Dynamics of Proteo- and Fibrinolytic Activity in Brain Structures of Rats with Diabetes Mellitus Complicated by Carotid Ischemia-Reperfusion

O. Tkachuk, M. Povar


The imbalance in the protease-antiprotease system is an integral part of the pathogenesis of acute disorder of cerebrovascular circulation and diabetes mellitus (DM), but its manifestations in the complication of diabetes by ischemia-reperfusion of the brain have not been investigated yet.

The objective of the work – is to study the dynamics of carotid ischemia-reperfusion effect on the proteo- and fibrinolytic activity in brain structures of rats with experimental DM.

Rats with the four-month streptozotocin DM were modeled bilateral carotene ischemia during 20 minutes. In homogenates of brain structures, indicators of proteo- fibrinolytic activity were determined after 1 hour from the beginning of reperfusion and during the 12th day of the post-ischemic period.

In the absence of DM, the proteolytic activity of all or individual indicators is increased in both periods of the post-ischemic period in the cortex of the frontal and occipital lobes, the fields of hippocampus CA2 and CA3, and during the 12th day in the field CA1. In rats with diabetes, in all brain structures, there are no changes in the lysis of azo-albumin and azo-casein in both terms of observation and lysis of collagen progressively decreases.

In rats without DM in the cortex of the studied particles, fields of the hippocampus CA1 and CA2, all or separate indices of fibrinolytic activity are increased in both periods of the post-ischemic period, in the field CA3 – all indices at the 12th day. In the presence of diabetes in the cortex of both studied lobes and the field CA1, the fibrinolytic activity decreases in the late post-ischemic period, in the fields of CA2 and CA3 – during both observation periods.

Conclusion. In the brain structures under investigation at both time intervals, the DM eliminates the reaction of low and high molecular weight proteins to the ischemia-reperfusion and suppresses fibrinolytic activity.



diabetes mellitus; ischemia-reperfusion of the brain; proteolysis; fibrinolysis

Full Text:



Skibo GN. The use of various experimental models for studying the cellular mechanisms of ischemic brain damage. Patologiya. 2004; 1(1): 22-30.

Magalas VM, Mikheev AO, Horny YuE et al. Modern methods of experimental and clinical research of the central scientific-research laboratory of the Bukovyna State Medical Academy. 2001; 42.

Tkachuk OV. Influence of streptozotocin-induced diabetes and incomplete global ischemia of the brain onto apoptosis in thymus of rats. Fiziolohichny zhurnal. 2011; 57(6): 58-64.

Hu J, Klein JD, Du J, Wang XH. Cardiac Muscle Protein Catabolism in Diabetes Mellitus: Activation of the Ubiquitin-Proteasome System by Insulin Deficiency. Endocrinology. 2008; 149(11): 5384-5390. DOI: https://doi.org/10.1210/en.2008-0132 [PMid:18653708 PMCid:PMC2734490]

Nagai R, Murray DB, Metz TO. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. Diabetes. 2012; 61(3): 549-559. DOI: https://doi.org/10.2337/db11-1120 [PMid:22354928 PMCid:PMC3282805]

Jotic A, Milicic T, Covickovic Sternic N, Kostic VS et al. Decreased Insulin Sensitivity and Impaired Fibrinolytic Activity in Type 2 Diabetes Patients and Nondiabetics with Ischemic Stroke. Int. J. Endocrinol. 2015; 2015: 934791.

Curcio M, Leal G, Salazar I L et al. Excitotoxic stimulation downregulates the ubiquitin-proteasome system through activation of NMDA receptors in cultured hippocampal neurons. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2013; 1832(1): 263-274. DOI: https://doi.org/10.1016/j.bbadis.2012.10.009 [PMid:23069389]

Fierabracci A. The putative role of proteolytic pathways in the pathogenesis of Type 1 diabetes mellitus: The 'autophagy' hypothesis. Medical Hypotheses. 2014; 82(5): 553-557. DOI: https://doi.org/10.1016/j.mehy.2014.02.010 [PMid:24582332]

Genomic approach to selective vulnerability of the hippocampus in brain ischemia-hypoxia. Schmidt-Kastner R. Neuroscience. 2015; 309: 259-279. DOI: https://doi.org/10.1016/j.neuroscience.2015.08.034 [PMid:26383255]

Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J. Clin. Endocrinol. Metab. 2009; 94(9): 3171-3182. DOI: https://doi.org/10.1210/jc.2008-2534 [PMid:19509100]

Queisser MA, Yao D, Geisler S et al. Hyperglycemia Impairs Proteasome Function by Methylglyoxal. Diabetes. 2010; 59(3): 670-678. DOI: https://doi.org/10.2337/db08-1565 [PMid:20009088 PMCid:PMC2828656]

Bandeira S de M, Fonseca LJ S da, Guedes G da S et al. Oxidative Stress as an Underlying Contributor in the Development of Chronic Complications in Diabetes Mellitus. Int. J. Mol. Sci. 2013; 14(2): 3265-3284. DOI: https://doi.org/10.3390/ijms14023265 [PMid:23385234 PMCid:PMC3588043]

Tjarnlund-Wolf A, Brogren H, Lo EH, Wang X. Plasminogen Activator Inhibitor-1 and Thrombotic Cerebrovascular Diseases. Stroke. 2012; 43(10): 2833-2839. DOI: https://doi.org/10.1161/STROKEAHA.111.622217 [PMid:22879095 PMCid:PMC3712849]

Hernandes MS, Lassegue B, Hilenski LL et al. Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain. J. Neuroinflammation. 2018; 15(1):45. DOI: https://doi.org/10.1186/s12974-017-1032-1 [PMid:29452577 PMCid:PMC5816395]

Kong L, Wang Y, Luo M et al. Prevention of Streptozotocin-Induced Diabetic Nephropathy by MG132: Possible Roles of Nrf2 and I?B. Oxid. Med. Cell. Longev. 2017; 2017: 3671751.

Sneha BB, Ashok DC, Rakesh SJ et al. Proteomic Analysis of Protease Resistant Proteins in the Diabetic Rat Kidney. Mol. Cell. Proteomics. 2013; 12(1): 228-236. DOI: https://doi.org/10.1074/mcp.M112.020651 [PMid:23118466 PMCid:PMC3536903]

Ramasamy R, Yan SF, Schmidt AM. Receptor for AGE (RAGE): signaling mechanisms in the pathogenesis of diabetes and its complications. Ann. N. Y. Acad. Sci. 2011; 1243: 88-102. DOI: https://doi.org/10.1111/j.1749-6632.2011.06320.x [PMid:22211895 PMCid:PMC4501013]

Sherwood NM, Timiras PS. A stereotaxis atlas of the developing rat brain. Berkely-Los Angeles-London: University of California Press. 1970; 208.

DOI: http://dx.doi.org/10.21802/gmj.2018.1.8

Copyright (c) 2018 O. Tkachuk, M. Povar

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


Free counters!