Neuroprotective Effect of Phloretin in Rotenone-Induced Mice Model of Parkinson’s Disease: Modulating mTOR-NRF2-p62 Mediated Autophagy-Oxidative Stress Crosstalk

Article type: Research Article

Authors: Shirgadwar, Shubhendu M. | Kumar, Rahul | Preeti, Kumari | Khatri, Dharmendra Kumar^{; *} | Singh, Shashi Bala^{; *}

Affiliations: Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER)-Hyderabad, Telangana, India

Correspondence: [*] Correspondence to: Dr. Dharmendra Kumar Khatri, M Pharm, PhD, Assistant Professor, Molecular & Cellular Neuroscience Lab, Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, India. Tel.: +91 40 23073741; Fax: +91 40 23073751; E-mail: [email protected] and Dr. Shashi Bala Singh, FNASc, FIAN, FAMS, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana-500037, India. Tel.: +91 40 23073741; Fax: +91 40 23073751; E-mail: [email protected].

Abstract: Background:Parkinson’s disease (PD) is an age-related progressive multifactorial, neurodegenerative disease. The autophagy and Keap1-Nrf2 axis system are both implicated in the oxidative-stress response, metabolic stress, and innate immunity, and their dysregulation is associated with pathogenic processes in PD. Phloretin (PLT) is a phenolic compound reported possessing anti-inflammatory and antioxidant activities. Objective:To evaluate the neuroprotective potential of PLT in PD via modulating the autophagy-antioxidant axis Methods:The neuroprotective effect of PLT was evaluated in vitro using rotenone (ROT) exposed SH-SY5Y cell line and in vivo using ROT administered C57BL/6 mice. Mice were administered with PLT (50 and 100 mg/kg, p.o.) concomitantly with ROT (1 mg/kg, i.p) for 3 weeks. Locomotive activity and anxiety behaviors were assessed using rotarod and open field tests respectively. Further apoptosis (Cytochrome-C, Bax), α-Synuclein (α-SYN), tyrosine hydroxylase (TH), antioxidant proteins (nuclear factor erythroid 2-related factor 2 (NRF2), and heme oxygenase-1 (HO-1), autophagic (mTOR, Atg5,7, p62, Beclin, and LC3B-I/II), were evaluated both in in vitro and in vivo. Results:PLT improved locomotive activity and anxiety-like behavior in mice. Further PLT diminished apoptotic cell death, and α-SYN expression and improved the expression of TH, antioxidant, and autophagic regulating protein. Conclusion:Taken together, present data deciphers that the PLT effectively improves motor and non-motor symptoms via modulating the mTOR/NRF2/p62 pathway-mediated feedback loop. Hence, PLT could emerge as a prospective disease-modifying drug for PD management.

Keywords: Apoptosis, autophagy, oxidative stress, Parkinson’s disease, phloretin

DOI: 10.3233/JAD-220793

Journal: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022