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Author Spotlight: Establishing a Reliable Distal MCA Occlusion Model in Mice for Stroke Research
Published on: December 15, 2023
Curcumin Ameliorates White Matter Injury after Ischemic Stroke by Inhibiting Microglia/Macrophage Pyroptosis through
Yuanyuan Ran1, Wei Su2, Fuhai Gao1
1Department of Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Xixiazhuang, Badachu Road, Shijingshan District, Beijing 100144, China.
Abstract:
NLRP3 inflammasome-mediated pyroptosis is a proinflammatory programmed cell death pathway, which plays a vital role in functional outcomes after stroke. We previously described the beneficial effects of curcumin against stroke-induced neuronal damage through modulating microglial polarization. However, the impact of curcumin on microglial pyroptosis remains unknown. Here, stroke was modeled in mice by middle cerebral artery occlusion (MCAO) for 60 minutes and treated with curcumin (150 mg/kg) intraperitoneally immediately after reperfusion, followed by daily administrations for 7 days. Curcumin ameliorated white matter (WM) lesions and brain tissue loss 21 days poststroke and improved sensorimotor function 3, 10, and 21 days after stroke. Furthermore, curcumin significantly reduced the number of gasdermin D+ (GSDMD+) Iba1+ and caspase-1+Iba1+ microglia/macrophage 21 days after stroke. In vitro, lipopolysaccharide (LPS) with ATP treatment was used to induce pyroptosis in primary microglia. Western blot revealed a decrease in pyroptosis-related proteins, e.g., GSDMD-N, cleaved caspase-1, NLRP3, IL-1β, and IL-18, following in vitro or in vivo curcumin treatment. Mechanistically, both in vivo and in vitro studies confirmed that curcumin inhibited the activation of the NF-κB pathway. NLRP3 knocked down by siRNA transfection markedly increased the inhibitory effects of curcumin on microglial pyroptosis and proinflammatory responses, both in vitro and in vivo. Furthermore, stereotaxic microinjection of AAV-based NLRP3 shRNA significantly improved sensorimotor function and reduced WM lesion following curcumin treatment in MCAO mice. Our study suggested that curcumin reduced stroke-induced WM damage, improved functional outcomes, and attenuated microglial pyroptosis, at least partially, through suppression of the NF-κB/NLRP3 signaling pathway, further supporting curcumin as a potential therapeutic drug for stroke.
Insights
Curcumin treatment reduced brain damage and improved function after stroke by inhibiting microglial pyroptosis, a key inflammatory cell death pathway, via the NF-κB/NLRP3 signaling pathway.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- NLRP3 inflammasome-mediated pyroptosis is a pro-inflammatory programmed cell death pathway implicated in stroke outcomes.
- Curcumin has shown neuroprotective effects in stroke models, but its impact on microglial pyroptosis was previously unknown.
Purpose of the Study:
- To investigate the effect of curcumin on microglial pyroptosis and its role in stroke recovery.
- To elucidate the underlying molecular mechanisms, specifically the NF-κB/NLRP3 signaling pathway.
Main Methods:
- Stroke was induced in mice using middle cerebral artery occlusion (MCAO) and treated with curcumin.
- Primary microglia were treated with lipopolysaccharide (LPS) and ATP in vitro to induce pyroptosis.
- Western blot, immunohistochemistry, and siRNA/shRNA techniques were used to assess pyroptosis markers and signaling pathways.
Main Results:
- Curcumin treatment significantly ameliorated white matter lesions, brain tissue loss, and improved sensorimotor function in MCAO mice.
- Curcumin reduced the number of pyroptotic microglia/macrophages (GSDMD+, caspase-1+) and decreased pyroptosis-related proteins in vitro and in vivo.
- Curcumin inhibited NF-κB pathway activation, and NLRP3 knockdown enhanced curcumin's inhibitory effects on pyroptosis.
Conclusions:
- Curcumin attenuates stroke-induced white matter damage and improves functional outcomes by suppressing microglial pyroptosis.
- The therapeutic effects of curcumin are mediated, at least partially, through the inhibition of the NF-κB/NLRP3 signaling pathway.
- Curcumin demonstrates potential as a therapeutic agent for stroke.
