Changes in the expression of DNA-binding/differentiation protein inhibitors in neurons and glial cells of the gerbil hippocampus following transient global cerebral ischemia

Lee,Jae‑Chul; Chen,Bai  Hui; Cho,Jeong‑Hwi; Kim,In  Hye; Ahn,Ji  Hyeon; Park,Joon  Ha; Tae,Hyun‑Jin; Cho,Geum‑Sil; Yan,Bing  Chun; Kim,Dae  Won; Hwang,In  Koo; Park,Jinseu; Lee,Yun  Lyul; Choi,Soo  Young; Won,Moo‑Ho

doi:10.3892/mmr.2014.3084

Changes in the expression of DNA-binding/differentiation protein inhibitors in neurons and glial cells of the gerbil hippocampus following transient global cerebral ischemia

Authors:
- Jae‑Chul Lee
- Bai Hui Chen
- Jeong‑Hwi Cho
- In Hye Kim
- Ji Hyeon Ahn
- Joon Ha Park
- Hyun‑Jin Tae
- Geum‑Sil Cho
- Bing Chun Yan
- Dae Won Kim
- In Koo Hwang
- Jinseu Park
- Yun Lyul Lee
- Soo Young Choi
- Moo‑Ho Won
View Affiliations

Affiliations: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 200‑701, Republic of Korea, Department of Physiology, Institute of Neurodegeneration and Neuroregeneration, College of Medicine, Hallym University, Chuncheon, Gangwon 200‑702, Republic of Korea, Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 200‑702, Republic of Korea, Department of Neuroscience, College of Medicine, Korea University, Seoul 136‑705, Republic of Korea, Institute of Integrative Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, P.R. China, Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Kangnung‑Wonju National University, Gangneung, Gangwon 210‑702, Republic of Korea, Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul 151‑742, Republic of Korea
Published online on: December 11, 2014 https://doi.org/10.3892/mmr.2014.3084
Pages: 2477-2485
Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

Inhibitors of DNA-binding/differentiation (ID) proteins bind to basic helix‑loop‑helix (bHLH) transcription factors, including those that regulate differentiation and cell‑cycle progression during development, and regulate gene transcription. However, little is known about the role of ID proteins in the brain under transient cerebral ischemic conditions. In the present study, we examined the effects of ischemia‑reperfusion (I-R) injury on the immunoreactivity and protein levels of IDs 1‑4 in the gerbil hippocampus proper Cornu Ammonis regions CA1‑3 following 5 min of transient cerebral ischemia. Strong ID1 immunoreactivity was detected in the nuclei of pyramidal neurons in the hippocampal CA1‑3 regions; immunoreactivity was significantly changed following I-R in the CA1 region, but not in the CA2/3 region. Five days following I-R, ID1 immunoreactivity was not detected in the CA1 pyramidal neurons. ID1 immunoreactivity was detected only in GABAergic interneurons in the ischemic CA1 region. Weak ID4 immunoreactivity was detected in non‑pyramidal cells, and immunoreactivity was again only changed in the ischemic CA1 region. Five days following I-R, strong ID4 immunoreactivity was detected in non‑pyramidal cells, which were identified as microglia, and not astrocytes, in the ischemic CA1 region. Furthermore, changes in the protein levels of ID1 and ID4 in the ischemic CA1 region studied by western blot were consistent with patterns of immunoreactivity. In summary, these results indicate that immunoreactivity and protein levels of ID1 and ID4 are distinctively altered following transient cerebral ischemia only in the CA1 region, and that the changes in ID1 and ID4 expression may relate to the ischemia‑induced delayed neuronal death.

