DOI: https://doi.org/10.22141/2224-0721.14.4.2018.140182

Early and delayed reaction of the Hif-1α protein in the hippocampal fields on ischemia-reperfusion in rats with streptozotocin-induced diabetes mellitus

T.M. Boychuk, S.S. Tkachuk, O.M. Nika

Abstract


Background. The role of the transcriptional hypoxia-inducible factor-1α (Hif-1α) in the pathogenesis of hypoxic damage and diabetes mellitus (DM) is proved, although molecular mechanisms underlying dysfunction of this factor, when DM is combined with ischemic-reperfusion damage of the brain, remain unknown. The purpose was to study the content of Hif-1α protein in the hippocampal neurons of rats with experimental DM in the dynamics of ischemic-reperfusion damage of the brain. Materials and methods. The study was performed on 6-month-old rats with DM modeled by single administration of 60 mg/kg weight streptozotocin (Sigma, USA). The cerebrovascular disorders were reproduced by occlusion of both carotid arteries for 20 minutes. The content of Hif1-α protein was determined by immunofluorescence method after 20-minute ischemia with one-hour reperfusion, and on the 12th day of the post-ischemiс period in the fields CA1, CA2, CA3, and CA4 of the hippocampus. Results. In rats without DM, 20-minute ische­mia with one-hour reperfusion increases the content of Hif-1α protein in all the fields of the hippocampus. On the 12th day of ischemic-reperfusion period, the values of certain examined indices of transcriptional Hif-1α activity continue to increase in the hippocampal fields CA2-CA4, and in СА1 field they normalize or approach to the values of animals in the control group. In rats with DM during early post-ischemic period, there are no changes of Hif-1α protein content in CA1 field, in CA2 field there are signs of its reduced activity, in CA3 field they are limited by the reaction of one index, in CA4 field they are similar to those of the control rats under experimental conditions. On the 12th day of ischemic-reperfusion period, all the indices of transcriptional Hif-1α activity in CA1 field increase exceeding the corresponding indices in animals of the control group by absolute values under the same experimental conditions. In СА2 and СА3 fields, changes of the examined parameters are limited as compared to those in animals from the control group, in CA4 field, the values that were increased in the control group decrease. Conclusions. DM restricts the reaction of Hif-1α protein on ischemia-reperfusion in the neurons of СА1-СА3 fields in the early ischemic-reperfusion period and in the neurons of СА2-СА4 fields — on the 12th day of observation.


Keywords


diabetes mellitus; cerebral ischemia-reperfusion; Hif-1α protein

References


Singh N, Sharma G, Mishra V. Hypoxia inducible factor-1: its potential role in cerebral ischemia. Cell Mol Neurobiol. 2012 May;32(4):491-507. doi: 10.1007/s10571-012-9803-9.

Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 2002;16(10):1151-1162. DOI: 10.1096/fj.01-0944rev.

Xu W, Xu R, Li X, Zhang H, Wang X, Zhu J. Downregulating hypoxia-inducible factor-1α expression with perfluorooctyl-bromide nanoparticles reduces early brain injury following experimental subarachnoid hemorrhage in rats. Am J Transl Res. 2016 May 15;8(5):2114-26.

Thelin EP, Frostell A, Mulder J, et al. Lesion Size Is Exacerbated in Hypoxic Rats Whereas Hypoxia-Inducible Factor-1 Alpha and Vascular Endothelial Growth Factor Increase in Injured Normoxic Rats: A Prospective Cohort Study of Secondary Hypoxia in Focal Traumatic Brain Injury. Front Neurol. 2016 Mar 7;7:23. doi: 10.3389/fneur.2016.00023.

Chen C, Hu Q, Yan J, et al. Multiple effects of 2ME2 and D609 on the cortical expression of HIF-1alpha and apoptotic genes in a middle cerebral artery occlusion-induced focal ischemia rat model. J Neurochem. 2007 Sep;102(6):1831-1841. doi: 10.1111/j.1471-4159.2007.04652.x.

Higashida T, Peng C, Li J, et al. Hypoxia-inducible factor-1α contributes to brain edema after stroke by regulating aquaporins and glycerol distribution in brain. Curr Neurovasc Res. 2011 Feb;8(1):44-51.

Shenaq M, Kassem H, Peng C, et al. Neuronal damage and functional deficits are ameliorated by inhibition of aquaporin and HIF1α after traumatic brain injury (TBI). J Neurol Sci. 2012 Dec 15;323(1-2):134-40. doi: 10.1016/j.jns.2012.08.036.

Chen C, Ostrowski RP, Zhou C, Tang J, Zhang JH. Suppression of hypoxia-inducible factor-1alpha and its downstream genes reduces acute hyperglycemia-enhanced hemorrаhagic transformation in a rat model of cerebral ischemia. J Neurosci Res. 2010 Jul;88(9):2046-55. doi: 10.1002/jnr.22361.

Higashida T, Kreipke CW, Rafols JA, et al. The role of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury. J Neurosurg. 2011 Jan;114(1):92-101. doi: 10.3171/2010.6.JNS10207.

Bento CF, Fernandes R, Ramalho J, et al. The Chaperone-Dependent Ubiquitin Ligase CHIP Targets HIF-1α for Degradation in the Presence of Methylglyoxal. PLoS One. 2010 Nov 29;5(11):e15062. doi: 10.1371/journal.pone.0015062.

Xiao H, Gu Z, Wang G, Zhao T. The Possible Mechanisms Underlying the Impairment of HIF-1α Pathway Signaling in Hyperglycemia and the Beneficial Effects of Certain Therapies. Int J Med Sci. 2013 Aug 22;10(10):1412-21. doi: 10.7150/ijms.5630.

Catrina SB, Zheng X. Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers. Diabetes Metab Res Rev. 2016 Jan;32 Suppl 1:179-85. doi: 10.1002/dmrr.2742.

Tkachuk SS, Lenkov AM. Еxpression of Hif-1α, р53 and Bcl-2 proteins in the brain under under the conditions of bilateral carotid ischemia-reperfusion in experimental diabetes mellitus in male rats. Klinicna ta eksperimentalʹna patologia. 2010;2(32):111–113. (in Ukrainian).

Kоnig JF, Klippel PA. The rat brain. A stereotaxis atlas of forebrain and lower part of the brain stem. Baltimora: The Williams and Wilkins Company; 1963. 162 p.

Kolesnik YM, Orlovsky MA. Image analysis system for quantitative immunofluorescence measurement. Microscopy and Analysis. 2002;5:19-21.




Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

 

© "Publishing House "Zaslavsky", 1997-2018

 

   Seo анализ сайта