BACKGROUND: Traumatic 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.
METHODS: Neurological 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.
RESULTS: The 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.
CONCLUSIONS: Our 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.