Introduction. The role of the transcription factor Hif-1α in pathogenesis of hypoxic lesions and diabetes mellitus (DM) has been confirmed, though molecular mechanisms underlying dysfunctions of the factor in the association of DM with ischemic-reperfusion lesion of the brain remain unknown.
Objective: the investigation of Hif-1α protein content in the neurons of the hippocampus fields of rats with experimental DM in the dynamics of ischemic-reperfusion lesion of the brain.
Materials and methods. The study was conducted on 60 6-month rats with DM simulated at the age of 2 months by means of a single administration of streptozotocin (60 mg/kg of the body weight) (Sigma, USA). Disorders of the cerebral circulation were simulated by means of occlusion of both carotid arteries for 20 minutes. The content of Hif1-α protein was determined by means of fluoroimmunoassay after 20-minute ischemia with one hour reperfusion, and on the 12th day of the post-ischemic period in the hippocampus fields: СА1, СА2, СА3, СА4.
Results. In rats without DM 20-minute ischemia with one hour reperfusion increases the content of Hif-1α protein in all the hippocampus fields. On the 12th day of ischemic-reperfusion period in СА2-СА4 hippocampus fields the values of certain examined activity indices of the transcription factor Hif-1α continue to increase, and in СА1 field they are normalized or come closer to the values of animals from the control group. In rats with DM at the early post-ischemic period changes of Hif-1α protein content are lacking in СА1 field, the signs of its reduced activity are found in СА2 field, in СА3 field they are limited by the response of one index, and in СА4 field they are similar to those of the control rats under the experimental conditions. On the 12th day of ischemic-reperfusion period all the activity indices of the transcription factor Hif-1α increase in СА1 filed. They are higher than the corresponding indices in animals from the control group by absolute values under similar experimental conditions; changes of the examined parameters are limited in СА2 and СА3 fields in comparison with those from the control group; the parameters, which increased in the control group of animals, decreased in СА4 field.
Conclusion. DM restricts Hif-1α protein response to ischemia-reperfusion in the neurons of СА1-СА3 field at the early ischemic-reperfusion period and in the neurons of СА2-СА4 fields — on the 12th day of the observation.
2. 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
3. Xu W, Xu R, Li X, Zhang H, Wang X, Zhu J. Down-regulating hypoxia-inducible factor-1α expression with perfluorooctyl-bromide nanoparticles reduces early brain injury following experimental subarachnoid hemorrhage in rats. Am. J. Transl. Res. 2016;8(5):2114-26
4. 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;7:23. doi: 10.3389/ fneur.2016.00023
5. 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;102(6):1831-1841. doi: 10.1111/j.1471- 4159.2007.04652.x
6. 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;8(1):44-51.
7. 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;323(1-2):134-140. doi: 10.1016/j. jns.2012.08.036
8. 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;88(9):2046-2055. doi: 10.1002/jnr.22361
9. 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;114(1):92-101. doi: 10.3171/2010.6.JNS10207
10. 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;5(11):e15062. doi: 10.1371/jour- nal.pone.0015062
11. Xiao H, Gu Z, Wang G, Zhao T. The Possible Mechanisms Underlying the Impairment of HIF-1α Path- way Signaling in Hyperglycemia and the Beneficial Ef- fects of Certain Therapies. Int. J. Med. Sci. 2013;10(10):1412-1421. doi: 10.7150/ijms.5630
12. Catrina SB, Zheng X. Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers. Diabetes Metab. Res. Rev. 2016;32(1):179-185. doi: 10.1002/dmrr.2742
13. 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.
14. Kolesnik YM, Orlovsky MA. Image analysis system for quantitative immunofluorescence measurement. Microscopy and Analysis. 2002;5:19-21.
This work is licensed under a Creative Commons Attribution 4.0 International License.