View Figures

View References

1	Kirino T: Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res. 239:57–69. 1982. View Article : Google Scholar : PubMed/NCBI
2	Lin CS, Polsky K, Nadler JV and Crain BJ: Selective neocortical and thalamic cell death in the gerbil after transient ischemia. Neuroscience. 35:289–299. 1990. View Article : Google Scholar : PubMed/NCBI
3	Pulsinelli WA, Brierley JB and Plum F: Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol. 11:491–498. 1982. View Article : Google Scholar : PubMed/NCBI
4	Won MH, Kang T, Park S, et al: The alterations of N-methyl-D-aspartate receptor expressions and oxidative DNA damage in the CA1 area at the early time after ischemia-reperfusion insult. Neurosci Lett. 301:139–142. 2001. View Article : Google Scholar : PubMed/NCBI
5	Rastogi L, Godbole MM, Ray M, et al: Reduction in oxidative stress and cell death explains hypothyroidism induced neuroprotection subsequent to ischemia/reperfusion insult. Exp Neurol. 200:290–300. 2006. View Article : Google Scholar : PubMed/NCBI
6	Candelario-Jalil E, Alvarez D, Merino N and Leon OS: Delayed treatment with nimesulide reduces measures of oxidative stress following global ischemic brain injury in gerbils. Neurosci Res. 47:245–253. 2003. View Article : Google Scholar : PubMed/NCBI
7	Kee Y and Bronner-Fraser M: To proliferate or to die: role of Id3 in cell cycle progression and survival of neural crest progenitors. Genes Dev. 19:744–755. 2005. View Article : Google Scholar : PubMed/NCBI
8	Massari ME and Murre C: Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol. 20:429–440. 2000. View Article : Google Scholar
9	Perk J, Iavarone A and Benezra R: Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer. 5:603–614. 2005. View Article : Google Scholar : PubMed/NCBI
10	Ruzinova MB and Benezra R: Id proteins in development, cell cycle and cancer. Trends Cell Biol. 13:410–418. 2003. View Article : Google Scholar : PubMed/NCBI
11	Kremer D, Aktas O, Hartung HP and Kury P: The complex world of oligodendroglial differentiation inhibitors. Ann Neurol. 69:602–618. 2011. View Article : Google Scholar : PubMed/NCBI
12	Norton JD: ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J Cell Sci. 113:3897–3905. 2000.PubMed/NCBI
13	Jen Y, Manova K and Benezra R: Each member of the Id gene family exhibits a unique expression pattern in mouse gastrulation and neurogenesis. Dev Dyn. 208:92–106. 1997. View Article : Google Scholar : PubMed/NCBI
14	Neuman T, Keen A, Zuber MX, Kristjansson GI, Gruss P and Nornes HO: Neuronal expression of regulatory helix-loop-helix factor Id2 gene in mouse. Dev Biol. 160:186–195. 1993. View Article : Google Scholar : PubMed/NCBI
15	Riechmann V and Sablitzky F: Mutually exclusive expression of two dominant-negative helix-loop-helix (dnHLH) genes, Id4 and Id3, in the developing brain of the mouse suggests distinct regulatory roles of these dnHLH proteins during cellular proliferation and differentiation of the nervous system. Cell Growth Differ. 6:837–843. 1995.PubMed/NCBI
16	Andres-Barquin PJ, Hernandez MC and Israel MA: Id genes in nervous system development. Histol Histopathol. 15:603–618. 2000.PubMed/NCBI
17	Elliott RC, Khademi S, Pleasure SJ, Parent JM and Lowenstein DH: Differential regulation of basic helix-loop-helix mRNAs in the dentate gyrus following status epilepticus. Neuroscience. 106:79–88. 2001. View Article : Google Scholar : PubMed/NCBI
18	Rubenstein JL, Anderson S, Shi L, Miyashita-Lin E, Bulfone A and Hevner R: Genetic control of cortical regionalization and connectivity. Cereb Cortex. 9:524–532. 1999. View Article : Google Scholar : PubMed/NCBI
19	Tzeng SF and de Vellis J: Id1, Id2 and Id3 gene expression in neural cells during development. Glia. 24:372–381. 1998. View Article : Google Scholar : PubMed/NCBI
