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Metformin Alleviates Delayed Hydrocephalus after Intraventricular Hemorrhage by Inhibiting Inflammation and Fibrosis
Yi Cao1,2, Chang Liu1, Gaowei Li1
1Department of Neurosurgery and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.
Insights
Metformin reduces brain damage and swelling after intraventricular hemorrhage (IVH). It also prevents delayed hydrocephalus by decreasing inflammation and fibrosis via the AMPK/SIRT1/NF-κB pathway.
Area of Science:
- Neuroscience
- Pharmacology
- Pathology
Background:
- Intraventricular hemorrhage (IVH) leads to significant morbidity and mortality.
- Posthemorrhagic hydrocephalus (PHH) is a common complication of IVH, driven by inflammation and fibrosis.
- The precise mechanisms underlying PHH development remain unclear.
Purpose of the Study:
- To investigate the neuroprotective effects of metformin in a mouse model of IVH.
- To elucidate the molecular mechanisms by which metformin influences IVH and subsequent PHH.
Main Methods:
- Adult male mice received varying doses of metformin following induced IVH.
- Neuroprotection, inflammation, fibrosis, neurocognitive function, and hydrocephalus were assessed.
- Molecular mechanisms involving AMPK, SIRT1, and NF-κB pathways were analyzed.
Main Results:
- Metformin demonstrated dose-dependent neuroprotection, reducing apoptosis, neuronal damage, and brain edema in the acute phase.
- High-dose metformin decreased inflammatory cell infiltration and pro-inflammatory factors.
- Metformin improved neurocognitive function, reduced hydrocephalus, inhibited fibrosis and glial scarring in the chronic phase.
Conclusions:
- Metformin attenuates neuroinflammation and fibrosis post-IVH by modulating the AMPK/SIRT1/NF-κB pathway.
- Metformin shows potential as a therapeutic agent to prevent delayed hydrocephalus following IVH.
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.
