THE RATIO OF P53-PROAPOPTOTIC AND BCL-2 ANTIAPOPTOTIC ACTIVITY IN THE HIPPOCAMPUS OF RATS WITH BRAIN ISCHEMIA-REPERFUSION AND EXPERIMENTAL DIABETES
T.M. Boychuk, O.M. Nika, S.S. Tkachuk
Higher State Educational Establishment of Ukraine;«Bukovinian State Medical University», Chernivtsi
The dynamics of the balance of indices of pro- and p53-
Bcl-2 anti-apoptotic processes in the hippocampus of rats
with experimental diabetes mellitus (DM) complicated
by incomplete global cerebral ischemia-reperfusion was
investigated. It is shown that p53 proapoptotic processes in
animals without diabetes after 20 minutes of ischemia/1 hour
reperfusion in all fields of the hippocampus are activated in
the background of increasing Bcl-2 antiapoptotic processes in
the fields CA1, CA2, CA4 and depression of it – in the CA3
field. In the early postischemic period in rats with DM activity
of the p53-proapoptotic processes in fields CA1, CA3, CA4
significantly exceeds that in non-diabetic rats (area of p53-
IRM increases on 110, 60 and 27 %), and was significantly
lower than that detected in CA2 field. On the 12th day of
post-ischemic period, activation of apoptosis in field CA1
occurs in the background of inert antiapoptotic processes, in
animals without diabetes, as well as in diabetic rats, but the
indicators characterizing of apoptotic activity in rats with
diabetes were higher (specific contents of p53 protein and area
of p53 -IRM increases on 38 and 43 %). During this period, in
the CA2 region of the non-diabetic animals, some depression
of the antiapoptotic processes with a slight predominance
of proapoptotic processes was detected. In the field of CA3
region of rats without diabetes, the retention of activity of
proapoptotic processes and the deepening in the dynamics of
depression of antiapoptotic processes were showed. In rats
with DM, the oppression of both mechanisms with a significant
depression of antiapoptotic processes was observed. On the
12th day of experiment in the field CA4, the most balanced
relationship were detected between the studied of the processes
due to their parallel and unidirectional changes both in the rats
without diabetes as well as with DM. The results point on the
modifying effect of DM on susceptibility of hippocampal fields
to ischemic-reperfusion injury.
hippocampus; diabetes mellitus; brain ischemiareperfusion; apoptosis.
- Liot G, Bossy B, Lubitz S, Kushnareva Y, Sejbuk N, Bossy-Wetzel E. Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway. Cell Death Dif. 2009;16:899-909.
- Luigi Titomanlio, David Fernandez-Lypez, Lucilla Manganozzi, Raffaella Moretti, Zinaida S. Vexler, and Pierre Gressens. Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models. Pediatr Neurol. 2015;52(6): 566-84.
- Olmez I, Ozyurt H. Reactive oxygen species and ischemic cerebrovascular disease. Neurochem Int. 2012;60(2):208- 12.
- Rodrigo R, Fernandez-Gajardo R, Gutiorrez R, Matamala JM, Carrasco R, Miranda-Merchak A, Feuerhake W. Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol Disord Drug Targ. 2013;12(5):698-714.
- Rodriguez-Rodriguez P, Fernandez E, Almeida A, Bolanos JP. Excitotoxic stimulus stabilizes PFKFB3 causing pentose-phosphate pathway to glycolysis switch and neurodegeneration. Cell Death Dif. 2012;19:1582-89.
- Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans. 2006; 34(Pt 2):232-37.
- Wang Y, Dong XX, Cao Y, Liang ZQ, Han R, Wu JC, Gu ZL, Qin ZH. p53 induction contributes to excitotoxic neuronaland autophagic mechanisms. Europ J Neurosci. 2009;30:2258-70.
- Endo H, Kamada H, Nito C, Nishi T, Chan PH. Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J Neurosci : the official journal of the Society for Neuroscience. 2006;26:7974-83.
- Cheng CY, Tang NY, Kao ST, Hsieh CL. Ferulic Acid Administered at Various Time Points Protects against Cerebral Infarction by Activating p38 MAPK/p90RSK/ CREB/Bcl-2 Anti-Apoptotic Signaling in the Subacute Phase of Cerebral Ischemia-Reperfusion Injury in Rats. PLoS One. 2016;11(5):e0155748.
- Li Z, Pang L, Fang F, Zhang G, Zhang J, Xie M, Wang L. Resveratrol attenuates brain damage in a rat model of focal cerebral ischemia via up-regulation of hippocampal Bcl-2. Brain Res. 2012;1450:116-24.
- Akram Sadeghi, Javad Hami, Shahnaz Razavi, Ebrahim Esfandiary, and Zahra Hejazi. The Effect of Diabetes Mellitus on Apoptosis in Hippocampus: Cellular and Molecular Aspects. Int J Prev Med. 2016;7(1):57.
- Sun LJ, Hou XH, Xue SH, Yan F, Dai YJ, Zhao CH, Wang F, Yang RH. Fish oil modulates glycogen synthase kinase-3 signaling pathway in diabetes-induced hippocampal neurons apoptosis. Brain Res. 2014;1574 (1):37-49.
- Zhao CH, Liu HQ, Cao R, Ji AL, Zhang L, Wang F, Yang RH. Effects of dietary fish oil on learning function and apoptosis of hippocampal pyramidal neurons in streptozotocin-diabetic rats. Brain Res. 2012;1457:33-43.
- Al-Rubeaan K, Al-Hussain F, Youssef AM, Subhani SN, Al-Sharqawi AH, Ibrahim HM. Ischemic Stroke and Its Risk Factors in a Registry-Based Large CrossSectional Diabetic Cohort in a Country Facing a Diabetes Epidemic. J Diabetes Res. 2016;2016:4132589. doi: 10.1155/2016/4132589.
- Guo L, Yu M, Zhong J, Wu H, Pan J, Gong W, Wang M, Fei F, Hu R. Stroke Risk among Patients with Type 2 Diabetes Mellitus in Zhejiang: A Population-Based Prospective Study in China. Int J Endocrinol. 2016;2016:6380620. doi: 10.1155/2016/6380620.
- Tkachuk OV. Effect of streptozotocin-induced diabetes and transient global brain ischemia on apoptosis in the thymus of rats. Fiziol Zh. 2011;57(6):58-64 [Ukrainian].
- Skibo GG. The use of various experimental models to study cellular mechanisms of cerebral ischemic lesions. Patologija. 2004;1(1):22-30 [Ukrainian].
- Konig 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, Abramov AV. Image analysis system for quantitative immunofluorescence measurement . Microsc Analys. 2002;5:12-16.