Method of rehabilitation after hypoxia causing brain dysfunction in laboratory animal models

FIELD: medicine.

SUBSTANCE: drug-free correction of structure functional brain dysfunction caused by severe hypoxia/ischemia is ensured by placing a model in 24 hours after severe hypoxia in a pressure chamber and hypoxic post-conditioning at atmospheric pressure 360 mm Hg for 2 hours every 24 hours for three days.

EFFECT: method extends the range of products for studying rehabilitation capabilities after hypoxia causing brain dysfunction.

2 dwg


The invention relates to experimental medicine and can be used for non-pharmacological correction of structural and functional disorders of the brain, caused by severe hypoxia/ischemia.

Over the next analogues accepted: neuroprotective way hypoxic preconditioning moderate hypobaric hypoxia [1], the method of postconditioning on the heart [2] and the brain [3], as well as the modes used to hypobaric hypoxic stimulation [4]. Method [1] was developed by us earlier with the aim of increasing the tolerance of the brain to damaging factors and prevention of post-hypoxic and post-stress disorders. Method [1] based on the exposure of the organism to episodes of moderate hypobaric hypoxia chamber (360 mm Hg corresponds to "rise" to a height of 5 km, 2 hours, three times with an interval of 24 hours. Such exposure causes multilevel activation urgent genome-dependent adaptation mechanisms, which increase the adaptive capabilities of the brain and the whole body to adverse factors (hypoxia/ischemia, stress). Method [1] effective, easy to use (easy to control and dosed) and is based on natural non-invasive treatment (hypobaric hypoxia occurs in natural conditions during the ascent to the height), but it is used only for the prevention of Vozniknovenie what I pathologies, and not to correct them. The correction of postischemic cardiac diseases, in particular reducing the size of the hearth damage after a heart attack, aimed way ischemic postconditioning infarction [2], namely, that early after myocardial infarction is temporary occlusion of coronary vessels and creates a transient myocardial ischemia. This method is described in 2003 by the American physiologists, who showed that if after 60 minutes of coronarography dogs in the reperfusion period to conduct three sessions of 30-second coronaryocclusion, interspersed with 30-second intervals resume coronary blood flow, the myocardium becomes resistant to reperfusion injury. The area of damage was decreased by 44% compared with controls [2]. Subsequently, the cardioprotective effect of ischemic postconditioning has been confirmed in studies on other animals and clinical observations on patients with acute myocardial infarction. A similar technique was proposed and brain [3]. According to [3] early after ischemic stroke by bilateral "ligation" (occlusion) of the carotid arteries creates a transient ischemia of the brain (four 20-minute episode of occlusion and 30-s reperfusion), which reduces the size of the evoked potential in the area of stroke by 80%. The drawback is this method limit its application in practice, should be attributed to poor controllability, insecurity and invasiveness of such effects. Currently, the effects of hypobaric hypoxia is widely used in practice to hypobaric hypoxic stimulation of various diseases, however, this mode of adaptation or training - regular daily UPS to a height of up to 3.5 km (20-30 sessions) [4, 5, and others].

Objective improving the adaptive capacity of the organism undergoing the influence of adverse factors (severe hypoxia).

The essence of the proposed method of recovery after hypoxia, including three hypobaric hypoxia, is that the individual has suffered severe ischemia/hypoxia, then subjected to moderate hypobaric hypoxia (360 mm Hg) duration : 2 hours in each of the next three days with an interval of 24 h, which greatly reduces the amount of neuronal damage and restores their function.

The claimed method is performed as follows. Hypoxic postconditioning (360 mm Hg is equivalent to the height of 5000 m, 2 hours with an interval of 24 hours) in the chamber flow type is carried out within 3 days after severe hypoxic stroke.

Figure 1 and 2 presents the results of the preclinical testing of the proposed method obtained in fashion is lnyh experiments on laboratory animals (rats).

The experiment demonstrated that hypoxic postconditioning in accordance with the stated Protocol significantly reduces the degree of neuronal brain damage caused by hypoxia stroke (severe hypobaric hypoxia - 180 mm Hg, equivalent to an altitude of 11,000 m).

