Ischemic preconditioning-induced neuroprotection against transient cerebral ischemic damage via attenuating ubiquitin aggregation

Jae-Chul Lee; In Hye Kim; Geum-Sil Cho; Joon Ha Park; Ji Hyeon Ahn; Bing Chun Yan; Hyuk Min Kwon; Young-Myeong Kim; Seung Hwan Cheon; Jun Hwi Cho; Hui Young Lee; Moo-Ho Won; Jeong Yeol Seo

doi:10.1016/j.jns.2013.10.010

Ischemic preconditioning-induced neuroprotection against transient cerebral ischemic damage via attenuating ubiquitin aggregation

J Neurol Sci. 2014 Jan 15;336(1-2):74-82. doi: 10.1016/j.jns.2013.10.010. Epub 2013 Oct 15.

Authors

Jae-Chul Lee¹, In Hye Kim¹, Geum-Sil Cho², Joon Ha Park¹, Ji Hyeon Ahn¹, Bing Chun Yan³, Hyuk Min Kwon⁴, Young-Myeong Kim⁵, Seung Hwan Cheon⁶, Jun Hwi Cho⁷, Hui Young Lee⁸, Moo-Ho Won⁹, Jeong Yeol Seo¹⁰

Affiliations

¹ Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701 South Korea.
² Department of Neuroscience, College of Medicine, Korea University, Seoul 136-705, South Korea.
³ Institute of Integrative traditional & Western Medicine, Medical College, Yangzhou University, Yangzhou 25001, China.
⁴ Department of Obstetrics and Gynecology, Kangwon National University Hospital, Chuncheon 200-701, South Korea.
⁵ Vascular System Research Center and Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea.
⁶ Department of Emergency Medicine, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea.
⁷ Department of Emergency Medicine, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea; Institute of Medical Sciences, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea.
⁸ Institute of Medical Sciences, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea; Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea.
⁹ Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701 South Korea; Institute of Medical Sciences, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea. Electronic address: mhwon@kangwon.ac.kr.
¹⁰ Department of Emergency Medicine, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon 200-702, South Korea. Electronic address: siris94@hanmail.net.

PMID: 24268923
DOI: 10.1016/j.jns.2013.10.010

Abstract

Ubiquitin binds to short-lived proteins, and denatured proteins are produced by various forms of injuries. In the present study, we investigated the effect of ischemic preconditioning (IPC) on free ubiquitin and its mutant form (ubiquitin(+1)) in the gerbil hippocampus induced by transient cerebral ischemia. The animals were randomly assigned to 4 groups (sham-operated-group, ischemia-operated-group, IPC plus (+)-sham-operated-group, and IPC+ischemia-operated-group). IPC was induced by subjecting gerbils to a 2 min of ischemia followed by 1 day of recovery. A significant loss of neurons was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) in the ischemia-operated-groups 5 days after ischemia-reperfusion (I-R). In all the IPC+ischemia-operated-groups, neurons in the SP were well protected. We found that strong ubiquitin immunoreactivity was detected in the SP in the sham-operated-group and the immunoreactivity was decreased with time after I-R. In all the IPC+ischemia-operated-groups, ubiquitin immunoreactivity in the SP was similar to that in the sham-operated group. Moderate ubiquitin(+1) immunoreactivity was detected in the SP of the sham-operated-group, and the immunoreactivity was markedly increased 2 days after I-R. Five days after I-R, ubiquitin(+1) immunoreactivity was very weak in the SP. In all the IPC+ischemia-operated-groups, ubiquitin(+1) immunoreactivity in the SP was slightly decreased with time after I-R. Western blot analysis showed that, in all the IPC+ischemia-ischemia-groups, the levels of ubiquitin and ubiquitin(+1) proteins were well maintained after I-R. In brief, our findings suggest that the inhibition of the depletion of free ubiquitin and the formation of ubiquitin(+1) may have an essential role in inducing cerebral ischemic tolerance by IPC.

Keywords: Delayed neuronal death; Hippocampus; Ischemia–reperfusion; Ischemic preconditioning; Pyramidal neurons; Ubiquitin system.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Gerbillinae
Ischemic Attack, Transient / metabolism*
Ischemic Attack, Transient / pathology
Ischemic Attack, Transient / prevention & control*
Ischemic Preconditioning / methods*
Male
Neuroprotective Agents / metabolism*
Pyramidal Cells / metabolism*
Pyramidal Cells / pathology
Ubiquitin / antagonists & inhibitors*
Ubiquitin / metabolism*

Substances

Neuroprotective Agents
Ubiquitin