20	Fukuchi T, Katayama Y, Kamiya T, McKee A, Kashiwagi F and Terashi A: The effect of duration of cerebral ischemia on brain pyruvate dehydrogenase activity, energy metabolites and blood flow during reperfusion in gerbil brain. Brain Res. 792:59–65. 1998. View Article : Google Scholar : PubMed/NCBI
21	Lorrio S, Negredo P, Roda JM, Garcia AG and Lopez MG: Effects of memantine and galantamine given separately or in association, on memory and hippocampal neuronal loss after transient global cerebral ischemia in gerbils. Brain Res. 1254:128–137. 2009. View Article : Google Scholar
22	Zhang YB, Kan MY, Yang ZH, et al: Neuroprotective effects of N-stearoyltyrosine on transient global cerebral ischemia in gerbils. Brain Res. 1287:146–156. 2009. View Article : Google Scholar : PubMed/NCBI
23	Wang Q, Sun AY, Pardeike J, Muller RH, Simonyi A and Sun GY: Neuroprotective effects of a nanocrystal formulation of sPLA₂ inhibitor PX-18 in cerebral ischemia/reperfusion in gerbils. Brain Res. 1285:188–195. 2009. View Article : Google Scholar : PubMed/NCBI
24	Hwang IK, Eum WS, Yoo KY, et al: Copper chaperone for Cu,Zn-SOD supplement potentiates the Cu,Zn-SOD function of neuroprotective effects against ischemic neuronal damage in the gerbil hippocampus. Free Radic Biol Med. 39:392–402. 2005. View Article : Google Scholar : PubMed/NCBI
25	Park OK, Yoo KY, Lee CH, et al: Arylalkylamine N-acetyltransferase (AANAT) is expressed in astrocytes and melatonin treatment maintains AANAT in the gerbil hippocampus induced by transient cerebral ischemia. J Neurol Sci. 294:7–17. 2010. View Article : Google Scholar : PubMed/NCBI
26	Schmued LC and Hopkins KJ: Fluoro-Jade B: A high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res. 874:123–130. 2000. View Article : Google Scholar : PubMed/NCBI
27	Loskota WJ, Lomax LP and Verity MA: A stereotaxic atlas of the Mongolian gerbil brain (Meriones unguiculatus). Loskota William James, Lomax Peter and Verity M Anthony: Ann Arbor Science; Ann Arbor, MI: 1974
28	Lee CH, Park JH, Choi JH, Yoo KY, Ryu PD and Won MH: Heat shock protein 90 and its cochaperone, p23, are markedly increased in the aged gerbil hippocampus. Exp Gerontol. 46:768–772. 2011. View Article : Google Scholar : PubMed/NCBI
29	Lee CH, Moon SM, Yoo KY, et al: 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. 2010. View Article : Google Scholar : PubMed/NCBI
30	Nguyen MD, Boudreau M, Kriz J, Couillard-Despres S, Kaplan DR and Julien JP: Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. J Neurosci. 23:2131–2140. 2003.PubMed/NCBI
31	Vincent I, Rosado M and Davies P: Mitotic mechanisms in Alzheimer’s disease? J Cell Biol. 132:413–425. 1996. View Article : Google Scholar : PubMed/NCBI
32	Byrnes KR and Faden AI: Role of cell cycle proteins in CNS injury. Neurochem Res. 32:1799–1807. 2007. View Article : Google Scholar : PubMed/NCBI
33	Broughton BR, Reutens DC and Sobey CG: Apoptotic mechanisms after cerebral ischemia. Stroke. 40:e331–e339. 2009. View Article : Google Scholar : PubMed/NCBI
34	Rashidian J, Iyirhiaro GO and Park DS: Cell cycle machinery and stroke. Biochim Biophys Acta. 1772:484–493. 2007. View Article : Google Scholar : PubMed/NCBI
35	Wen Y, Yang S, Liu R, Brun-Zinkernagel AM, Koulen P and Simpkins JW: Transient cerebral ischemia induces aberrant neuronal cell cycle re-entry and Alzheimer’s disease-like tauopathy in female rats. J Biol Chem. 279:22684–22692. 2004. View Article : Google Scholar : PubMed/NCBI
36	Wang F, Corbett D, Osuga H, et al: Inhibition of cyclin-dependent kinases improves CA1 neuronal survival and behavioral performance after global ischemia in the rat. J Cereb Blood Flow Metab. 22:171–182. 2002. View Article : Google Scholar : PubMed/NCBI
