Abstract
The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor of the immunoglobulin superfamily that has been implicated in multiple neuronal and inflammatory stress processes. In this study, we examined changes in RAGE immunoreactivity and its protein levels in the gerbil hippocampus (CA1-3 regions) after 5 min of transient global cerebral ischemia. The ischemic hippocampus was stained with cresyl violet, neuronal nuclei (a neuron-specific soluble nuclear antigen) antibody and Fluoro-Jade B (a marker for neuronal degeneration). 5 days after ischemia–reperfusion, delayed neuronal death occurred in the stratum pyramidale of the CA1 region. RAGE immunoreactivity was not detected in any regions of the CA1-3 regions of the sham-group; the immunoreactivity was markedly increased only in the CA1 region from 3 days after ischemia–reperfusion. On the other hand, RAGE immunoreactivity was newly expressed in astrocytes, not in microglia. Western blot analysis showed that RAGE protein level was highest at 5 days post-ischemia. In brief, both the RAGE immunoreactivity and protein level were distinctively increased in astrocytes in the ischemic CA1 region from 3 days after transient cerebral ischemia. These results indicate that the increase of RAGE expression in astrocytes after ischemia–reperfusion may be related to the ischemia-caused activation of astrocytes in the ischemic CA1 region.
Similar content being viewed by others
References
Meairs S, Wahlgren N, Dirnagl U et al (2006) Stroke research priorities for the next decade: a representative view of the European scientific community. Cerebrovasc Dis 22:75–82
Rosamond W, Flegal K, Friday G et al (2007) Heart disease and stroke statistics-2007 update: a report from the American heart association statistics committee and stroke statistics subcommittee. Circulation 115:e69–171
Yu DK, Yoo KY, Shin BN et al (2012) Neuronal damage in hippocampal subregions induced by various durations of transient cerebral ischemia in gerbils using fluoro-jade B histofluorescence. Brain Res 1437:50–57
Horn M, Schlote W (1992) Delayed neuronal death and delayed neuronal recovery in the human brain following global ischemia. Acta Neuropathol 85:79–87
Petito CK, Feldmann E, Pulsinelli WA et al (1987) Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology 37:1281–1286
Kirino T, Sano K (1984) Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol 62:201–208
Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57–69
Yan BC, Park JH, Lee CH et al (2011) Increases of antioxidants are related to more delayed neuronal death in the hippocampal CA1 region of the young gerbil induced by transient cerebral ischemia. Brain Res 1425:142–154
Hwang IK, Yoo KY, Suh HW et al (2008) Folic acid deficiency increases delayed neuronal death, DNA damage, platelet endothelial cell adhesion molecule-1 immunoreactivity, and gliosis in the hippocampus after transient cerebral ischemia. J Neurosci Res 86:2003–2015
Lee CH, Park JH, Yoo KY et al (2011) Pre- and post-treatments with escitalopram protect against experimental ischemic neuronal damage via regulation of BDNF expression and oxidative stress. Exp Neurol 229:450–459
Bierhaus A, Humpert PM, Morcos M et al (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 83:876–886
Yan SD, Chen X, Fu J et al (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691
Fang F, Lue LF, Yan S et al (2010) RAGE-dependent signaling in microglia contributes to neuroinflammation, abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease. FASEB J 24:1043–1055
Hassid BG, Nair MN, Ducruet AF et al (2009) Neuronal RAGE expression modulates severity of injury following transient focal cerebral ischemia. J Clin Neurosci 16:302–306
Kamide T, Kitao Y, Takeichi T et al (2012) RAGE mediates vascular injury and inflammation after global cerebral ischemia. Neurochem Int 60:220–228
Ma L, Carter RJ, Morton AJ et al (2003) RAGE is expressed in pyramidal cells of the hippocampus following moderate hypoxic-ischemic brain injury in rats. Brain Res 966:167–174
Muhammad S, Barakat W, Stoyanov S et al (2008) The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci 28:12023–12031
Hofmann MA, Drury S, Fu C et al (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97:889–901
Neeper M, Schmidt AM, Brett J et al (1992) Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 267:14998–15004
Kim JB, Sig Choi J, Yu YM et al (2006) HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 26:6413–6421
Zimmerman GA, Meistrell M 3rd, Bloom O et al (1995) Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine. Proc Natl Acad Sci USA 92:3744–3748
Donato R (2007) RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins. Curr Mol Med 7:711–724
