Omarigliptin attenuates rotenone-induced Parkinson's disease in rats: Possible role of oxidative stress, endoplasmic reticulum stress and immune modulation

Haidy E Michel; Mariam M Tadros; Moataz S Hendy; Shereen Mowaka; Bassam M Ayoub

doi:10.1016/j.fct.2022.113015

Omarigliptin attenuates rotenone-induced Parkinson's disease in rats: Possible role of oxidative stress, endoplasmic reticulum stress and immune modulation

Food Chem Toxicol. 2022 Jun:164:113015. doi: 10.1016/j.fct.2022.113015. Epub 2022 Apr 16.

Authors

Haidy E Michel¹, Mariam M Tadros², Moataz S Hendy³, Shereen Mowaka⁴, Bassam M Ayoub⁵

Affiliations

¹ Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abassia, Cairo, 11566, Egypt. Electronic address: heidieffat@pharma.asu.edu.eg.
² Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Or-ganization of African Unity Street, Abassia, Cairo, 11566, Egypt.
³ Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt; Analytical Chemistry Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Cairo, 11795, Egypt.
⁵ Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt. Electronic address: Bassam.ayoub@bue.edu.eg.

PMID: 35439590
DOI: 10.1016/j.fct.2022.113015

Abstract

The current study aimed to explore the potential neuroprotective effect of omarigliptin (OG), an antidiabetic drug that crosses the blood-brain barrier (BBB), in a Parkinson's disease (PD) rotenone-based rat-model. Results showed that OG attenuated motor impairment, histological aberrations, α-synuclein accumulation, and rescued the dopaminergic neurons in rotenone-administered rats. Furthermore, OG halted rotenone-induced oxidative stress; as shown by reduced lipid peroxidation, decline in the oxidative stress sensor (nuclear factor erythroid 2-related factor 2) and its downstream heme oxygenase-1. In addition, OG abrogated neuroinflammation and apoptosis in rotenone-treated rats. Moreover, OG ameliorated endoplasmic reticulum (ER) stress in rotenone-administered rats; as evidenced by reduced levels of ER resident proteins such as glucose-regulated protein 78, C/EBP homologous protein and apoptotic caspase-12. In conclusion, this study implies repurposing of OG, as a novel neuroprotective agent due to its antioxidant properties, its effects on ER stress in addition to its anti-inflammatory and anti-apoptotic activities.

Keywords: Endoplasmic reticulum stress; Omarigliptin; Parkinson's disease; Repurposing; Rotenone.

MeSH terms

Animals
Dopaminergic Neurons
Endoplasmic Reticulum Stress
Heterocyclic Compounds, 2-Ring
Neuroprotective Agents* / pharmacology
Neuroprotective Agents* / therapeutic use
Oxidative Stress
Parkinson Disease* / drug therapy
Parkinson Disease* / etiology
Parkinson Disease* / metabolism
Pyrans
Rats
Rotenone / toxicity

Substances

2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo(3,4-c)pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-amine
Heterocyclic Compounds, 2-Ring
Neuroprotective Agents
Pyrans
Rotenone