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Mechanistic Insight on Autophagy Modulated Molecular Pathways in Cerebral Ischemic Injury: From Preclinical to Clinical Perspective

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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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Acknowledgements

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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  1. Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India

    Palak Kalra, Heena Khan, Amarjot Kaur & Thakur Gurjeet Singh

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  1. Palak Kalra
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  2. Heena Khan
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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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Correspondence to Thakur Gurjeet Singh.

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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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