Figure 1 survival Analysis of neurons sensitive to hypoxia of the brain area - CA1 field of the hippocampus after severe hypoxia (black bar) and severe hypoxia with postconditioning (grey column). White column control. * - differences from control are statistically significant, p≤0.05. Y - axis the number of surviving neurons.

Severe hypoxia induces extensive neuronal loss in the hippocampus and neocortex of rats. The loss of neurons in the most vulnerable areas - CA1 field of the hippocampus to 7 days after the damaging effects reached 32% of the total number of cells. Postconditioning contributes vyjivaniyu% of neurons in the neocortex and CA4 field of the hippocampus, and in the CA1 killed only 9% of neurons, and 32%as not-postconditioning individuals.

Along with this postconditioning has a pronounced anxiolytic effect on behavior, reducing the anxiety levels of individuals after severe hypoxia.

Figure 2 Postconditioning has a pronounced anxiolytic effect, reducing pathological anxiety in animals after heavy is OI hypoxia, manifested in the avoidance of open and lit places.

Legend: white column control; black bar - severe hypoxia; grey column - severe hypoxia with postconditioning. * - differences from control are statistically significant, p<0.05

And the behavior of animals in open-field test. Y - axis the number of crossed-lit squares in the center of the "open field", 5-th day after hypoxic insult;

B - behavior of animals in the test, the elevated plus maze". Y - axis time (s) stay in the open, lit sleeves elevated cross maze, the 6th day after hypoxic stroke.

Individuals who suffer severe hypoxia, characterized by a sharp decline paces in the middle of the "open fields" and the time spent in the open arms of the maze, indicating that the increase in their level of anxiety. Postconditioning prevents the development of this pathological condition and normalizes the behavior of individuals, providing a pronounced anxiolytic effect.

Thus, the application of the proposed method provides structural and functional rehabilitation of the brain after severe hypoxia.

The characteristics of the prototype [1], which coincides with the essential features saleemul of the invention: parameters of moderate hypobaric hypoxia - 360 mm rtsenable 5000 m, 2 hours with an interval of 24 hours. Differences from the similar [1] - exposure moderate hypobaric hypoxia after damaging impact, i.e. in the mode of postconditioning.

Similarly, [2] and [3] in the proposed method uses the mode of postconditioning, but is used as postconditioning factor not ischemic, and combined hypoxic/hypobaric exposure.

Signs analogues [4] and [5], coinciding with the essential features of the claimed invention: the use of hypobaric hypoxia in a pressure chamber. Differences from analogues [4] and [5] - parameters hypoxia (high altitude "UPS") and the number of sessions (3 and not 20-30).

Thus, the claimed technical solution meets the criterion of "novelty", as it has significant distinguishing features of the prototype and model, thanks to which we can make a conclusion about conformity of the proposed method inventive step.

Sources of information

1. Samoilov MO, Rybnikova E.A., Tjulkov H., Wateva L.A., Amelin VA, Hogy LI, Pelto-Hucka M. the Effect of hypobaric hypoxia on the behavioural responses and the expression of early genes in the rat brain: corrective effect preconditioning impact// Reports of Academy of Sciences. 2001, 381, 1, 1-3.

2. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, and Vinten-Johansen J (2003) Inhibitin of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol 285: H579-H588.

3. Zhao H., Sapolsky R., Steinberg G. (2006) Interrupting reperfusion as a stroke therapy: ischemic postconditioning reduces infarct dementia size after focal ischemia in rats. 166: J. Cereb. Blood Flow. Metab. 26 (9): 1114-1121.

4. The method of adaptation to chronic intermittent hypobaric hypoxia in therapy and prevention. Methodical recommendations. - M.: the Ministry of health of the RSFSR, 1989.

5. Chieftains A.A., Buoys, VA hypobaric therapy of anxiety disorders neuroses and psychosomatic diseases. Patent RU (11) 2193382 (13) C2 (51) 7 A61G 10/02.

The method of rehabilitation after hypoxia, which causes dysfunction of the brain in models in laboratory animals, including the effects of hypobaric hypoxia in the chamber, characterized in that at 24 h after severe hypoxia model is placed in a pressure chamber and implement hypoxic postconditioning at atmospheric pressure 360 mm RT. Art., duration 2 h with an interval of 24 h for three days.


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