Hypothermia exerts early neuroprotective effects involving protein conjugation of SUMO‑2/3 in a rat model of middle cerebral artery occlusion

Li,Gang; Liu,Xiaozhi; Su,Zhiguo; Zhang,Dong

doi:10.3892/mmr.2017.6994

Hypothermia exerts early neuroprotective effects involving protein conjugation of SUMO‑2/3 in a rat model of middle cerebral artery occlusion

Authors:
- Gang Li
- Xiaozhi Liu
- Zhiguo Su
- Dong Zhang
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Affiliations: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China, Department of Neurosurgery, Tianjin 5th Central Hospital, Tianjin 300450, P.R. China
Published online on: July 15, 2017 https://doi.org/10.3892/mmr.2017.6994
Pages: 3217-3223
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

How hypothermia serves an early protective role against cerebral ischemia remains to be determined. The small ubiquitin‑related modifier protein (SUMO) functions as a post‑translational modification system and SUMO‑2/3 subtypes are often activated in early stress. The present study investigated changes in the protein level of SUMO using western blotting and immunocytochemistry when neurons were exposed to oxygen‑glucose deprivation (OGD) in vitro, as well as in a rat model of middle cerebral artery occlusion (MCAO) in vivo. The results demonstrated that a large number of proteins were conjugated to SUMO‑2/3 in OGD‑injured neurons (within 10 min, peaking at 12 h), and was markedly enhanced under conditions of hypothermia (33˚C). Concordantly, lactate dehydrogenase (LDH) release and the apoptosis rate, as determined by LDH and TUNEL assays, respectively, were lower in hypothermia‑treated neurons. Similar results were obtained in a rat model of MCAO. Neurological deficit scores were lower in the hypothermia group than in the sham group in the early stage of cerebral ischemia (P<0.05). However, no significant differences in neurological deficit scores were detected between the hypothermia group and the sham group in the late stage of ischemia (21 days; P>0.05). This study implicates a role for SUMO‑2/3 in early hypothermia‑induced neuroprotection against stroke. The development of small molecule therapeutics based on SUMO‑2/3 may benefit patients with cerebral ischemia.

