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We have studied the effect of a GABA conjugate with arachidonic acid (AA) on the morphological state of rat brain tissues after left median cerebral artery occlusion. The results showed that a 6- and 12-day course administration of the GABA - AA conjugate at dose of 2 mg/kg (i.p.) in rats with this model of local permanent brain ischemia led to significant recovery processes in brain tissues. The tissue morphology pattern in the group of animals treated with the GABSA - AA conjugate for 12 days was almost identical to that in intact tissues.

In experiments on rats, measurements of the local blood flow in the cortex of cerebrum with the aid of a laser Doppler flow meter showed that docosahexaenoic acid (DHA) enhanced the local cerebral circulation in animals with global transient cerebral ischemia, while not influencing that in intact animals. This vasodilatory effect of DHA in ischemized rats is blocked by bicuculline (specific GABA(A) receptor blocker), which is indicative of a GABA-ergic mechanisms of the vascular tone regulation. The results of radioligand binding assay in vitro showed the possibility of direct DHA interaction with cerebrovascular GABA(A) receptors.

Experiments have shown that GABA conjugate with prostaglandin E2 enhances cerebral blood flow in rats after global transient ischemia, while not affecting the cerebral hemoperfusion in intact animals. It is established that cerebrovascular activity of the GABA conjugate with prostaglandin E2 under conditions of cerebral ischemia is based on GABAergic mechanisms of vascular tone regulation, since it is removed by GABA(A)-receptor blocker bicuculline. At the same time, cerebral blood flow of intact rats and rats after global transient ischemia of brain is equally enhanced by prostaglandin E2 alone. This effect is not neutralized by bicuculline.

A GABA conjugate with docosahexaenoyl dophamine (DHED) enhanced local cerebral blood flow in rats under conditions of global transient cerebral ischemia, experimental myocardial infarction, and combined vascular pathology of brain and heart. At the same time, the GABA-DHED conjugate did not influence brain hemoperfusion in intact animals. The cerebrovascular effect of this conjugate is determined by its direct action on the vascular tone, since no changes in blood pressure have been observed. Under conditions of the combined vascular pathology of brain and heart, the cerebrovascular effect of GABA-DHED conjugate is inhibited by bicuculline, which is evidence for the involvement of GABAergic mechanisms in the drug action upon cerebrovascular tone.

Experiments on rats showed that, under conditions of global transient ischemia, a conjugate of GABA with arachidonic acid enhances the local cerebral blood flow due to a decrease in the vascular tone. In intact rats, the examined neurolipin did not show unidirectional changes in the cerebral perfusion. Under conditions of experimental myocardial infarction and combined vascular pathology of brain and heart, the GABA conjugate with arachidonic acid increased the blood flow in the parietal region of brain cortex in most experiments, while decreasing the level of blood pressure.

The effect of derivatives of arachidonic and docosahexaenoic acids on AMPA receptors in Purkinje cells from the rat cerebellum was studied using the patch-clamp electrophysiological method. It was shown that derivatives of arachidonic acid-arachidonoyl dopamine and docosahexaenoic acid-docosahexaenoyl dopamine and ester of docosahexaenoic acid with ethylene glycol in nanomolar concentrations effectively potentiated the ionic currents caused by activation of AMPA receptors of kainic acid. Ester of docosahexaenoic acid with nitroethylene glycol blocked AMPA receptors, and anandamide (ethanolamide of arachidonic acid) was not effective. A behavioral test showed that docosahexaenoyl dopamine in doses of 0.1-20 mg/kg had no effect on the learning and memory abilities of the animals tested.

The effects of GABA - docosahexaenoyldopamine (DHED) conjugate on the cerebral haemodynamics and thrombocyte aggregation were evaluated and compared to these of docosahexaenoyldopamine alone. The GABA - DHED conjugate was shown to significantly enhance the cerebral circulation in rats with a model of global transient cerebral ischemia, as compared to the intact animals. Administered alone, DHED increased the blood supply of both intact and ischemic brains to an equal extent. The GABA-DHED conjugate demonstrated the antiaggregative activity, but the effect was less expressed than that of DHED alone.

