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

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.

Keywords: Fibrosis; Inflammation; Intraventricular hemorrhage; Metformin; Post-hemorrhage hydrocephalus.