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Repetitive Ischemic Preconditioning Attenuates Inflammatory Reaction and Brain Damage After Focal Cerebral Ischemia in Rats: Involvement of PI3K/Akt and ERK1/2 Signaling Pathway

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Abstract

Ischemic preconditioning (IPC) has been demonstrated to provide a neuroprotection against brain damage produced by focal cerebral ischemia. However, it is elusive whether ischemic preconditioning attenuates ischemic brain damage through modulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. In the present study, we first explored the best scheme of repetitive ischemic preconditioning (RIPC) to protect rat brain against ischemic damage and then further investigated the underlying mechanisms in RIPC’s neuroprotection. Adult male Sprague-Dawley rats underwent ischemic preconditioning or (and) middle cerebral artery occlusion (MCAO). LY294002 or (and) PD98059 were injected intracerebroventricularly to selectively inhibit the activation of PI3K/Akt or ERK1/2. Neurological deficit scores, cerebral infarct volume, and morphological characteristic were detected at corresponding time after cerebral ischemia. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after cerebral ischemia. Expressions of p-Akt, t-Akt, p-ERK1/2, t-ERK1/2, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in ischemic brain were determined by Western blot. The release of tumor necrosis factor-α (TNF-α) in blood was examined by ELISA. In the various schemes of RIPC, IPC2 × 5 min causes less neuronal damage in the cortex and subcortex of ischemic brain and provides an obvious alleviation of cerebral infarction and neurological deficit after lethal ischemia. IPC2 × 5 min significantly reduces cerebral infarct volume, neurological deficit scores, and MPO activity; all of which were diminished by LY294002 or (and) PD98059. IPC2 × 5 min significantly upregulates the expressions of p-Akt and p-ERK1/2, which were inhibited by LY294002 or (and) PD98059. IPC2 × 5 min significantly downregulates the expressions of NF-κB p65 and COX-2 and attenuates the release of TNF-α; all of which were abolished by LY294002 or (and) PD98059. IPC2 × 5 min is the best scheme of RIPC to protect rat brain against cerebral ischemia. IPC2 × 5 min attenuates brain damage in rats subjected to lethal ischemia, and this neuroprotection is associated with inhibition of neuroinflammation through modulating PI3K/Akt and ERK1/2 signaling pathway.

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Abbreviations

AIS:

Acute ischemic stroke

BBB:

Blood-brain barrier

COX-2:

Cyclooxygenase-2

DMSO:

Dimethyl sulfoxide

ELISA:

Enzyme-linked immunosorbent assay

ERK1/2:

Extracellular signal-regulated kinase 1/2

HE:

Hematoxylin and eosin

ICV:

Intracerebroventricular

IPC:

Ischemic preconditioning

MCAO:

Middle cerebral artery occlusion

MMP-9:

Matrix metalloproteinase-9

MPO:

Myeloperoxidase

NF-κB:

Nuclear factor-kappa B

NT:

Neuroprotective therapy

PI3K/Akt:

Phosphatidylinositol 3-kinase/Akt

RIPC:

Repetitive ischemic preconditioning

TNF-α:

Tumor necrosis factor-α

t-PA:

Tissue-plasminogen activator

TT:

Thrombolytic therapy

TTC:

2,3,5-Triphenyltetrazolium chloride

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Acknowledgments

The National Natural Science Foundation of China (81100987), the Natural Science Foundation of Fujian Province of China (2011J05066), the Doctoral Program Foundation of Institutions of Higher Education of China (20113518120005), the Clinical Key Subject (Neurosurgery) Funding of Fujian Medical University, and the Key Laboratory (Neurosurgical Department) Funding from the Affiliated Union Hospital of Fujian Medical University supported this work.

Competing Interests

The authors declare that they have no competing interests.

Authors’ Contributions

Xian-kun Tu, Song-sheng Shi, Quan Chen, and Ping-ping Chen performed all experimental studies and data acquisition and contributed to the study conception, design, analysis, and data interpretation. Xian-kun Tu, Song-sheng Shi, Jian-ping Chen, and Yan Chen collected samples, performed data analysis, and drafted the manuscript. Wei-zhong Yang revised the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Neurosurgery, Fujian Medical University Union Hospital, 29# Xinquan Road, Fuzhou, Fujian, 350001, China

    Xian-kun Tu, Wei-zhong Yang, Jian-ping Chen, Yan Chen, Quan Chen, Ping-ping Chen & Song-sheng Shi

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  1. Xian-kun Tu
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Correspondence to Xian-kun Tu or Song-sheng Shi.

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Tu, Xk., Yang, Wz., Chen, Jp. et al. Repetitive Ischemic Preconditioning Attenuates Inflammatory Reaction and Brain Damage After Focal Cerebral Ischemia in Rats: Involvement of PI3K/Akt and ERK1/2 Signaling Pathway. J Mol Neurosci 55, 912–922 (2015). https://doi.org/10.1007/s12031-014-0446-9

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