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

Repaglinide Elicits a Neuroprotective Effect in Rotenone-Induced Parkinson’s Disease in Rats: Emphasis on Targeting the DREAM-ER Stress BiP/ATF6/CHOP Trajectory and Activation of Mitophagy

“…Second, the neuroprotective impact of repaglinide was studied on male Wistar rats, preferably it should be evaluated in different gender and species due to the difference in the metabolic rates. Third, the employed rotenone model is the low aggressive dose which is a well-reproducible model validated in multiple studies. ,, Fourth, we did not use a positive control group using approved drugs; however, future studies could evaluate the effect of repaglinide on levodopa-induced dyskinesia. Nevertheless, this study is the initiative to prove the neuroprotective action of the antidiabetic drug repaglinide on striatal ER stress, which needs to be extended on the remaining UPR arms.…”

“…As recapitulated in our study, rotenone administration to rats is known to induce marked weight loss. 22,29 Herein, treatment with repaglinide obviously increased the chow/water intake and improved the weight loss as reflected in the net body weight gain recorded in the treated group. Similarly, a multicenter 16-week clinical trial testing the efficacy and safety of repaglinide monotherapy in type 2 diabetic patients revealed an increase in the mean body weight at the end of the study.…”

“…Our results were similar to those reported in prior PD rat models using the same rotenone regimen, where rotenone-only treated groups showed nonsignificant blood glucose levels with normal control. 22,32,33 Interestingly, rotenone seems to promote normoglycemia and adjust glucose homeostasis in several studies. In a prior investigation on diabetic mice, rotenone enhanced insulin sensitivity, glucose metabolism, and alleviated hyperglycemia by boosting glycolysis, reducing hepatic glucose generation and regulating the cellular NAD + /NADH ratio through complex I inhibition.…”

“…To note, in our previous work, we have pioneered in proving the state of ER stress in association with α-synucleinopathy, neuroinflammation, and motor dysfunction in a rat model of rotenone-induced PD through upregulation of the GRP78/ PERK/eukaryotic initiation factor 2 α (eIF2α)/CHOP pathway, which was ameliorated by treatment with the antidiabetic drug empagliflozin. 22 Whether the amelioration of ER stress and its associated pathologic mechanisms in PD extends to the antidiabetic drug repaglinide remains to be investigated.…”

“…To note, in our previous work, we have pioneered in proving the state of ER stress in association with α-synucleinopathy, neuroinflammation, and motor dysfunction in a rat model of rotenone-induced PD through upregulation of the GRP78/ PERK/eukaryotic initiation factor 2 α (eIF2α)/CHOP pathway, which was ameliorated by treatment with the antidiabetic drug empagliflozin. 22 Whether the amelioration of ER stress and its associated pathologic mechanisms in PD extends to the antidiabetic drug repaglinide remains to be investigated. Herein, this study manifests for the first time the critical neuroprotective effects of repaglinide in rotenone-induced PD in rats via exploring its impact on striatal DREAM, the ER stress BiP/ATF6/CHOP trajectory, mitophagy, autophagy, apoptosis, oxidative stress, astrocyte/microglial activation, and neuroinflammation, along with the histopathological alterations and neurobehavioral functions.…”