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Emerging Role of Microglia-Mediated Neuroinflammation in Epilepsy after Subarachnoid Hemorrhage

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Abstract

Epilepsy is a common and serious complication of subarachnoid hemorrhage (SAH), giving rise to increased morbidity and mortality. It’s difficult to identify patients at high risk of epilepsy and the application of anti-epileptic drugs (AEDs) following SAH is a controversial topic. Therefore, it’s pressingly needed to gain a better understanding of the risk factors, underlying mechanisms and the optimization of therapeutic strategies for epilepsy after SAH. Neuroinflammation, characterized by microglial activation and the release of inflammatory cytokines, has drawn growing attention due to its influence on patients with epilepsy after SAH. In this review, we discuss the risk factors for epilepsy after SAH and emphasize the critical role of microglia. Then we discuss how various molecules arising from pathophysiological changes after SAH activate specific receptors such as TLR4, NLRP3, RAGE, P2X7R and initiate the downstream inflammatory pathways. Additionally, we focus on the significant responses implicated in epilepsy including neuronal excitotoxicity, the disruption of blood-brain barrier (BBB) and the change of immune responses. As the application of AEDs for seizure prophylaxis after SAH remains controversial, the regulation of neuroinflammation targeting the key pathological molecules could be a promising therapeutic method. While neuroinflammation appears to contribute to epilepsy after SAH, more comprehensive experiments on their relationships are needed.

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Data Availability

All material and datasets are available as required.

Abbreviations

SAH:

subarachnoid hemorrhage

CNS:

central nervous system

AEDs:

anti-epileptic drugs

BBB:

blood-brain barrier

MCA:

middle cerebral artery

NCSz:

nonconvulsive seizures

VAM:

vessel-associated microglia

MMP-9:

Matrix metalloproteinase 9

HMGB1:

high mobility group box-1

VSMCs:

vascular smooth muscle cells

HO:

heme oxygenase

CO:

carbon monoxide

NMDA:

N-methyl-D-aspartate

TLR4:

Toll-like receptor 4

NLRP3:

NOD-like receptor 3

RAGE:

receptor for advanced glycation end products

P2X7R:

P2X7 receptor

NF-κB:

nuclear factor-κB

MAPKs:

mitogen-activated protein kinases

AP-1:

transcription factor activator protein-1

NEK7:

NIMA related kinase 7

TWIK2:

two-pore domain weak inwardly rectifying K + channel 2

Kir2:

the inward rectifier K+

CLICs:

Cl − intracellular channels

ELISA:

enzyme-linked immunosorbent assay

TGF-βR:

transforming growth factor-β receptor

MLV:

meningeal lymphatic vessels

GR:

glucocorticoid receptor

ANXA1:

annexin A1

(VPA):

valproic acid

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Acknowledgments

This work was supported by grants from the Natural Science Fund of Guangdong Province (No. 2017A030313597), “Climbing Program” Special Fund of Guangdong Province (No. pdjh2019b0100, No. pdjh2020b0112) and Southern Medical University (No. LX2016N006, No. KJ20161102, No.201912121004S, No.201912121013, No. S202012121088, No. X202012121354, No. 19NJ-YB03).

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  1. Jingxue Liang, Jiahong Deng and Xiaolin Liang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Jun Wang, Kewan Wang, Hongxiao Wang, Dadi Qian, Hao Long, Kaijun Yang & Songtao Qi

  2. The First Clinical Medicine College, Southern Medical University, Guangzhou, China

    Jun Wang, Jingxue Liang, Jiahong Deng, Xiaolin Liang, Kewan Wang, Hongxiao Wang, Dadi Qian, Hao Long, Kaijun Yang & Songtao Qi

  3. Neural Networks Surgery Team, Southern Medical University, Guangzhou, China

    Jun Wang, Jingxue Liang, Jiahong Deng & Xiaolin Liang

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Jun Wang initiated this project. Jingxue Liang and Jiahong Deng performed the literature research and contributed to the original draft. Other authors participated in the revision of the manuscript.

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Highlights

1. There is a close relationship between epilepsy and inflammatory state after SAH.

2. Microglia and specific receptors are involved in neuroinflammation after SAH.

3. Several anti-inflammatory therapies have been reported to exert neuroprotective effects on epilepsy.

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Wang, J., Liang, J., Deng, J. et al. Emerging Role of Microglia-Mediated Neuroinflammation in Epilepsy after Subarachnoid Hemorrhage. Mol Neurobiol 58, 2780–2791 (2021). https://doi.org/10.1007/s12035-021-02288-y

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