Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury

Abstract

BackgroundTraumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to substantial neuronal damage and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of thiscascade. In the current study, we tested the hypothesis that curcumin, a phytochemical compound with potent anti-inflammatory properties that is extracted from the rhizome Curcuma longa, alleviates acute inflammatory injury mediated by TLR4 following TBI.MethodsNeurological function, brain water content and cytokine levels were tested in TLR4-/- mice subjected to weight-drop contusion injury. Wild-type (WT) mice were injected intraperitoneally with different concentrations of curcumin or vehicle 15 minutes after TBI. At 24 hours post-injury, the activation of microglia/macrophages and TLR4 was detected by immunohistochemistry; neuronal apoptosis was measured by FJB and TUNEL staining; cytokines were assayed by ELISA; and TLR4, MyD88 and NF-κB levels were measured by Western blotting. In vitro, a co-culture system comprised of microglia and neurons was treated with curcumin following lipopolysaccharide (LPS) stimulation. TLR4 expression and morphological activation in microglia and morphological damage to neurons were detected by immunohistochemistry 24 hours post-stimulation.ResultsThe protein expression of TLR4 in pericontusional tissue reached a maximum at 24 hours post-TBI. Compared with WT mice, TLR4-/- mice showed attenuated functional impairment, brain edema and cytokine release post-TBI. In addition to improvement in the above aspects, 100 mg/kg curcumin treatment post-TBI significantly reduced the number of TLR4-positive microglia/macrophages as well as inflammatory mediator release and neuronal apoptosis in WT mice. Furthermore, Western blot analysis indicated that the levels of TLR4 and its known downstream effectors (MyD88, and NF-κB) were also decreased after curcumin treatment. Similar outcomes were observed in the microglia and neuron co-culture following treatment with curcumin after LPS stimulation. LPS increased TLR4 immunoreactivity and morphological activation in microglia and increased neuronal apoptosis, whereas curcumin normalized this upregulation. The increased protein levels of TLR4, MyD88 and NF-κB in microglia were attenuated by curcumin treatment.ConclusionsOur results suggest that post-injury, curcumin administration may improve patient outcome by reducing acute activation of microglia/macrophages and neuronal apoptosis through a mechanism involving the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages in TBI.

Oral Administration of Nano-Emulsion Curcumin in Mice Suppresses Inflammatory-Induced NFκB Signaling and Macrophage Migration

“…These data suggest that the curcumin-mediated suppression of NFκB signaling with LPS treatment is due to downregulation of TLR4 upstream of NFκB. In concordance, downregulation of TLR4 expression on the surface of cells has previously been demonstrated with curcumin administration in microglial cells [32] and endothelial cells [33]. Similarly, a recent study by Fu et al using an LPS-induced mouse model of mastitis reported reduced recruitment of inflammatory cells and inhibited TLR4 expression in breast tissue with curcumin treatment [34].…”

Prolonged hydrocephalus induced by intraventricular hemorrhage in rats is reduced by curcumin therapy

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Curcumin improves neural function after spinal cord injury by the joint inhibition of the intracellular and extracellular components of glial scar

“…Because cur has various functions, such as powerful anti-inflammation, anticancer, antifibrosis, and anti-oxidation effects, it has been studied in various disease models [10e12]. In the central nervous system, cur has neuroprotective effects and can significantly improve the recovery of neurologic function after neurodegenerative diseases and injury [13,14]. Despite many studies focusing on the relationship between cur and glial scar, the specific mechanism of action requires further study.…”