Neuroprotective effect of Ac-SDKP peptide in SH-SY5Y cells and rat model of Parkinson's disease against 6-OHDA-induced oxidative stress and ER stress

Abstract

Oxidative stress and endoplasmic reticulum (ER) stress are key contributors to the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD), for which no definitive cure currently exists. This study investigated the neuroprotective potential of the N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) tetrapeptide in both in vitro and in vivo PD models. In cell-based analyses, pre-treatment with 20 nM Ac-SDKP provided significant protection against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. In vivo, the neuroprotective potential of the peptide was also supported through daily administration of rats with Ac-SDKP (800 μg/kg) after 6-OHDA lesioning, which unveiled a series of significant observations. Treated animals demonstrated highly preserved dopaminergic neurons through reduced activation of apoptotic markers such as caspase-3 and caspase-12. In addition to cytoprotection, Ac-SDKP also produced striking behavioral improvement. Treated animals exhibited improved motor coordination and ability on spatial memory tasks, as well as the significant attenuation of anxiety-like and depressive-like behaviors. Such behavioral improvement is probable because Ac-SDKP possesses the ability to modulate several pathological features of PD. In fact, the peptide was able to decrease oxidative stress, diminish ER stress, and inhibit neuroinflammatory signaling. Collectively, these findings position Ac-SDKP as a promising neuroprotection candidate, and as a candidate with potential to be developed as a multifactorial treatment for the complex pathophysiology of PD.