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Empagliflozin alleviates endoplasmic reticulum stress and augments autophagy in rotenone-induced Parkinson's disease in rats: Targeting the GRP78/PERK/eIF2α/CHOP pathway and miR-211-5p.
- Source :
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Chemico-biological interactions [Chem Biol Interact] 2022 Aug 01; Vol. 362, pp. 110002. Date of Electronic Publication: 2022 May 30. - Publication Year :
- 2022
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Abstract
- Empagliflozin, a selective sodium-glucose co-transporter-2 inhibitor, has been demonstrated to provide additional non-glycemic benefits, including neuroprotection. Endoplasmic reticulum (ER) stress is a key player in neurodegeneration and occurs at the crossroads of other pathologic mechanisms; however, its role in the pathogenesis of Parkinson's disease (PD) is still elusive. miR-211-5p regulates neuronal differentiation and viability and was predicted to target CHOP, a downstream effector in the ER stress pathway. For the first time, this study investigated the possible neuroprotective effect of empagliflozin in a rotenone-induced rat model of PD from the perspective of ER stress. Rotenone (1.5 mg/kg) was administered subcutaneously every other day for 3 weeks. Meanwhile, the treated group received empagliflozin 10 mg/kg/day orally for 15 consecutive days post-PD induction. On the molecular level, the ER stress pathway components; GRP78, total and phosphorylated PERK, eIF2α and CHOP, along with miR-211-5p expression were upregulated in the striatum of rotenone-injected rats. Concurrently, the untreated rats showed elevated striatal α-synuclein levels along with diminished autophagy and the proteasome system as evidenced by reduced beclin-1 protein and ELF2/NERF mRNA expression levels. The rotenone-induced striatal oxidative stress and neuroinflammation were expressed by reduced catalase activity and elevated interleukin (IL)-1β levels. miR-211-5p was positively correlated with PERK/eIF2α/CHOP, IL-1β and α-synuclein, while negatively correlated with ELF2/NERF, beclin-1 and catalase activity. Empagliflozin treatment showed a restorative effect on all biochemical alterations and improved the motor function of rats tested by open field, grip strength and footprint gait analysis. In the histopathological examination, empagliflozin increased the intact neuron count and attenuated astrogliosis and microgliosis by reducing the glial fibrillary acidic protein and ionized calcium-binding adaptor protein 1 immunostaining. Conclusively, these results emphasize the neurotherapeutic impact of empagliflozin in PD by moderating the GRP78/PERK/eIF2α/CHOP ER stress pathway, downregulating miR-211-5p, resolving oxidative stress, lessening astrocyte/microglial activation and neuroinflammation, along with augmenting autophagy.<br /> (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Apoptosis drug effects
Autophagy drug effects
Beclin-1 metabolism
Catalase
Endoplasmic Reticulum Chaperone BiP
Eukaryotic Initiation Factor-2 metabolism
Heat-Shock Proteins metabolism
Rats
Rotenone toxicity
Transcription Factor CHOP metabolism
alpha-Synuclein
eIF-2 Kinase metabolism
Benzhydryl Compounds pharmacology
Endoplasmic Reticulum Stress drug effects
Glucosides pharmacology
MicroRNAs metabolism
Parkinson Disease drug therapy
Parkinson Disease metabolism
Parkinson Disease pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7786
- Volume :
- 362
- Database :
- MEDLINE
- Journal :
- Chemico-biological interactions
- Publication Type :
- Academic Journal
- Accession number :
- 35654124
- Full Text :
- https://doi.org/10.1016/j.cbi.2022.110002