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Journal Biomedical Radioelectronics №4 for 2014 г.
Article in number:
Volume of brain infarct and ischemic stroke outcome depends on the genome CPG-rich repeats circulating in blood plasma
Authors:
I. L. Konorova - Dr.Sc. (Biol.), Professor, Leading Research Scientist, Research Center of Neurology Russian Academy of Medical Sciences, Moscow. E-mail: konorova.irina@yandex.ru
M. Yu. Maksimova - Dr.Sc. (Меd.), Professor, Chief Research Scientist, Research Center of Neurology Russian Academy of Medical Sciences, Moscow. E-mail: ncnmaximova@mail.ru
I. N. Smirnova - Ph.D. (Med.), Senior Research Scientist, Research Center of Neurology Russian Academy of Medical Sciences, Moscow. E-mail: in-2so@eandex.ru
Т. A. Bolotova - Ph.D. (Med.), Senior Research Scientist, Research Center of Neurology Russian Academy of Medical Sciences, Moscow. E-mail: in-2so@eandex.ru N. N. Veiko - Dr.Sc. (Biol.), Professor, Head of Laboratory, Research Centre for Medical Genetics, Russian Academy of Medical Sciences, Moscow. E-mail: ribgene@rambler.ru
E. S. Ershova - Ph.D. (Biol), Senior Research Scientist, Research Centre for Medical Genetics, Russian Academy of Medical Sciences, Moscow. E-mail: ribgene@rambler.ru
Abstract:
Usually ischemic stroke that occurs after a psycho-emotional stress (PES) has a fatal outcome [May et al., 2002]. We found that animals predisposed to PES are highly sensitive to brain ischemia and sensitized to the transcribed region of the genome ribosomal repeat (rDNA) [Konorova and Veiko, 2012]. rDNA has a high frequency of unmethylated CpG dinucleotides which are Toll-like receptor 9 (TLR9) ligand. TLR9, being a sensor to damage-associated molecular patterns, trigger sterile inflammation in focal ischemia / reperfusion [Kono and Rock, 2008]. Agents that stimulate the innate pattern recognition receptor, TLR9, have been shown to induce tolerance (precondition) to ischemic brain injury in a mouse model of stroke [Stevens et al., 2008]. Moreover, neuroprotection can be caused by both systemic and intranasal administration of TLR9 ligand CpG [Bahjat et al., 2011; Packard et al., 2012]. The purpose of the study was to identify the relationship between rDNA level in blood plasma, the volume of ischemic brain damage and disease outcome in patients with ischemic stroke. Material and methods. The total concentration of cell-free DNA (cfDNA) by fluorimetry using a fluorescent dye Hoechst 33258; rDNA concentration in plasma and rDNA content in 1 ng of circulating cfDNA by quantitative nonradioactive dot-hybridization with biotinylated probe; plasma nuclease activity, as an index of cfDNA elimination effectiveness were tested. In the blood plasma of 25 healthy donors and 25 patients with ischemic stroke, which did not require the intensive care conditions, were examined on admission to the Research Center of Neurology (13 days ) and at 7 and 15 day after. The findings obtained were compared with the volume of brain infarct according to the results of neurovisualisation at the day of hospitalization, and subsequent neurological deficit dynamics in the acute stage according to NIHSS. Results. When hospitalization, the plasma concentration of cfDNA was increased in 26 times (p < 0.001) compared to that of donors (196 [117, 240] ng/ml), and of rDNA - two fold too (p < 0.001). A not strong direct relationship between the brain infarct volume and the plasma nuclease activity (r = 0,39, p = 0,040) was revealed. The last, being increased (p < 0.05), has reduced inefficiently the total cfDNA concentration (r = - 0,41, p = 0,043) which remained at a level three times higher than normal (p < 0,05) during the acute stage of stroke. At the same time the rDNA concentration in plasma was changed slightly too, and the rDNA content in 1 ng of cfDNA inversely correlated with cfDNA concentration (r = - 0,69, p = 0,0004). It was noted that the volume of brain infarct was smaller (r = - 0,63, p = 0,012) and stroke outcome was better (r = 0,55, p = 0,013) in patients who had more rDNA fragments circulating in in blood plasma at first hours of stroke, and in some cases there was a full recovery of neurological functions. Conclusions. Fragments of rDNA circulating in blood plasma pool of cfDNA, affect the brain infarct formation and outcome of ischemic stroke. When their content at first hours is elevated significantly, the outcome of stroke becomes better, but in the conditions of sensitization it may contribute to fatal outcome.
Pages: 38-39
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