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1	Tu Y, Chen C, Sun HT, Cheng SX, Liu XZ, Qu Y, Li XH and Zhang S: Combination of temperature-sensitive stem cells and mild hypothermia: A new potential therapy for severe traumatic brain injury. J Neurotrauma. 29:2393–2403. 2012. View Article : Google Scholar : PubMed/NCBI
2	Kirton A and Deveber G: Life after perinatal stroke. Stroke. 44:3265–3271. 2013. View Article : Google Scholar : PubMed/NCBI
3	Wu S, Sena E, Egan K, Macleod M and Mead G: Edaravone improves functional and structural outcomes in animal models of focal cerebralischemia: A systematic review. Int J Stroke. 9:101–106. 2014. View Article : Google Scholar : PubMed/NCBI
4	Wu TC and Grotta JC: Hypothermia for acute ischaemic stroke. Lancet Neurol. 12:275–284. 2013. View Article : Google Scholar : PubMed/NCBI
5	Zhang M, Wang H, Zhao J, Chen C, Leak RK, Xu Y, Vosler P, Chen J, Gao Y and Zhang F: Drug-induced hypothermia in stroke models: Does it always protect? CNS Neurol Disord Drug Targets. 12:371–380. 2013. View Article : Google Scholar : PubMed/NCBI
6	Kallmünzer B, Kollmar R and Schwab S: Therapeutic hypothermia in acute brain injury. Nervenarzt. 83:975–981. 2012. View Article : Google Scholar : PubMed/NCBI
7	Droescher M, Chaugule VK and Pichler A: SUMO rules: Regulatory concepts and their implication in neurologic functions. Neuromolecular Med. 15:639–660. 2013. View Article : Google Scholar : PubMed/NCBI
8	Cubeñas-Potts C and Matunis MJ: SUMO: A multifaceted modifier of chromatin structure and function. Dev Cell. 24:1–12. 2013. View Article : Google Scholar : PubMed/NCBI
9	Lee YJ, Mou Y, Maric D, Klimanis D, Auh S and Hallenbeck JM: Elevated global SUMOylation in Ubc9 transgenic mice protects their brains against focal cerebral ischemic damage. PLoS One. 6:e258522011. View Article : Google Scholar : PubMed/NCBI
10	Guide for the care and use of laboratory animals. Public Health Service, National Institute of Health: NIH Publication No. 86–23. Revised. 1985.
11	Reglodi D, Tamás A and Lengvári I: Examination of sensorimotor performance following middle cerebral artery occlusion in rats. Brain Res Bull. 59:459–466. 2003. View Article : Google Scholar : PubMed/NCBI
12	Meixensberger J and Renner C: Therapeutic hypothermia in the intensive care unit. Anaesthesist. 56:945–948. 2007.(In German). View Article : Google Scholar : PubMed/NCBI
13	Jordan JD and Carhuapoma JR: Hypothermia: Comparing technology. J Neurol Sci. 261:35–38. 2007. View Article : Google Scholar : PubMed/NCBI
14	Ramani R: Hypothermia for brain protection and resuscitation. Curr Opin Anaesthesiol. 19:487–491. 2006. View Article : Google Scholar : PubMed/NCBI
15	Alzaga AG, Cerdan M and Varon J: Therapeutic hypothermia. Resuscitation. 70:369–380. 2006. View Article : Google Scholar : PubMed/NCBI
16	Nogoy N: Neuroproteomics: The hunt for biomarkers of neurotrauma. Andrew ottens talks to nicole nogoy. Expert Rev Proteomics. 4:343–345. 2007. View Article : Google Scholar : PubMed/NCBI
17	Han HS, Qiao Y, Karabiyikoglu M, Giffard RG and Yenari MA: Influence of mild hypothermia on inducible nitric oxide synthase expression and reactive nitrogen production in experimental stroke and inflammation. J Neurosci. 22:3921–3928. 2002.PubMed/NCBI
18	Guo C and Henley JM: Wrestling with stress: Roles of protein SUMOylation and deSUMOylation in cell stress response. IUBMB Life. 66:71–77. 2014. View Article : Google Scholar : PubMed/NCBI
19	Feligioni M and Nisticò R: SUMO: A (oxidative) stressed protein. Neuromolecular Med. 15:707–719. 2013. View Article : Google Scholar : PubMed/NCBI
20	Sriramachandran AM and Dohmen RJ: SUMO-targeted ubiquitin ligases. Biochim Biophys Acta. 1843:75–85. 2014. View Article : Google Scholar : PubMed/NCBI
21	Huang CJ, Wu D, Khan FA and Huo LJ: DeSUMOylation: An important therapeutic target and protein regulatory event. DNA Cell Biol. 34:652–660. 2015. View Article : Google Scholar : PubMed/NCBI
22	Abeywardana T and Pratt MR: Extent of inhibition of α-synuclein aggregation in vitro by SUMOylation is conjugation site- and SUMOisoform-selective. Biochemistry. 54:959–961. 2015. View Article : Google Scholar : PubMed/NCBI
23	Yang W, Thompson JW, Wang Z, Wang L, Sheng H, Foster MW, Moseley MA and Paschen W: Analysis of oxygen/glucose-deprivation-induced changes in SUMO3 conjugation using SILAC-based quantitative proteomics. J Proteome Res. 11:1108–1117. 2012. View Article : Google Scholar : PubMed/NCBI
24	Yang W, Wang L and Paschen W: Development of a high-throughput screening assay for inhibitors of small ubiquitin-like modifier proteases. J Biomol Screen. 18:621–628. 2013. View Article : Google Scholar : PubMed/NCBI
25	Yang W, Sheng H, Homi HM, Warner DS and Paschen W: Cerebral ischemia/stroke and small ubiquitin-like modifier (SUMO) conjugation-a new target for therapeutic intervention? J Neurochem. 106:989–999. 2008. View Article : Google Scholar : PubMed/NCBI
26	Olsen TS, Weber UJ and Kammersgaard LP: Therapeutic hypothermia for acute stroke. Lancet Neurol. 2:410–416. 2003. View Article : Google Scholar : PubMed/NCBI