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Metformin Alleviates Delayed Hydrocephalus after Intraventricular Hemorrhage by Inhibiting Inflammation and Fibrosis

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Abstract

Intraventricular hemorrhage (IVH) is a subtype of intracerebral hemorrhage (ICH) with high morbidity and mortality. Posthemorrhagic hydrocephalus (PHH) is a common and major complication that affects prognosis, but the mechanism is still unclear. Inflammation and fibrosis have been well established as the major causes of PHH after IVH. In this study, we aimed to investigate the effects of metformin on IVH in adult male mice and further explored the underlying molecular mechanisms of these effects. In the acute phase, metformin treatment exerted dose-dependent neuroprotective effects by reducing periependymal apoptosis and neuronal degeneration and decreasing brain edema. Moreover, high-dose metformin reduced inflammatory cell infiltration and the release of proinflammatory factors, thus protecting ependymal structure integrity and subependymal neurons. In the chronic phase, metformin administration improved neurocognitive function and reduced delayed hydrocephalus. Additionally, metformin significantly inhibited basal subarachnoid fibrosis and ependymal glial scarring. The ependymal structures partially restored. Mechanically, IVH reduced phospho-AMPK (p-AMPK) and SIRT1 expression and activated the phospho-NF-κB (p-NF-κB) inflammatory signaling pathway. However, metformin treatment increased AMPK/SIRT1 expression and lowered the protein expression of p-NF-κB and its downstream inflammation. Compound C and EX527 administration reversed the anti-inflammatory effect of metformin. In conclusion, metformin attenuated neuroinflammation and subsequent fibrosis after IVH by regulating AMPK /SIRT1/ NF-κB pathways, thereby reducing delayed hydrocephalus. Metformin may be a promising therapeutic agent to prevent delayed hydrocephalus following IVH.

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Abbreviations

IVH :

Intraventricular hemorrhage

PHH :

Posthemorrhagic hydrocephalus

ICH :

Intracerebral hemorrhage

GMH :

Germinal matrix hemorrhage

ICP :

Intracranial pressure

ETV :

Endoscopic third ventriculostomy

CSF :

Cerebrospinal fluid

CPe :

Choroid plexus epithelium

SVZ :

Subventricular zone

CNS :

Central nervous system

AMPK :

AMP-activated protein kinase

NF-κB :

Nuclear factor-κB

MRI :

Magnetic resonance imaging

TUNEL :

Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling

FJC :

Fluoro-Jade C

HE :

Hematoxylin and eosin

PBS :

Phosphate-buffered saline

Iba-1 :

Ionized calcium bindingadaptor molecule-1

GFAP :

Glial fibrillary acidic protein

SEM :

Scanning electron microscopy

PBST :

PBS plus Tween-2

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Author notes

  1. Yi Cao, Chang Liu, Gaowei Li, and Weina Gao contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China

    Yi Cao, Chang Liu, Gaowei Li, Shuanmin Fan, Xin Tang, Long Zhao, Haoxiang Wang, Chao You & Liangxue Zhou

  2. Department of Neurosurgery, Chengdu Second People’s Hospital, Chengdu, Sichuan, People’s Republic of China

    Yi Cao

  3. Department of Intensive Care Unit, The Affiliated Chengdu 363 Hospital of Southwest Medical University, Chengdu, Sichuan, People’s Republic of China

    Weina Gao

  4. Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China

    Hui Tang

  5. Department of Neurosurgery, The Affiliated Hospital of Yangzhou University, Jiangsu, People’s Republic of China

    Aijun Peng

  6. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Aiping Tong

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  1. Yi Cao
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Cao, Y., Liu, C., Li, G. et al. Metformin Alleviates Delayed Hydrocephalus after Intraventricular Hemorrhage by Inhibiting Inflammation and Fibrosis. Transl. Stroke Res. 14, 364–382 (2023). https://doi.org/10.1007/s12975-022-01026-3

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