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We aimed to investigate whether geniposide, a main component extracted from Gardenia jasminoides Ellis fruit, could exert neuroprotective functions against traumatic brain injury (TBI). Enzyme-linked immunosorbent assay (ELISA) was used for detection of plasma cytokines. Real-time polymerase chain reaction (RT-PCR) was employed for measurements of mRNA levels of cytokines. Neurological outcomes were evaluated by modified neurological severity score (mNSS) and Rota-Rod. Blood–brain barrier (BBB) integrity and brain edema were assessed. Protein expression was tested by Western blot. The plasma levels of interleukin (IL)-1β, IL-6, IL-8 and IL-10 were all elevated in patients with TBI compared to those of healthy controls. TBI rats treated with geniposide showed lower mNSS and longer fall latency time than untreated TBI rats. BBB integrity was maintained and brain edema was reduced by geniposide treatment in TBI rats. Plasma levels of IL-1β, IL-6 and IL-8 were significantly repressed by geniposide treatment in TBI rats, whereas IL-10 level was upregulated. mRNA expression levels of these cytokines in the brain tissues of TBI rats exhibited the same trends of changes. By testing p38 mitogen-activated protein kinase and NF-κB p65 activities, it was observed that phosphorylated (p)-p38 and p-p65 were dramatically inhibited by geniposide. In conclusion, geniposide exerts neuroprotective functions against TBI by inhibiting p-p38 and p-p65. [ABSTRACT FROM AUTHOR]