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Adenosine as a Key Mediator of Neuronal Survival in Cerebral Ischemic Injury

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Abstract

Several experimental studies have linked adenosine’s neuroprotective role in cerebral ischemia. During ischemia, adenosine is formed due to intracellular ATP breakdown into ADP, further when phosphate is released from ADP, the adenosine monophosphate is formed. It acts via A1, A2, and A3 receptors found on neurons, blood vessels, glial cells, platelets, and leukocytes. It is related to various effector systems such as adenyl cyclase and membrane ion channels via G-proteins. Pharmacological manipulation of adenosine receptors by agonists (CCPA, ADAC, IB-MECA) increases ischemic brain damage in various in vivo and in vitro models of cerebral ischemia whereas, agonist can also be neuroprotective. Mainly, receptor antagonists (CGS15943, MRS1706) indicated neuroprotection. Later, various studies also revealed that the downregulation or upregulation of specific adenosine receptors is necessary during the recovery of cerebral ischemia by activating several downstream signaling pathways. In the current review, we elaborate on the dual roles of adenosine and its receptor subtypes A1, A2, and A3 and their involvement in the pathobiology of cerebral ischemic injury. Adenosine-based therapies have the potential to improve the outcomes of cerebral injury patients, thereby providing them with a more optimistic future.

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Abbreviations

ADAC:

Agonist adenosine amine congener

ATP:

Adenosine triphosphate

ADP:

Adenosine diphosphate

cAMP:

Cyclic adenosine monophosphate

CBF:

Cerebral blood flow

ERK 1/2:

Extracellular signal-regulated protein kinase ½

GPCR:

G-protein coupled receptor

iNOS:

Inducible nitric oxide synthase

MAP-2:

Microtubule-associated protein-2

NMDA:

N-Methyl-d-aspartate

NO:

Nitric oxide

OGD:

Oxygen glucose deprivation

P13K:

Phosphoinositide 3-kinase pathway

p38 MAPK:

P38 mitogen-activated protein kinase

R-PIA:

R-phenyl isopropyl-adenosine

TNF-α:

Tumour necrosis factor-alpha

TSG:

Tetrahydroxy stilbene glycoside

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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

    Heena Khan, Parneet Kaur, Thakur Gurejet Singh, Amarjot Kaur Grewal & Shreya Sood

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  1. Heena Khan
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  2. Parneet Kaur
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Conceptualization: Conceived and designed the experiments: TGS. Analyzed the data: HK, TGS. Wrote the manuscript: HK, PK Editing of the Manuscript: AKG. Critically reviewed the article: TGS.

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Correspondence to Thakur Gurejet Singh.

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Khan, H., Kaur, P., Singh, T.G. et al. Adenosine as a Key Mediator of Neuronal Survival in Cerebral Ischemic Injury. Neurochem Res 47, 3543–3555 (2022). https://doi.org/10.1007/s11064-022-03737-3

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