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G-Protein-Coupled Receptors and Ischemic Stroke: a Focus on Molecular Function and Therapeutic Potential

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Abstract

In ischemic stroke, there is only one approved drug, tissue plasminogen activator, to be used in clinical conditions for thrombolysis. New neuroprotective therapies for ischemic stroke are desperately needed. Several targets and pathways have been shown to confer neuroprotective effects in ischemic stroke. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for developing novel therapeutics for central nervous system disorders. GPCRs are a large family of cell surface receptors that response to a wide variety of extracellular stimuli. GPCRs are involved in a wide range of physiological and pathological processes. More than 90% of the identified non-sensory GPCRs are expressed in the brain, where they play important roles in regulating mood, pain, vision, immune responses, cognition, and synaptic transmission. There is also good evidence that GPCRs are implicated in the pathogenesis of stroke. This review narrates the pathophysiological role and possible targeted therapy of GPCRs in ischemic stroke.

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Abbreviations

2-AG:

2-Arachidonoylglycerol

2VO:

2-vessel occlusion

ACEA:

Arachidonyl-2′-chloroethylamide

AEA:

Anandamide

AKT:

Protein kinase B

AMPK:

AMP-activated protein kinase

APEC:

2-[[2-[4-[2-(2-Aminoethyl)-aminocarbonyl]ethyl]phenyl]ethylamino]-5′-N-ethyl-carboxamidoadenosine

ATP:

Adenosine triphosphate

BBB:

Blood–brain barrier

BCL-2:

B-cell lymphoma 2

BDNF:

Brain-derived neurotrophic factor

CAD:

Coronary artery disease

cAMP:

Cyclic adenosine monophosphate

CBF:

Cerebral blood flow

CNS:

Central nervous system

COX-2:

Cyclooxygenase 2

CREB:

cAMP response element-binding protein

CRTH2:

Chemoattractant receptor T helper type 2

DAG:

Diacylglycerol

ERK:

Extracellular-signal-regulated kinase

FDA:

Food and Drug Administration

GABA:

Gamma-aminobutyric acid

GCI/R:

Global cerebral ischemia/reperfusion

GDP:

Guanine diphosphate

GluR2:

Glutamate receptor subunit 2

GPCR:

G-protein-coupled receptor

GSK3β:

Glycogen synthase kinase 3 beta

GTP:

Guanosine triphosphate

HIF-1α:

Hypoxia-inducible factor 1-alpha

HI:

Hypoxia–ischemia

HPGDS:

Hematopoietic PGD synthase

HT:

Hemorrhagic transformation

iGluR:

Ionotropic glutamate receptor

IL-1β:

Interleukin-1 beta

IL-6:

Interleukin-6

iNOS:

Inducible nitric oxide synthase

IP3:

Inositol triphosphate

I/R:

Ischemia/reperfusion

LPGDS:

Lipocalin-type synthase

LPS:

Lipopolysaccharides

MAPKs:

Mitogen-activated protein kinases

MCAO:

Middle cerebral artery occlusion

MCP-1:

Monocyte chemoattractant protein-1

mGluR:

Metabotropic glutamate receptor

MMP:

Matrix metallopeptidase

mPTP:

Mitochondrial permeability transition pore

MS:

Multiple sclerosis

NADPH:

Nicotinamide adenine dinucleotide phosphate

NAIP:

Neuronal apoptosis inhibitory protein

NMDA:

N-Methyl-D-aspartate

NF-κB:

Nuclear factor kappa B

NO:

Nitric oxide

OGD:

Oxygen glucose deprivation

OGD/R:

Oxygen–glucose deprivation/reperfusion

PI3K:

Phosphoinositide 3-kinases

PKA:

Protein kinase A

PKCα:

Protein kinase C alpha

PLC:

Phospholipase C

PKCε:

Protein kinase C epsilon

PMCAO:

Permanent middle cerebral artery occlusion

PP1:

Protein phosphatase 1

PSD:

Post-stroke depression

ROS:

Reactive oxygen species

SMCs:

Smooth muscle cells

TBI:

Traumatic brain injury

TGF-β:

Transforming growth factor-beta

TIM-3:

T-cell immunoglobulin and mucin domain protein 3

5-HT:

Serotonin

tMCAO:

Transient middle cerebral artery occlusion

TNFα:

Tumor necrosis factor alpha

TP:

Thromboxane prostanoid

TPA:

Tissue plasminogen activator

TrkB:

Tropomyosin receptor kinase B

TxB2:

Thromboxane B2

VTA:

Ventral tegmental area

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Acknowledgements

We thank all the people who consult us in this work.

Funding

This work was supported by a grant from Kashan University of Medical Sciences (grant no. 92071).

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Authors and Affiliations

  1. Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Zeinab Vahidinia & Mohammad Taghi Joghataei

  2. Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran

    Zeinab Vahidinia & Abolfazl Azami Tameh

  3. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran

    Mohammad Taghi Joghataei

  4. Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany

    Cordian Beyer

  5. Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, 47416-95447, Iran

    Mohammad Karimian

  6. Department of Anatomy, School of Medicine, Kashan University of Medical Sciences, Qotb-e Ravandi Blvd., Kashan, 8715988141, Iran

    Abolfazl Azami Tameh

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  1. Zeinab Vahidinia
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  2. Mohammad Taghi Joghataei
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Contributions

MK and AAT designed and supervised this work. ZV provided the draft of the manuscript. MTJ and CB initially revised the manuscript. All authors read and approved the manuscript.

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Correspondence to Mohammad Karimian or Abolfazl Azami Tameh.

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Vahidinia, Z., Joghataei, M.T., Beyer, C. et al. G-Protein-Coupled Receptors and Ischemic Stroke: a Focus on Molecular Function and Therapeutic Potential. Mol Neurobiol 58, 4588–4614 (2021). https://doi.org/10.1007/s12035-021-02435-5

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