Effect of Jun N-terminal kinase signaling pathway on inflammatory response after traumatic brain injury in rats

Abstract

Objective To investigate the effect of Jun N-terminal kinase (JNK) signaling pathway on inflammatory response,neuron apoptosis,brain edema,and neurobehavioral outcome after traumatic brain injury (TBI) in rats.Methods Fifty-four healthy male SD rats were randomly divided into 3 groups:sham-operated group,TBI group and JNK inhibitor group (n=18).Rats in the later two groups were established TBI animal models by using Feeney's method; rats in the sham-operated group were only opened the bone window without beating.Half h after TBI,intraperitoneal injection of SP600125 (15 mg/kg) was performed in rats of the JNK inhibitor group,while the same volume of solvent was given to rats in the other two groups.One,3 and 7 d after TBI,rat behavioral outcomes were measured by modified neurologic severity scale (mNSS),brain water content was measured with wet-dry weight method,and apoptosis neurons were detected by TUNEL.Three d after TBI,immunohistochemistry staining was used to determine the apoptosis relative proteins (caspase-3 and Bcl-2 associated X protein [Bax]) expressions in the cerebral cortex,real time PCR was employed to detect the mRNA expressions of inflammatory cytokines (tumor necrosis factor-α [TNFα],interleukin [IL]-1α,IL-1β,IL-6),and Western blotting was used to detect the protein expressions of TNFα,IL-1α,IL-1β,IL-6,JNK and phosphorylation-JNK (p-JNK).Results As compared with those in the sham-operated group,the mNSS scores,brain water content and apoptosis rate in TBI group and JNK inhibitor group were significantly higher 1,3 and 7 d after TBI (P＜0.05); the mNSS scores in the JNK inhibitor group was statistically lower than those in the TBI group 3 and 7 d after TBI (P＜0.05),and significantly reduced brain edema and improved neurobehavioral outcomes were noted in the JNK inhibitor group as compared with those in the TBI group 1,3 and 7 d after TBI (P＜0.05).As compared with the TBI group,the JNK inhibitor group had significantly lower caspase-3 expression and increased Bcl-2 expression.As compared with those in the sham-operated group,the TNFα,IL-1α,IL-1β and IL-6 mRNA and protein expressions and p-JNK protein expression were significantly increased in the TBI group and JNK inhibitor group,and those in the JNK inhibitor group were statistically lower than those in the TBI group (P＜0.05).Conclusion Suppressing activation of JNK signaling pathway can markedly improve the neurological outcomes after TBI,reduce brain edema and neuron apoptosis,which might be mediated by inhibiting TBI-induced cerebral inflammatory response and reducing the expression of TNFα,IL-1α,IL-1β and IL-6. Key words: Traumatic brain injury; Neuroprotection; Inflammatory response; JNK signaling pathway