recently showed efficacy in ameliorating streptozotocin-induced Alzheimer's disease; however, its effect on Parkinson's disease (PD) has not yet been elucidated. In a rat rotenone (ROT) model, SAX prominently improved motor performance as well as muscle coordination and corrected akinesia. Moreover, SAX preserved substantia nigra pars compacta tyrosine hydroxylase (TH) immunoreactivity while halting the reduction in the striatal TH, dopamine (DA) and complex I. Meanwhile, SAX prevented the ROT-induced increment of striatal DPP-4 and the decline in cAMP, ATP/ADP and brain-derived neurotropic factor levels. Improvement in striatal energy level was associated with partial hindrance of ROT-induced body weight reduction. In addition, through its anti-inflammatory potential, SAX decreased the ROT-induced nuclear factor-κΒ, inducible nitric oxide synthase, tumor necrosis factor-α, intracellular adhesion molecule-1 and myeloperoxidase. The antiapoptotic marker B-cell lymphoma-2 was enhanced by SAX, versus reduction in caspase-3 and its intrinsic apoptotic activator cytochrome C. Furthermore, SAX amended alterations induced by ROT in the thiobarbituric acid reactive substances and the transcriptional factor Nrf-2 level. In conclusion, SAX can be introduced as a novel approach for the management of PD based on the remarkable improvement in motor functions denoting antiparkinsonian efficacy via antioxidant, anti-inflammatory, antiapoptotic, neuroprotective and neurorestorative mechanisms. These effects were linked to DPP-4 inhibition, reduced neurodegeneration and enhanced DA synthesis.