Abstract
Cerebral ischemia is one of the most devastating brain injuries and a primary cause of acquired and persistent disability worldwide. Despite ongoing therapeutic interventions at both the experimental and clinical levels, options for stroke-related brain injury are still limited. Several evidence suggests that autophagy is triggered in response to cerebral ischemia, therefore targeting autophagy-related signaling pathways can provide a new direction for the therapeutic implications in the ischemic injury. Autophagy is a highly conserved lysosomal-dependent pathway that degrades and recycles damaged or non-essential cellular components to maintain neuronal homeostasis. But, whether autophagy activation promotes cell survival against ischemic injury or, on the contrary, causes neuronal death is still under debate. We performed an extensive literature search from PubMed, Bentham and Elsevier for various aspects related to molecular mechanisms and pathobiology involved in autophagy and several pre-clinical studies justifiable further in the clinical trials. Autophagy modulates various downstream molecular cascades, i.e., mTOR, NF-κB, HIF-1, PPAR-γ, MAPK, UPR, and ROS pathways in cerebral ischemic injury. In this review, the various approaches and their implementation in the translational research in ischemic injury into practices has been covered. It will assist researchers in finding a way to cross the unbridgeable chasm between the pre-clinical and clinical studies.
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Abbreviations
- 3-MA:
-
3-Methyladenine
- Aβ:
-
Amyloid-β (Aβ)
- AIS:
-
Acute ischemic stroke
- Akt/PKB:
-
Protein kinase B
- AMP:
-
Adenosine monophosphate
- AMPA:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
- AMPK:
-
Adenosine monophosphate–activated protein kinase
- ATG:
-
Autophagy-related genes
- ATF6:
-
Activating transcription factor 6
- ATP:
-
Adenosine triphosphate
- BAX:
-
Bcl 2-associated X protein
- BI:
-
Barthel Scale/Index
- BBB:
-
Blood–brain barrier
- BCAO:
-
Bilateral common carotid artery occlusion
- Bcl-2:
-
B-cell lymphoma 2
- BNIP3:
-
Bcl2 interacting protein 3
- BNIP3L:
-
Bcl2 interacting protein 3 like
- BMECs:
-
Brain microvascular endothelial cells
- Ca2+:
-
Calcium ion
- CMA:
-
Chaperone-mediated autophagy
- CNS:
-
Central nervous system
- CHOP:
-
C/EBP-homologous protein
- DRAM:
-
Damage-regulated autophagy modulator
- DRP1:
-
Dynamin-related protein 1
- ER:
-
Endoplasmic reticulum
- ERK:
-
Extracellular regulated protein kinases
- eIF2α :
-
Eukaryotic initiation factor 2α
- Elk1:
-
ETS transcription factor ELK1
- FDA:
-
Food and Drug Administration
- FOXO3:
-
Forkhead box O3
- G-CSF:
-
Granulocyte-colony stimulating factor
- GDP:
-
Guanosine diphosphate
- GRP78:
-
Glucose regulatory protein 78
- GTP:
-
Guanosine triphosphate
- HHcy:
-
Hyperhomocysteinemia
- HIF-1:
-
Hypoxia-Inducible Factor-1
- HUK:
-
Human urinary kallidinogenase
- HUVECs:
-
Human umbilical vein endothelial cells
- IKK:
-
IκB kinase
- IRE1:
-
Inositol requiring kinase 1
- I/R injury:
-
Ischemia/reperfusion injury
- JNK:
-
C-Jun N-terminal kinase
- K+:
-
Potassium ion
- LC3:
-
Microtubule-associated protein 1A/1B-light chain 3
- MAPK:
-
Mitogen-activated protein kinase
- MCAO:
-
Middle cerebral artery occlusion
- MEK:
-
Mitogen-activated protein kinase kinase
- mRS:
-
Modified Rankin Scale
- mTOR:
-
Mammalian target of rapamycin
- NF-κB:
-
Nuclear factor-kappa B
- NIHSS:
-
National Institutes of Health Stroke Scale
- NLRP3:
-
NLR family pyrin domain containing 3
- NMDA:
-
N-methyl d-aspartate
- NO:
-
Nitric oxide
- Nrf2:
-
Nuclear factor erythroid 2–related factor 2
- OGD/R:
-
Oxygen and glucose deprivation/reoxygenation
- PDK1:
-
3-Phosphoinositide-dependent kinase 1
- PE:
-
Phosphoethanolamine
- PERK:
-
Protein kinase RNA-like ER kinase
- PHQ-9 scale:
-
Patient Health Questionnaire-9 scale
- PI3K:
-
Phosphoinositide 3-kinase
- PI(3)P:
-
Phosphatidylinositol 3-phosphate
- PMCAO:
-
Permanent middle cerebral artery occlusion
- PPAR-γ:
-
Peroxisome proliferator-activated receptor gamma
- Rheb:
-
Ras homolog enriched in brain
- ROS:
-
Reactive oxygen species
- SIRT1:
-
Sirtuin 1
- sLOX-1:
-
Soluble LOX-1
- TBI:
-
Traumatic brain injury
- TIGAR:
-
Tp53-induced glycolysis and apoptosis regulator
- tMCAO:
-
Transient middle cerebral artery occlusion
- TNFα:
-
Tumor necrosis factor- α
- tPA:
-
Tissue plasminogen activator
- TRAF-2:
-
Tumor necrosis factor receptor-associated factor-2
- TSC1 and TSC2:
-
Tuberous sclerosis proteins 1 and 2
- ULK1/2:
-
Unc-51 like autophagy activating kinase
- UPR:
-
Unfolded protein response
- Vps34:
-
Vacuolar protein sorting 34
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The authors are grateful to the Chitkara College of Pharmacy, Chitkara University, Rajpura, Patiala, Punjab, India, for providing the necessary facilities to carry out the research work.
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Conceptualization: conceived and designed the experiments: TGS. Analyzed the data: AK. Wrote the manuscript: PK, HK. Visualization: AK, TGS. Editing of the Manuscript: HK, AK, TGS Critically reviewed the article: TGS. Supervision: TGS. All authors read and approved the final manuscript.
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Kalra, P., Khan, H., Kaur, A. et al. Mechanistic Insight on Autophagy Modulated Molecular Pathways in Cerebral Ischemic Injury: From Preclinical to Clinical Perspective. Neurochem Res 47, 825–843 (2022). https://doi.org/10.1007/s11064-021-03500-0
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DOI: https://doi.org/10.1007/s11064-021-03500-0