37	Yokota Y and Mori S: Role of Id family proteins in growth control. J Cell Physiol. 190:21–28. 2002. View Article : Google Scholar : PubMed/NCBI
38	Hara E, Yamaguchi T, Nojima H, et al: Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J Biol Chem. 269:2139–2145. 1994.PubMed/NCBI
39	Barone MV, Pepperkok R, Peverali FA and Philipson L: Id proteins control growth induction in mammalian cells. Proc Natl Acad Sci USA. 91:4985–4988. 1994. View Article : Google Scholar : PubMed/NCBI
40	Fukuda T, Nakano S, Yoshiya I and Hashimoto PH: Persistent degenerative state of non-pyramidal neurons in the CA1 region of the gerbil hippocampus following transient forebrain ischemia. Neuroscience. 53:23–38. 1993. View Article : Google Scholar : PubMed/NCBI
41	Tortosa A and Ferrer I: Parvalbumin immunoreactivity in the hippocampus of the gerbil after transient forebrain ischaemia: a qualitative and quantitative sequential study. Neuroscience. 55:33–43. 1993. View Article : Google Scholar : PubMed/NCBI
42	Benezra R, Davis RL, Lockshon D, Turner DL and Weintraub H: The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell. 61:49–59. 1990. View Article : Google Scholar : PubMed/NCBI
43	Nagata Y and Todokoro K: Activation of helix-loop-helix proteins Id1, Id2 and Id3 during neural differentiation. Biochem Biophys Res Commun. 199:1355–1362. 1994. View Article : Google Scholar : PubMed/NCBI
44	Lyden D, Young AZ, Zagzag D, et al: Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature. 401:670–677. 1999. View Article : Google Scholar : PubMed/NCBI
45	Fontemaggi G, Dell’Orso S, Trisciuoglio D, et al: The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis. Nat Struct Mol Biol. 16:1086–1093. 2009. View Article : Google Scholar : PubMed/NCBI
46	Sugawara T, Lewen A, Noshita N, Gasche Y and Chan PH: Effects of global ischemia duration on neuronal, astroglial, oligodendroglial and microglial reactions in the vulnerable hippocampal CA1 subregion in rats. J Neurotrauma. 19:85–98. 2002. View Article : Google Scholar : PubMed/NCBI
47	Hailer NP, Jarhult JD and Nitsch R: Resting microglial cells in vitro: analysis of morphology and adhesion molecule expression in organotypic hippocampal slice cultures. Glia. 18:319–331. 1996. View Article : Google Scholar : PubMed/NCBI
48	Hwang IK, Yoo KY, Kim DW, et al: Ionized calcium-binding adapter molecule 1 immunoreactive cells change in the gerbil hippocampal CA1 region after ischemia/reperfusion. Neurochem Res. 31:957–965. 2006. View Article : Google Scholar : PubMed/NCBI
49	Schwartz M, Butovsky O, Bruck W and Hanisch UK: Microglial phenotype: is the commitment reversible? Trends Neurosci. 29:68–74. 2006. View Article : Google Scholar : PubMed/NCBI
50	Colton CA and Gilbert DL: Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett. 223:284–288. 1987. View Article : Google Scholar : PubMed/NCBI
51	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
52	Suzuki S, Tanaka K, Nogawa S, et al: Temporal profile and cellular localization of interleukin-6 protein after focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 19:1256–1262. 1999. View Article : Google Scholar : PubMed/NCBI
53	Hashimoto M, Nitta A, Fukumitsu H, Nomoto H, Shen L and Furukawa S: Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages. J Neurosci Res. 79:476–487. 2005. View Article : Google Scholar : PubMed/NCBI
54	Laurenzi MA, Arcuri C, Rossi R, Marconi P and Bocchini V: Effects of microenvironment on morphology and function of the microglial cell line BV-2. Neurochem Res. 26:1209–1216. 2001. View Article : Google Scholar
55	Lu YZ, Lin CH, Cheng FC and Hsueh CM: Molecular mechanisms responsible for microglia-derived protection of Sprague-Dawley rat brain cells during in vitro ischemia. Neurosci Lett. 373:159–164. 2005. View Article : Google Scholar