[The influence of adenosine receptor ligands and hypoxic preconditioning on the metabolism of the brain tissue in the experiment].

Aim: To study the influence of adenosine receptor ligands and hypoxic preconditioning on carbohydrate metabolism in global brain ischemia.

Material And Methods: The study included 51 outbred white male mice weighing 20-25 g. An effect of adenosine receptor ligands and hypoxic preconditioning on brain tissue metabolism, heat exchange and longevity was explored.

[Importance of selective A1 agonists for the protection of brain and heart against injuring factors].

Powerful selective A1 agonist N6-cyclopentyladenosine (CPA) effectively protects the brain (upon decapitation) and the heart (upon intoxication by KCl or ethylen glycol tetra acetate (EGTA)) against the action of injuring factors on experimental animals. CPA weakens or removes damages and/or cell death and probably promotes the regeneration of tissue structures and restoration of their functions. Thus, CPA increases the tolerance of the heart and brain with respect to the introduction of two strong toxicants and even upon decapitation.

[Different types of hypoxic preconditioning protect the brain against complete global ischemia].

Different types of hypoxia, including several new models, protect the brain against complete global ischemia. Hypoxic (stay in hermetic chamber without or with consumption of CO2 and H2O exhaled), circulatory (bleeding), hematic (injections of NaNO2, CoCl2, NiCl2) and tissue (histotoxic) hypoxia (K2-malonate injection) increases cerebral ischemic tolerance in early terms (in hours). Intracerebroventricular injections of NaNO2, CoCl2, NiCl2 and K2-malonate in nontoxic doses have weak effects.

[New approaches to brain protection against global ischemia].

Three pathways to increase tolerance to global cerebral ischemia have been worked out: (1) the use of inhibitory neurotransmitters and their analogues; (2) injection of neuroleptics; (3) hypoxic preconditioning. We revealed the importance of receptors, K(ATP) channels and induction of hypothermia in neuroprotective mechanisms of these influences.

[The role of hypothermia in brain protection by adenosine receptor agonists].

Agonists of A1 adenosine receptors induce a profound hypothermia that is correlated with a considerable increase in tolerance with respect to the global cerebral ischemia. Thermal irradiation of the head considerably decreases and the thermoneutral temperature completely prevents (i) the development of hypothermia in the body and, especially, in the cortex and (ii) the neuroprotection, so that a correlation of these two effects disappears. The induction of hypothermia is the most important but not single mechanism of neuroprotective action of A1-receptor agonists.

[Biochemical and pharmacological mechanisms of different types of hypoxic preconditioning in cerebral ischemia in mice].

Different types of hypoxic preconditioning (hypoxic, circulatory, hemic and tissue hypoxia) increase the tolerance to complete global cerebral ischemia at early terms (hours). Biochemico-pharmacological analysis with the use of selective agonists and antagonists showed the importance of adenosine A1-receptors and K+(ATP)-channels in the mechanisms of the neuroprotective effect and natural tolerance. The general scheme of the investigated mechanisms of different types of hypoxic preconditioning has been proposed.

[The importance of hypothermia in the preconditioning increase of ischemic tolerance to global cerebral ischemia].

Various types of preconditioning including the main hypoxia (hypoxic, circulatory, hematic/hypemic and tissue/histotoxic), agonists of adenosine A-receptors and openers of K(ATP)-channels induce a hypothermia. A-agonists act through A1-receptors, CoCl2 and NiCl2--via endogenous adenosine and activation by it A1-receptors. The developing hypothermia correlates with neuroprotective effect and is important, but not the only mechanism of tolerance increase to global ischemia.

Neuroprotective effect of hypoxic preconditioning: phenomenon and mechanisms.

We developed a new model of hypoxic preconditioning improving tolerance of complete global cerebral ischemia. The role of adenosine receptors in the realization of this effect and in the mechanisms of hypoxic tolerance is demonstrated. Preconditioning decreases of body temperature, which correlates with the neuroprotective effect, but this effect does not directly result from hypothermia.

[Comparative characteristics of A1-receptor agonists as neuroprotective agents].

Comparative characteristics of a series of selective A1 agonists influencing the complex global cerebral ischemia (CGCI) are presented and the optimum conditions for realization of the neuroprotective effect are selected. The degree of the neuroprotective action blocking by theophylline and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) decreases in the following order: CPA CHA ADAC. The A1-receptor agonists exhibit both direct action upon brain (maximum for ADAC) and a peripheral mechanism (especially pronounced for CPA).

Role of adenosine receptors in neuroprotective effect during global cerebral ischemia.

Selective A(1)adenosine receptor agonists produced a considerable neuroprotective effect during global cerebral ischemia. The neuroprotective effect decreased in the order: A(1)agonists-NECA-adenosine-A(2A)agonist CGS 21680, while selective A(3)adenosine receptor agonist was ineffective. Inhibitory analysis showed that A(1)adenosine receptors mediate the neuroprotective effect of CPA, are involved in the effects of NECA and adenosine (but not CGS 21680), and participate in natural resistance to cerebral ischemia.

[Importance of adenosine A2A receptors in resistance to complete global cerebral ischemia].

Selective A2A agonists (CGS 21680 and DPMA) produce a moderate neuroprotector effect with respect to the complete global cerebral ischemia (GCI). At the same time, selective A2A antagonists 8-(3-chlorostyrylcaffeine (CSC) and ZM 241385 somewhat reduce the brain resistance to complete GCI, completely prevent the neuroprotector effect of CGS 21680, partly suppress the neuroprotector activity of adenosine and 5'-N-ethylcarboxamidoadenosine (NECA), and do not affect (CSC) or potentiate (ZM 241385) the neuroprotector effect of N6-cyclopentyladenosine. The A2A-receptors are probably mediating in the neuroprotector activity of CGS 21680 and participating in the natural brain stability with respect to complete GCI, as well as in the effects of NECA and adenosine.