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Targeting PI3K/Akt in Cerebral Ischemia Reperfusion Injury Alleviation: From Signaling Networks to Targeted Therapy

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Ischemia/reperfusion (I/R) injury is a pathological event that results in reperfusion due to low blood flow to an organ. Cerebral ischemia is a common cerebrovascular disease with high mortality, and reperfusion is the current standard intervention. However, reperfusion may further induce cellular damage and dysfunction known as cerebral ischemia/reperfusion injury (CIRI). Currently, strategies for the clinical management of CIRI are limited, necessitating the exploration of novel and efficacious treatment modalities for the benefit of patients. PI3K/Akt signaling pathway is an important cellular process associated with the disease. Stimulation of the PI3K/Akt pathway enhances I/R injury in multiple organs such as heart, brain, lung, and liver. It stands as a pivotal signaling pathway crucial for diminishing cerebral infarction size and safeguarding the functionality of brain tissue after CIRI. During CIRI, activation of the PI3K/Akt pathway exhibits a protective effect on CIRI. Furthermore, activation of the PI3K/Akt pathway has the potential to augment the activity of antioxidant enzymes, resulting in a decrease in reactive oxygen species (ROS) and the associated oxidative stress. Meanwhile, PI3K/Akt plays a neuroprotective role by inhibiting inflammatory responses and apoptosis. For example, PI3K/Akt interacts with NF-κB, Nrf2, and MAPK signaling pathways to mitigate CIRI. This article is aimed to explore the pivotal role and underlying mechanism of PI3K/Akt in ameliorating CIRI and investigate the influence of ischemic preconditioning and post-processing, as well as the impact of pertinent drugs or activators targeting the PI3K/Akt pathway on CIRI. The primary objective is to furnish compelling evidence supporting the activation of PI3K/Akt in the context of CIRI, elucidating its mechanistic intricacies. By doing so, the paper aims to underscore the critical contribution of PI3K/Akt in mitigating CIRI, providing a theoretical foundation for considering the PI3K/Akt pathway as a viable target for CIRI treatment.

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Data Availability

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Abbreviations

CIRI:

Cerebral ischemia–reperfusion injury

NF-κB:

Nuclear transcription factor-κB

PI3K/Akt:

Phosphatidylinosine 3 kinase/protein kinase B

Nrf2:

Nuclear factor erythroid-2-related factor 2

Akt:

Protein kinase B

IGF-1:

Insulin-like growth factor-1

FGF:

Fibroblast growth factor

EGF:

Epidermal growth factor

RTK:

Receptor tyrosine kinase

ROS:

Reactive oxygen

RNS:

Reactive nitrogen species

BBB:

Blood-brain barrier

CAT:

Catalase

SOD:

Superoxide dismutase

GSH:

Glutathione

I/R:

Ischemia/reperfusion

TLR4:

Toll-like receptor-4

PTEN:

Tensin homologous protein

MMPs:

Matrix metalloproteinase

MCAO:

Middle cerebral artery occlusion

MAPK:

Mitogen activated protein kinase

OGD/R:

Oxygen-glucose deprivation/reoxygenation

IPC:

Ischemic preconditioning

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Acknowledgements

We are grateful the support from Cuiying Scientific and Techhnological Innovationn Program of The Second Hospital & Clinical Medical School, Lanzhou University.

Funding

This work has been co-financed by Research project of Traditional Chinese Medicine in Gansu province [GZKZ-2021-9]; Cuiying Scientific and Technological Innovation Program of' The Second Hospital & Clinical Medical School, Lanzhou University(CY2022-MS-A17, CY2021-MS18, CY2023-QN-B02); The Science and Technology Plan Project of Chengguan District of Lanzhou City(2019RCCX0068) and Lanzhou Talent Innovation and Entrepreneurship Project Foundation of China (2021-RC-98)..

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Authors and Affiliations

  1. The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730000, People’s Republic of China

    Ting Zheng, Taotao Jiang, Hongxiang Ma, Yanping Zhu & Manxia Wang

  2. Department of Neurology, The Second Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of China

    Ting Zheng, Taotao Jiang, Hongxiang Ma, Yanping Zhu & Manxia Wang

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  1. Ting Zheng
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  2. Taotao Jiang
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  3. Hongxiang Ma
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Ting Zheng and Taotao Jiang wrote the manuscript. Manxia Wang conceived and designed the review; Ting Zheng drafted the manuscript; Hongxiang Ma and Yanping Zhu assisted in the preparation of the charts. All authors contributed to the article and approved the submitted version.

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Correspondence to Manxia Wang.

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Zheng, T., Jiang, T., Ma, H. et al. Targeting PI3K/Akt in Cerebral Ischemia Reperfusion Injury Alleviation: From Signaling Networks to Targeted Therapy. Mol Neurobiol 61, 7930–7949 (2024). https://doi.org/10.1007/s12035-024-04039-1

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