Российская академия наук


CELL-FREE DNA – TWO-FACED JANUS FOR THE NERVOUS SYSTEM CELLS AT A FOCAL BRAIN ISCHEMIA



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CELL-FREE DNA – TWO-FACED JANUS FOR THE NERVOUS SYSTEM CELLS AT A FOCAL BRAIN ISCHEMIA

Konorova I.L.1, Glebova K.V.2, Barskov I.V.1, Veiko N.N. 2, Khaspekov L.G.1

1Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, Russia; konorova.irina@yandex.ru

2Research Centre for Medical Genetics, Russian Academy of Medical Sciences, Moscow, Russia; krglebova@gmail.com
Cell-free DNA (cfDNA) of endogenous origin is constantly present in body fluids in vivo as well as in cultural medium of any cells in vitro, it contains ligands for transmembrane "toll-like" receptors TLR9 that are actively expressed by the nervous system cells. In the conditions of focal brain ischemia the markers of oxidative DNA damage are revealed in blood plasma, which quantitative dynamics corresponds to that of the damaged tissue volume. In the previous reports (Glebova K.V. et al., 2011; Konorova I.L. et al., 2012) we have shown that in vitro the presence of oxidized DNA (DNAox) in cultural medium reduced neurons’ survival in glutamate excitotoxicity conditions in contrast to the neuroprotective effect of native gDNA. The aim of the work is to find out in vivo whether changes in quantity and molecular properties of cfDNA influence a size of the ischemic lesion in focal brain ischemia.

95 male Wistar rats (170-180 g) anesthetized with Chloral hydrate (350 mg/kg, intraperitonealy (i/p)) were used. The effect of homologous gDNA, oxDNA (1 mkg/ml of blood) and the same volume of physiological solution (control) injected intravenously (i/v) 1 day before the photoinduced thrombosis of superficial brain vessels (effect of i/v gDNA injection was compared with that of i/p one), or 30 min after a 15 min compression ischemia/reperfusion of the same area of neocortex was investigated. Lesion volume determination by morphometry (methylene blue staining) and morphological changes in penumbra estimation (Nissl staining) were made 1 and 4 days later.

Results. A preventive effect of gDNA administration in vivo was observed in 1 day after photothrombosis and was more considerable at i/p way introduction: after i/p injection the lesion volume was less (p<0.05) than in control, but after i/v introduction was not, however around the infarct there was no penumbra area. On the contrary, after i/v oxDNA administration the tendency to increase in the damage size took place. The therapeutic effect of gDNA i/v administration after the compression ischemia/reperfusion was observed in 4 days (p<0.01) while in a case of oxDNA the effect was not found.

Conclusion. In focal brain ischemia conditions cfDNA, possessing gDNA properties, can act as neuroprotector, interfering with brain infarct extending, however, being exposed to oxidizing modifications, on the contrary, can promote the involvement of new neurons’ mass in pathological process and to increase in the ischemic lesion volume.


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