Trehalose Neuroprotective Effects on the Substantia Nigra Dopaminergic Cells by Activating Autophagy and Non-canonical Nrf2 Pathways

Trehalose, as a natural disaccharide, is known as an autophagy inducer. The neuroprotectiveeffects of trehalose in the rat model of Parkinson′s disease were the aim of the present study.Parkinson′s disease model was induced by injecting 6-hydroxydopamine (6-OHDA) in thestriatum of male Wistar rats. Apomorphine-induced behavior and substantia nigra neuronalcounts were applied to evaluate the neuroprotective effects of trehalose. The autophagy wasstudied using the expression of p62 and LC3II/LC3I ratio. In addition, the antioxidant effectsof trehalose were assessed by analyzing the levels of nuclear factor (erythroid-derived 2)-like2 (Nrf2) and also glutathione reductase (GR), glutathione peroxidase (GPx) and Catalase(CAT) enzymes. Moreover, the levels of 3, 4-dihydroxyphenylacetic acid (DOPAC) anddopamine (DA) were assessed.The behavioral test showed that trehalose in the treatment groupreduced the damage to the substantial nigra dopaminergic neurons, which was characterizedby improved motor and reduced rotations in the treatment group as compared with the lesiongroup. In the histological examinations of the treatment group, trehalose prevented thedestruction of dopaminergic neurons. Trehalose treatments increased autophagy (high LC3II/LC3I ratio) and the expression of the p62 protein as well. Through p62-dependent manner,it led to increased nuclear translocation of Nrf2 transcription factor and elevated expressionof downstream antioxidant enzymes, such as GR, GPx, and CAT, restoring DA and DOPACcontents of the cells. In the current study, trehalose simultaneously protects substantia nigradopaminergic cells by activating both non-canonical p62/SQSTM1-Keap1-Nrf2 and autophagypathways.