Abstract
The protein kinase R-like endoplasmic reticulum kinase/eukaryotic initiation factor 2ɑ (PERK/eIF2α), the branch of unfolded protein response (UPR), is responsible for transient arrest in translation to counter the enhanced levels of misfolded or unfolded proteins in the endoplasmic reticulum (ER) following any acute condition. In neurological disorders, overactivation of PERK-P/eIF2-P signaling, leads to a prolonged decline in global protein synthesis resulting in synaptic failure and neuronal death. Our study has shown, PERK/ATF4/CHOP pathway gets activated following cerebral ischemia in rats. We have further demonstrated, PERK inhibitor, GSK2606414 ameliorates ischemia induced neuronal damage by preventing additional neuronal loss, minimizing brain infarct, reducing brain edema, and preventing neurological symptoms from appearing. GSK2606414 was found to improve the neurobehavioral deficits and reduce the pyknotic neurons in ischemic rats. Also, it decreased glial activation and apoptotic protein mRNA expression while enhanced the synaptic protein mRNA expression in rat brain following cerebral ischemia. In conclusion, our findings suggest that PERK/ATF4/CHOP activation play a vital role in cerebral ischemia. Thus, PERK inhibitor, GSK2606414 might be a potential neuroprotective agent in cerebral ischemia.
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Abbreviations
- ATF4:
-
Activating transcription factor 4
- ATF6:
-
Activating transcription factor 6
- CHOP:
-
C/EBP homologous protein
- EIF2AK3:
-
Eukaryotic translational initiation factor 2α kinase-3
- IRE1:
-
Inositol requiring enzyme 1
- ER:
-
Endoplasmic reticulum
- MCAO:
-
Middle cerebral artery occlusion
- PERK:
-
Protein kinase R-like endoplasmic reticulum kinase
- MWM:
-
Morris water maze
- NOR:
-
Novel object recognition
- P-eIF2ɑ:
-
Phosphorylated eukaryotic initiation factor 2ɑ
- SAH:
-
Subarachnoid hemorrhage
- UPR:
-
Unfolded protein response
- TTC:
-
2,3,5-triphenyl-tetrazolium chloride
- IHC:
-
Immunohistochemistry
- RT-PCR:
-
Real time polymerase chain reaction
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Acknowledgements
The authors acknowledge the Department of Health Research (DHR), under the Ministry of Health and Family Welfare, Government of India for awarding the Young Scientist fellowship to Ms. Neha Dhir. Also, the authors gratefully appreciate GlaxoSmithKline (GSK) Pharmaceuticals Ltd. for providing the drug (GSK260414) to conduct this study. Authors also acknowledge PGIMER, Chandigarh, India for providing the facilities and resources to conduct this study.
Funding
The project was funded by the Department of Health Research (DHR), under the Ministry of Health and Family Welfare, Government of India. (Grant No. R 12014/18/2018-HR).
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Neha Dhir, Biksah Medhi and Ajay Prakash have designed the study protocol and experiments. Neha Dhir, Ashish Jain and Amit Raj Sharma performed the experimental and molecular experiments. Bishan Das Radotra helped in analysing histopathological data. All authors have analysed the data. Neha Dhir has written the manuscript. All authors have read, corrected and approved the manuscript.
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The Institutional Animal Ethics Committee (IAEC) at the Postgraduate Institute of Medical Education and Research in Chandigarh, India, approved the study protocol. (IAEC Approval No. 93/IAEC/653).
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Dhir, N., Jain, A., Sharma, A.R. et al. PERK inhibitor, GSK2606414, ameliorates neuropathological damage, memory and motor functional impairments in cerebral ischemia via PERK/p-eIF2ɑ/ATF4/CHOP signaling. Metab Brain Dis 38, 1177–1192 (2023). https://doi.org/10.1007/s11011-023-01183-w
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DOI: https://doi.org/10.1007/s11011-023-01183-w