RU2281765C1 - Method for treatment of cerebral ischemia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a method for treatment of cerebral ischemia on its model in mammal. Method involves administration in mammal the effective doses of bis-[(2-hydroxyethyl)-N,N,N-trimethylaminium] succinate. This provides prophylaxis of development of unfavorable results of cerebral ischemia and/or insult based on prevention of cerebral neurons death, reducing rate of pathological decreasing the energetic metabolism in ischemia being without by-side effects.

EFFECT: improved and enhanced method of treatment of cerebral ischemia.

3 tbl, 2 ex

Description

The invention relates to medicine, in particular to a method for the treatment of cerebral ischemia.

Stroke is the second leading cause of death in the world. In Russia, cerebral stroke is the second leading cause of death after myocardial infarction. Among all types of strokes, 80% are ischemic strokes. Ischemic stroke occurs at the time of cerebral vascular occlusion, which prevents the flow of blood to parts of the brain and the occurrence of cerebral ischemia.

A well-known approach to the treatment of stroke is the creation of neuroprotectors that would protect the nervous tissue from damage in conditions of ischemia. As neuroprotectors, agents have been proposed that block individual reactions of pathological cascades leading to the death of neurons during ischemia. Such agents include N-methyl-D-aspartate (NMDA) receptor antagonists (selfotel, dextrorphan), opiate agonists (nalmefen), sodium channel blockers (lubeluzole), gamma-aminobutyric acid agonists (clomethiazole), calcium channel blockers, antiradical agents and antioxidants, monoclonal antibodies, membrane stabilizers, growth factors (the main fibroblast growth factor). All of these agents did not show a positive effect in clinical trials. Cheng YD et al., NeuroRx 1: 36-45, 2004.

Thus, there is a need for safe and effective methods of protecting nerve tissue from damage in conditions of cerebral ischemia.

The objective of the invention is to provide an effective method of treating cerebral ischemia without side effects and complications.

RF patent 2228174 discloses the use of succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] for the treatment of insulin resistance, diabetes mellitus, hyperlipidemia and dyslipidemia. However, the ability of bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] to protect brain neurons from damage in conditions of cerebral ischemia is not known from the prior art.

We found that the administration of succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] to mammals can protect brain neurons from damage in conditions of cerebral ischemia.

The essence of the invention lies in the fact that in a method of treating cerebral ischemia in its model in a mammal, the mammal is administered effective amounts of succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium].

Preferably, the succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] is administered in an amount of 1-50 mg / kg body weight of a mammal. Preferably, the mammal in need of treatment for cerebral ischemia is a human.

In the method of treating cerebral ischemia, succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] can be administered to a mammal in various dosage forms, including tablets, capsules, lozenges, powders, spray solutions, aerosols, aqueous solutions, elixirs, syrups and injections. Preferably, in the method of treating cerebral ischemia, succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] is administered by injection.

Using the present invention, through the protection of brain neurons in ischemic conditions, it becomes possible to prevent the development of the adverse effects of cerebral ischemia and / or stroke.

The following example demonstrates the invention.

Example 1

The introduction of succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] prevents the death of brain neurons in rats with chronic brain ischemia caused by ligation of the carotid arteries.

The effect of reducing the death of brain neurons with the introduction of succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] was evaluated in a rat model with chronic cerebral ischemia caused by ligation of the carotid arteries. The nature and mechanism of damage to brain neurons in this model corresponds to that observed in ischemic stroke. The death of brain neurons was quantified by ¹ H NMR in vivo by reducing the level of the neuronal marker N-acetyl aspartate (NAA) in the brain. NAA is a well-known non-invasive marker for neuronal integrity. NAA is found exclusively in neurons. The decrease in NAA or the ratio of NAA to creatine (relative level of NAA) is strongly correlated with the loss of neurons when they are damaged or degenerate. Demougeot C et al. J Neurochem. 2004 90 (4): 776-83. Roitberg B et al. Neurol Res. 2003 25 (1): 68-78. Schuhmann MU et al. J Neurotrauma. 2003 20 (8): 725-43.

Carotid ligation was performed in Wistar male rats 3 hours before the first injection. Then, rats were injected with ip for seven days. injections physical R-RA (control), 1 mg / kg or 50 mg / kg of succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium]. On day 15 from the time of ligation, the level of NAA in the brain was measured by ¹ H NMR in vivo. The data are presented in table 1 in% as mean ± standard deviation (n = 5) of the relative level of NAA in the brain. The NAA level in mock-operated rats without ischemia was taken as 100% (100.0 ± 13.7). Statistically significant differences in the results were evaluated using Student's t-test.

Table 1

Treatment The level of NAA in the brain,% Fiz. solution (control) 81.6 ± 6.7 Succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium], 1 mg / kg 103.1 ± 6.9 * Succinic bis [(2- 99.7 ± 7.1 * hydroxyethyl) -N, N, N-trimethylaminium], 50 mg / kg * Significantly different from control (p <0.05)

Thus, the introduction of succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] in rats with chronic cerebral ischemia reliably prevents the death of brain neurons compared to the control and keeps the number of neurons at the level of healthy rats without ischemia.

The loss of memory and learning ability of rats was associated with the death of brain neurons in cerebral ischemia, as was shown later in the passive avoidance test. The delay time of entry into the shock compartment before shock and after shock (after 24 hours) characterizes learning and memory. The data are presented in table 2 in sec as mean ± standard deviation (n = 8) of the delay time. The delay level in mock-operated rats without ischemia was 9.3 ± 2.5 seconds before shock and 104.2 ± 22.9 seconds 24 hours after shock. Statistically significant differences in the results were evaluated using Student's t-test.

table 2 Treatment Delay time, sec Before the shock 24 hours after the shock Fiz. solution (control) 29.0 ± 10.9 30.7 ± 13.1 Succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium], 1 mg / kg 13.5 ± 4.3 * 99.3 ± 24.5 * Succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium], 50 mg / kg 27.7 ± 13.1 53.3 ± 16.3 * * Significantly different from control (p <0.05)

Example 2

The preliminary introduction of succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] reduces the rate of pathological decrease in energy metabolism in acute total cerebral ischemia caused by cardiac arrest.

Rats were injected intiperitoneally for 7 days with succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] (YATMA) in an amount of 10 mg / kg or physical. solution (control). The effect of preconditioning JATMA was evaluated on day 8 by ¹ H NMR in vivo to reduce the rate of decrease in ATP concentration in rat brain during the first minutes after cardiac arrest. The data are presented in table 3 as the average value of ATP level in% of the initial value until cardiac arrest in the brain of the rat from time to time.

Table 3. Time min ATP,% (n = 8) The control YATMA 3 74 ± 26 76 ± 20 four 44 ± 27 65 ± 16 * 5 35 ± 22 63 ± 21 * 6 30 ± 15 54 ± 23 * * Significantly different from control (p <0.05).

Thus, the administration of succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium] significantly reduces the rate of pathological decrease in energy metabolism in acute total cerebral ischemia.

Claims (1)

A method of treating cerebral ischemia in its model in a mammal, characterized in that it is administered an effective amount of succinic bis [(2-hydroxyethyl) -N, N, N-trimethylaminium].