Effect of autophagy response on neurological functions and its mechanism in rats after traumatic brain injury

Abstract

Objective To investigate the effect of autophagy response on neurological functions and the role of mitogen-activated protein kinases (MAPKs) signaling pathway in rats after traumatic brain injury (TBI). Methods Fifty-four healthy male SD rats were randomly divided into sham-operated group, TBI group and TBI+autophagy inhibitor 3-methyladenine (3-MA) group (n=18). TBI animal models of the later two groups were established using Feeney's method. Rats in the sham-operated group were only performed bone window opening without knock; rats in the TBI+3-MA group were given intraperitoneal injection of 3-MA(5 mg/kg) 30 min after modeling and rats in the other two groups were given the same volume of normal saline. Three and 7 d after modeling, the protein levels of S100B and neuron specific enolase (NSE) in serum were tested with enzyme linked immunosorbent assay (ELISA); modified neurologic severity scale (mNSS) was used to detect the movement, sense and reflex functions; brain water content was measured with wet-dry weight method. The autophagy related factors (LC3-II and Beclin-1) and MAPKs signaling pathway related factors (c-Jun N-terminal kinase [JNK], phosphorylated [p]-JNK, extracellular signal-regulated kinase [ERK]1/2, p-ERK1/2, p38MAPK and p-p38MAPK) protein expressions in TBI cerebral cortex were determined by Western blotting. Results As compared with those in the sham-operated group, the brain edema level, mNSS scores, and S100B and NSE protein levels in the TBI group and TBI+3-MA group were significantly increased (P< 0.05); TBI+3-MA group had significantly lower brain edema level, mNSS scores, and S100B and NSE protein levels than TBI group (P<0.05). The expression levels of autophagy and MAPKs signaling pathway related factors in the TBI group and TBI+3-MA group were significantly higher as compared with those in the sham-operated group (P<0.05). As compared with the TBI group, TBI+3-MA group had significantly decreased levels of LC3-II, Beclin-1 and activation of JNK and p-p38MAPK signaling pathways (P<0.05). Conclusion Suppressing autophagy response markedly improves neurological outcomes after TBI, possibly mediated by inhibiting activation of JNK and p38MAPK signaling pathways. Key words: Traumatic brain injury; Neuroprotection; Autophagy; Mitogen-activated protein kinase signaling pathway