Curcumin Protects against Ischemic Stroke by Titrating Microglia/Macrophage Polarization

Abstract

Stroke is the most common type of cerebrovascular disease and is a leading cause of disability and death. Ischemic stroke accounts for approximately 80% of all strokes. The remaining 20% of strokes are hemorrhagic in nature. To date, therapeutic options for acute ischemic stroke are very limited. Recent research suggests that shifting microglial phenotype from the pro-inflammatory M1 state toward the anti-inflammatory and tissue-reparative M2 phenotype may be an effective therapeutic strategy for ischemic stroke. The dietary phytochemical curcumin has shown promise in experimental stroke models, but its effects on microglial polarization and long-term recovery after stroke are unknown. Here we address these gaps by subjecting mice to distal middle cerebral artery occlusion (dMCAO) and administering curcumin intraperitoneally (150 mg/kg) immediately after ischemia and 24 h later. Histological studies revealed that curcumin post-treatment significantly reduced cerebral ischemic damage 3 days after dMCAO. Sensorimotor functions—as measured by the adhesive removal test and modified Garcia scores—were superior in curcumin-treated mice at 3, 5, 7 and 10 days after stroke. RT-PCR measurements revealed an elevation of M2 microglia/macrophage phenotypic markers and a reduction in M1 markers in curcumin-treated brains 3 days after dMCAO. Immunofluorescent staining further showed that curcumin treatment significantly increased the number of CD206+Iba1+ M2 microglia/macrophages and reduced the number of CD16+Iba1+ M1 cells 10 days after stroke. In vitro studies using the BV2 microglial cell line confirmed that curcumin inhibited lipopolysaccharide (LPS) and interferon-γ (IFN-γ)-induced M1 polarization. Curcumin treatment concentration-dependently reduced the expression of pro-inflammatory cytokines, including TNF-α, IL-6 and IL-12p70, in the absence of any toxic effect on microglial cell survival. In conclusion, we demonstrate that curcumin has a profound regulatory effect on microglial responses, promoting M2 microglial polarization and inhibiting microglia-mediated pro-inflammatory responses. Curcumin post-treatment reduces ischemic stroke-induced brain damage and improves functional outcomes, providing new evidence that curcumin might be a promising therapeutic strategy for stroke.

Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti‐inflammatory phenotype through STAT3 pathway

“…Distal middle cerebral artery occlusion (dMCAO) model was induced according to our previous report . Briefly, anesthesia was induced with 2% isoflurane in N 2 /O 2 (70%:30%) mixture.…”

“…Distal middle cerebral artery occlusion (dMCAO) model was induced according to our previous report. 15 Briefly, anesthesia was induced with 2% isoflurane in N 2 /O 2 (70%:30%) mixture. A ~ 2 cm skin incision was created between the right margin of the orbit and the tragus, and the temporalis muscle was dissected to expose right zygomatic arches and squamosal bone.…”

“…In vivo and vitro studies revealed that inhibiting pro‐inflammatory microglia phenotype and/or stimulating anti‐inflammatory microglia state were neuroprotective . For example, some drugs, including ginkgolide B, malibatol A, thiamet G, baicalein, isosteviol sodium, curcumin, oxytocin, and dimethyl fumarate have been reported to protect against brain injury through regulating microglia/macrophage polarization and inflammatory responses in experimental models of brain ischemia or hypoperfusion. Some physiological factors, such as hypothermia, also altered microglia/macrophage phenotype.…”

Melatonin improves functional recovery in female rats after acute spinal cord injury by modulating polarization of spinal microglial/macrophages

“…Protein concentrations were determined by the Bradford assay (BioRad Laboratories, Richmond, CA, USA) with BSA as the standard (Bradford, ). Levels of cytokines (TNF‐α, IL‐6, IL‐1β, TGF‐β, and IL‐13) in the spinal cord were detected by ELISA (Cusabio Co., Ltd., Wuhan, China) according to the manufacturer's instructions (Liu et al, ). Each sample was assayed in six duplicates.…”

Benefits of curcumin in brain disorders

“…Curcumin exerts its protective effects mainly through four important mechanisms: Free radical scavenging potential and inhibiting the increase in nitric oxide synthesis and lipid peroxidation levels Anti‐inflammatory activity by suppressing the production of interleukins (IL‐1, IL‐8, and TNF) Anti‐lipidemic activity by lowering cholesterol and boosting up HDL levels Curcumin inhibits platelet aggregation factor by interfering with the kinase activity of Syk and the subsequent activation of PLCgamma2 …”