NQDI-1, an inhibitor of ASK1 attenuates acute perinatal hypoxic-ischemic cerebral injury by modulating cell death

Hao,Hu; Li,Sitao; Tang,Hui; Liu,Bingqing; Cai,Yao; Shi,Congcong; Xiao,Xin

doi:10.3892/mmr.2016.5123

NQDI-1, an inhibitor of ASK1 attenuates acute perinatal hypoxic-ischemic cerebral injury by modulating cell death

Authors:
- Hu Hao
- Sitao Li
- Hui Tang
- Bingqing Liu
- Yao Cai
- Congcong Shi
- Xin Xiao
View Affiliations

Affiliations: Department of Pediatrics, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China, Central Laboratory, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630 P.R. China
Published online on: April 13, 2016 https://doi.org/10.3892/mmr.2016.5123
Pages: 4585-4592
Copyright: © Hao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed protein kinase, which regulates cell fate in numerous injury conditions. Therefore, ASK1 may be a promising novel therapeutic target for injury. However, the expression and distribution of ASK1 in the perinatal brain following hypoxia-ischemia (HI) remains to be elucidated. In the present study, western blotting and immunofluorescence were used to determine the expression and distribution of ASK1 and any associated downstream targets in the perinatal rat brain following HI. NQDI‑1, a specific inhibitor of ASK1 was intracerebroventricularly injected following neonatal rats brain insult for neuroprotection. The results revealed an increased expression of ASK1 and this expression was localized to the neurons and astrocytes, compared with the sham controls. Additionally, it was demonstrated that the ASK1/ c‑Jun N‑terminal kinases (JNK) pathway was involved in the brain damage following HI in neonatal rats. Notably, NQDI‑1 significantly inhibited the in vivo expression levels of ASK1, phosphorylated (p‑)JNK, p‑c‑Jun, p53 and caspase 3. Reduced acute hypoxic‑ischemic cerebral injury and cell apoptosis was observed following the injection of NQDI‑1. Collectively, NQDI-1 attenuated acute perinatal hypoxic‑ischemic cerebral injury by inhibiting the expression of ASK1 and cell apoptosis. This may be a promising novel neuroprotective inhibitor for perinatal cerebra injury.