Hu Z, Zeng L, Xie L et al (2007) Morphological alteration of Golgi apparatus and subcellular compartmentalization of TGF-beta1 in golgi apparatus in gerbils following transient forebrain ischemia. Neurochem Res 32:1927–1931
Beresewicz M, Kowalczyk JE, Zablocka B (2008) Kalirin-7, a protein enriched in postsynaptic density, is involved in ischemic signal transduction. Neurochem Res 33:1789–1794
Fang KM, Cheng FC, Huang YL et al (2013) Trace element, antioxidant activity, and lipid peroxidation levels in brain cortex of gerbils after cerebral ischemic injury. Biol Trace Elem Res 152:66–74
Ahn HC, Yoo KY, Hwang IK et al (2009) Ischemia-related changes in naive and mutant forms of ubiquitin and neuroprotective effects of ubiquitin in the hippocampus following experimental transient ischemic damage. Exp Neurol 220:120–132
Lee CH, Moon SM, Yoo KY et al (2010) Long-term changes in neuronal degeneration and microglial activation in the hippocampal CA1 region after experimental transient cerebral ischemic damage. Brain Res 1342:138–149
Candelario-Jalil E, Alvarez D, Merino N et al (2003) Delayed treatment with nimesulide reduces measures of oxidative stress following global ischemic brain injury in gerbils. Neurosci Res 47:245–253
Schmued LC, Hopkins KJ (2000) Fluoro-jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res 874:123–130
Loskota WJ, Lomax LP, Verity MA (1974) A stereotaxic atlas of the Mongolian gerbil brain (Meriones unguiculatus). In: Peter Lomax M, Verity Anthony (eds) William James Loskota. Ann Arbor Science, Michigan
Lee CH, Park JH, Choi JH et al (2011) Heat shock protein 90 and its cochaperone, p23, are markedly increased in the aged gerbil hippocampus. Exp Gerontol 46:768–772
Yan SF, Ramasamy R, Schmidt AM (2010) The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ Res 106:842–853
Ramasamy R, Yan SF, Schmidt AM (2012) Advanced glycation endproducts: from precursors to RAGE: round and round we go. Amino Acids 42:1151–1161
Koistinaho M, Koistinaho J (2005) Interactions between Alzheimer’s disease and cerebral ischemia–focus on inflammation. Brain Res Brain Res Rev 48:240–250
Kogel D, Peters M, Konig HG et al (2004) S100B potently activates p65/c-Rel transcriptional complexes in hippocampal neurons: clinical implications for the role of S100B in excitotoxic brain injury. Neuroscience 127:913–920
Degryse B, Bonaldi T, Scaffidi P et al (2001) The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol 152:1197–1206
Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195
Zhang L, Bukulin M, Kojro E et al (2008) Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases. J Biol Chem 283:35507–35516
Pichiule P, Chavez JC, Schmidt AM et al (2007) Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia. J Biol Chem 282:36330–36340
Vincent AM, Perrone L, Sullivan KA et al (2007) Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress. Endocrinology 148:548–558
Greco R, Amantea D, Mangione AS et al (2012) Modulation of RAGE isoforms expression in the brain and plasma of rats exposed to transient focal cerebral ischemia. Neurochem Res 37:1508–1516
Wang DD, Bordey A (2008) The astrocyte odyssey. Prog Neurobiol 86:342–367
Rossi DJ, Brady JD, Mohr C (2007) Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci 10:1377–1386
Yu AC, Lau LT (2000) Expression of interleukin-1 alpha, tumor necrosis factor alpha and interleukin-6 genes in astrocytes under ischemic injury. Neurochem Int 36:369–377
Ridet JL, Malhotra SK, Privat A et al (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577
Sofroniew MV (2005) Reactive astrocytes in neural repair and protection. Neuroscientist 11:400–407
Panickar KS, Norenberg MD (2005) Astrocytes in cerebral ischemic injury: morphological and general considerations. Glia 50:287–298
Takano T, Oberheim N, Cotrina ML et al (2009) Astrocytes and ischemic injury. Stroke 40:S8–12
Acknowledgments
The authors would like to thank Mr. Seung Uk Lee for his technical help in this study. This work was supported by a grant from the Gangwon Cardiovascular Health Research Institute, and by a Priority Research Centers Program grant (NRF-2009-0093812) through the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning.
Conflict of interest
The authors have no financial conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Jae-Chul Lee and Jun Hwi Cho have equally contributed to this article.
Rights and permissions
About this article
Cite this article
Lee, JC., Cho, J.H., Cho, GS. et al. Effect of Transient Cerebral Ischemia on the Expression of Receptor for Advanced Glycation End Products (RAGE) in the Gerbil Hippocampus Proper. Neurochem Res 39, 1553–1563 (2014). https://doi.org/10.1007/s11064-014-1345-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-014-1345-8