Role of c-Jun N-terminal kinase-mediated FOXO3a nuclear translocation in neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage
LI De-Yuan, WU Jin-Lin, LUO Li-Li, QIAO Li-Na, LIU Zhong-Qiang, LU Guo-Yan, WANG Yang
Department of Pediatrics, West China Second Hospital, Sichuan University/Key Laboratory of Birth Defectts and Related Disease of Women and Children(Sichuan University), Ministry of Education, Chengdu 610041, China
Abstract：Objective To explore the mechanisms of neuroprotective effects of c-Jun N-terminal kinase (JNK)/FOXO3a transcription factor signaling pathway inhibition on hypoxic-ischemic neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage (HIBD). Methods Sixty-four 7-day-old Sprague-Dawley rats were divided into four groups:hypoxia-ischemia (HI), sham-operated, JNK specific inhibitor AS601245-treated, and DMSO vehicle. Rats' cerebral cortexes were collected at 24 hours after HI. Western blot was used to detect the protein expression of JNK, p-JNK, FOXO3a, nuclear and cytoplasmic FOXO3a, Bim, and CC3. TUNEL staining was used to detect the apoptotic cells. Results Compared with the sham-operated group, p-JNK protein increased (P < 0.01), nuclear protein of FOXO3a increased (P < 0.01), cytoplasmic protein decreased (P < 0.01), and pro-apoptotic proteins Bim and CC3 increased 24 hours after HI (P < 0.01). Compared with the HI and DMSO vehicle groups, p-JNK protein was reduced (P < 0.01), nuclear protein of FOXO3a was also reduced (P < 0.01), cytoplasmic protein increased (P < 0.01), and Bim and CC3 proteins decreased (P < 0.01) in the AS601245-treated group 24 hours after HI. TUNEL positive cells were reduced in the AS601245-treated rats compared with the HI and DMSO vehicle groups 24 hours after HI (P < 0.01). Conclusions JNK activity increases in the neonatal rat brain with HI damage. JNK activity inhibition can inhibit FOXO3a translocation from cytoplasm to nucleus and downregulate the levels of pro-apoptotic proteins Bim and CC3, leading to the reduction of neuronal apoptosis.
LI De-Yuan,WU Jin-Lin,LUO Li-Li et al. Role of c-Jun N-terminal kinase-mediated FOXO3a nuclear translocation in neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage[J]. CJCP, 2017, 19(4): 458-462.
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