View Figures

View References

1	du Plessis AJ and Volpe JJ: Perinatal brain injury in the preterm and term newborn. Curr Opin Neurol. 15:151–157. 2002. View Article : Google Scholar : PubMed/NCBI
2	Ferriero DM: Neonatal brain injury. N Engl J Med. 351:1985–1995. 2004. View Article : Google Scholar : PubMed/NCBI
3	Johnston MV, Fatemi A, Wilson MA and Northington F: Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol. 10:372–382. 2011. View Article : Google Scholar : PubMed/NCBI
4	Selway LD: State of the science: Hypoxic ischemic encephalopathy and hypothermic intervention for neonates. Adv Neonatal Care. 10:60–66; quiz 67–68. 2010. View Article : Google Scholar : PubMed/NCBI
5	Wachtel EV and Hendricks-Munoz KD: Current management of the infant who presents with neonatal encephalopathy. Curr Probl Pediatr Adolesc Health Care. 41:132–153. 2011. View Article : Google Scholar : PubMed/NCBI
6	Bass JL, Corwin M, Gozal D, Moore C, Nishida H, Parker S, Schonwald A, Wilker RE, Stehle S and Kinane TB: The effect of chronic or intermittent hypoxia on cognition in childhood: A review of the evidence. Pediatrics. 114:805–816. 2004. View Article : Google Scholar : PubMed/NCBI
7	Nelson KB and Lynch JK: Stroke in newborn infants. Lancet Neurol. 3:150–158. 2004. View Article : Google Scholar : PubMed/NCBI
8	Thornton C, Rousset CI, Kichev A, Miyakuni Y, Vontell R, Baburamani AA, Fleiss B, Gressens P and Hagberg H: Molecular mechanisms of neonatal brain injury. Neurol Res Int. 2012:5063202012. View Article : Google Scholar : PubMed/NCBI
9	Adekeye A, Haeri M, Solessio E and Knox BE: Ablation of the proapoptotic genes CHOP or Ask1 does not prevent or delay loss of visual function in a P23H transgenic mouse model of retinitis pigmentosa. PloS One. 9:e838712014. View Article : Google Scholar : PubMed/NCBI
10	Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K and Gotoh Y: Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 275:90–94. 1997. View Article : Google Scholar : PubMed/NCBI
11	Chen Z, Seimiya H, Naito M, Mashima T, Kizaki A, Dan S, Imaizumi M, Ichijo H, Miyazono K and Tsuruo T: ASK1 mediates apoptotic cell death induced by genotoxic stress. Oncogene. 18:173–180. 1999. View Article : Google Scholar : PubMed/NCBI
12	McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ and Lefkowitz RJ: Beta-arrestin 2: A receptor-regulated MAPK scaffold for the activation of JNK3. Science. 290:1574–1577. 2000. View Article : Google Scholar : PubMed/NCBI
13	Matsuzawa A, Nishitoh H, Tobiume K, Takeda K and Ichijo H: Physiological roles of ASK1-mediated signal transduction in oxidative stress- and endoplasmic reticulum stress-induced apoptosis: Advanced findings from ASK1 knockout mice. Antioxid Redox Signal. 4:415–425. 2002. View Article : Google Scholar : PubMed/NCBI
14	Matsukawa J, Matsuzawa A, Takeda K and Ichijo H: The ASK1-MAP kinase cascades in mammalian stress response. J Biochem. 136:261–265. 2004. View Article : Google Scholar : PubMed/NCBI
15	Hatai T, Matsuzawa A, Inoshita S, Mochida Y, Kuroda T, Sakamaki K, Kuida K, Yonehara S, Ichijo H and Takeda K: Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. J Biol Chem. 275:26576–26581. 2000. View Article : Google Scholar : PubMed/NCBI
16	Hao W, Takano T, Guillemette J, Papillon J, Ren G and Cybulsky AV: Induction of apoptosis by the Ste20-like kinase SLK, a germinal center kinase that activates apoptosis signal-regulating kinase and p38. J Biol Chem. 281:3075–3084. 2006. View Article : Google Scholar
17	Song J, Cho KJ, Cheon SY, Kim SH, Park KA, Lee WT and Lee JE: Apoptosis signal-regulating kinase 1 (ASK1) is linked to neural stem cell differentiation after ischemic brain injury. Exp Mol Med. 45:e692013. View Article : Google Scholar : PubMed/NCBI
18	Kim HW, Cho KJ, Lee SK and Kim GW: Apoptosis signal-regulating kinase 1 (Ask1) targeted small interfering RNA on ischemic neuronal cell death. Brain Res. 1412:73–78. 2011. View Article : Google Scholar : PubMed/NCBI
19	Wu DN, Pei DS, Wang Q and Zhang GY: Down-regulation of PTEN by sodium orthovanadate inhibits ASK1 activation via PI3-K/Akt during cerebral ischemia in rat hippocampus. Neurosci Lett. 404:98–102. 2006. View Article : Google Scholar : PubMed/NCBI
20	Zhang Q and Zhang G: Activation and autophosphorylation of apoptosis signal-regulating kinase 1 (ASK1) following cerebral ischemia in rat hippocampus. Neurosci Lett. 329:232–236. 2002. View Article : Google Scholar : PubMed/NCBI
21	Currie RW, Ellison JA, White RF, Feuerstein GZ, Wang X and Barone FC: Benign focal ischemic preconditioning induces neuronal Hsp70 and prolonged astrogliosis with expression of Hsp27. Brain Res. 863:169–181. 2000. View Article : Google Scholar : PubMed/NCBI
22	Stetler RA, Cao G, Gao Y, Zhang F, Wang S, Weng Z, Vosler P, Zhang L, Signore A, Graham SH and Chen J: Hsp27 protects against ischemic brain injury via attenuation of a novel stress-response cascade upstream of mitochondrial cell death signaling. J Neurosci. 28:13038–13055. 2008. View Article : Google Scholar : PubMed/NCBI
23	Kichev A, Rousset CI, Baburamani AA, Levison SW, Wood TL, Gressens P, Thornton C and Hagberg H: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling and cell death in the immature central nervous system after hypoxia-ischemia and inflammation. J Biol Chem. 289:9430–9439. 2014. View Article : Google Scholar : PubMed/NCBI
24	Li D, Qu Y, Mao M, Zhang X, Li J, Ferriero D and Mu D: Involvement of the PTEN-AKT-FOXO3a pathway in neuronal apoptosis in developing rat brain after hypoxia-ischemia. J Cereb Blood Flow Metab. 29:1903–1913. 2009. View Article : Google Scholar : PubMed/NCBI
25	El Eter E: NQDI 1, an inhibitor of ASK1 attenuates acute ischemic renal injury by modulating oxidative stress and cell death. Cardiovasc Hematol Agents Med Chem. 11:179–186. 2013. View Article : Google Scholar : PubMed/NCBI
26	Tian SF, Yang HH, Xiao DP, Huang YJ, He GY, Ma HR, Xia F and Shi XC: Mechanisms of neuroprotection from hypoxia-ischemia (HI) brain injury by up-regulation of cytoglobin (CYGB) in a neonatal rat model. J Biol Chem. 288:15988–16003. 2013. View Article : Google Scholar : PubMed/NCBI
27	Matsuzawa A and Ichijo H: Molecular mechanisms of the decision between life and death: Regulation of apoptosis by apoptosis signal-regulating kinase 1. J Biochem. 130:1–8. 2001. View Article : Google Scholar : PubMed/NCBI
28	Harding SJ, Browne GJ, Miller BW, Prigent SA and Dickens M: Activation of ASK1, downstream MAPKK and MAPK isoforms during cardiac ischaemia. Biochim Biophys Acta. 1802:733–740. 2010. View Article : Google Scholar : PubMed/NCBI
29	Nako H, Kataoka K, Koibuchi N, Dong YF, Toyama K, Yamamoto E, Yasuda O, Ichijo H, Ogawa H and Kim-Mitsuyama S: Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: The critical role of ASK1 and VEGF. Hypertens Res. 35:194–200. 2012. View Article : Google Scholar
30	Zhu Y, Mao XO, Sun Y, Xia Z and Greenberg DA: p38 Mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons. J Biol Chem. 277:22909–22914. 2002. View Article : Google Scholar : PubMed/NCBI
31	Liu G, Zhao J, Chang Z and Guo G: CaMKII activates ASK1 to induce apoptosis of spinal astrocytes under oxygen-glucose deprivation. Cell Mol Neurobiol. 33:543–549. 2013. View Article : Google Scholar : PubMed/NCBI