A series of original dopaminamides of polyunsaturated fatty acids were synthesized and characterized with respect to antiaggregant and cerebrovascular stimulant properties. It was established that dopaminamides of linolic, dimethyllinolic, docosapentaenoic, docosahexaenoic (DHEA) and stearidonic (C18:4 and C18:3) acids decrease ADP and arachidonic acid (AA) induced human thrombocyte aggregation in vitro. The most pronounced antiaggregant effect was observed for DHEA dopaminamide: in a dose of 10 mg/kg, this agent produced a significant decrease in the AA induced thrombocyte aggregation. DHEA per se in the same dose increases the activated partial thromboplastin time (APTT), while not affecting the prothrombin time. The synthesized dopaminamides of arachidonic, eicosapentaenoic, and docosahexaenoic acids stimulate local circulation in the cerebral cortex. The most pronounced cerebrovascular effect was also produced by DHEA dopaminamide.

The main arachidonic acid metabolites released into the medium by mouse splenocytes have been identified on the basis of chromatographic and spectral studies as well as by mass spectrometry of the derivatives. In the absence or presence of exogenous arachidonic acid mouse splenocytes produce mainly 12-hydroxy-5,8,10,14-eicosatetraenoic and 12,20-dihydroxy-5,8,10,14-eicosatetraenoic acids. Both products are constantly released by intact cells into surrounding media without stimulation by exogenous substrate or other modulators. For the first time it is shown that exogenously added ganglioside GM3 lactone as well as ganglioside GM3 itself can influence the arachidonic acid metabolism in splenocytes.

The effects of fluorodeoxy prostanoids on platelet aggregability were studied. It was shown that introduction of fluorine into positions 9, 11 or 15 of prostaglandin F2 alpha led to enhanced proaggregation activity. The most active compound among fluorodeoxy analogs was 15-fluoro derivative; bisfluoro analog was moderately active, and 11-fluoro compound had the least activity. In the group of fluorodeoxy prostaglandins E2, a contrary effect was registered. Thus, the most active compound was 1-fluoride and the least, 15-fluoride. The incorporation of fluorine into position 15 of prostacyclin led to insignificantly lower antiaggregatory activity just as this modification of 6-keto-prostaglandin F1 alpha was accompanied by a dramatic increase in its ability to inhibit platelet aggregation.

In a search for stable thromboxanomimetics the action of 11-fluoro-11-deoxyprostaglandin F2 alpha (11-fluoro-PGF2 alpha) on the aggregatory properties of platelets and the tone of the vascular, respiratory and gastrointestinal smooth muscles was studied. It was found that 11-fluoro-PGF2 alpha, in contrast to PGF2 alpha, induces platelet aggregation and exhibits a high activity with respect to smooth muscles sensitive to thromboxane A2 alpha (TXA2) and a low activity for smooth muscles sensitive to PGF2 alpha 9-11-epoxyimino-PGH2 (a specific antagonist of TXA2 receptors) competitively blocked the action of 11-fluoro-PGF2 alpha on vascular smooth muscles. Thus, 11-fluoro-PGF2 exhibits properties of a thromboxanomimetic that makes it possible to propose it for modelling TXA2-induced biological effects.

The effect of exchange of 15-hydroxyl for fluor on biological activity of PGF2 alpha and PGE2 on isolated smooth muscles of different organs has been studied. The exchange leads to significant increase in contractile (100-fold) and relaxation (1000-fold) activity of PGF2 alpha on smooth respiratory muscles. At the same time, the effect of 15-fluor-15-deoxyprostaglandin F2 alpha on smooth muscles of intestinal and vascular tracts did not differ from that of PGF2 alpha. Similar modification of PGE2 led to the decrease (10-fold) both in contractile and relaxation activity on all studied types of smooth muscles. The data obtained have been discussed within the boundaries of prostanoid receptor classification (Kennedy, 1982). Fluor derivative of PGF2 alpha may be used for pharmacological differentiation of EP-receptors.