RESUMEN
It was investigated the effect of two adamantane derivatives, memantine and 5-hydroxyadamantan-2-one (5-HA), in patients with cerebrovascular disorders. In vitro studies showed that 5-HA, unlike memantine, exhibited antiplatelet activity. Experiments showed that memantine reduced cerebral blood flow in the brain cortex of intact rats and those under conditions of transient global ischemia, whereas 5-HA only selectively improved blood flow in ischemic brain and was superior to the reference drug nimodipine. The obtained data indicate the leading role of the GABA-ergic (rather than glutamatergic mechanisms) in implementation of the anti-ischemic cerebrovascular activity.
Asunto(s)
Adamantano/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Ataque Isquémico Transitorio/tratamiento farmacológico , Memantina/farmacología , Adamantano/análogos & derivados , Adenosina Difosfato/farmacología , Anciano , Animales , Animales no Consanguíneos , Plaquetas/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Circulación Cerebrovascular/efectos de los fármacos , Epinefrina/farmacología , Femenino , Humanos , Hipoxia-Isquemia Encefálica/patología , Ataque Isquémico Transitorio/patología , Flujometría por Láser-Doppler , Masculino , Persona de Mediana Edad , Nimodipina/farmacología , Agregación Plaquetaria/efectos de los fármacos , Ratas , Vasodilatadores/farmacologíaRESUMEN
Experiments on nonlinear rats subjected to global transient cerebral ischemia revealed the ability of glutamic acid to improve cerebral circulation. Consequently, the excitatory amino acid can produce adverse (neurotoxic) and positive (anti-ischemic) effects in cerebral ischemia. The cerebrovascular effect of glutamic acid in cerebral ischemia is attenuated on the background action of the MNDA receptor blocker MK-801 (0.5 mg/kg intravenously) and eliminated by bicuculline. When glutamic acid is combined with the non-competitive MNDA receptor antagonist MK-801, neither one nor another drug shows its vasodilator effect. The results are indicative of the interaction between excitatory and inhibitory systems on the level of cerebral vessels and once again confirm our previous conclusion about the decisive role of GABA(A) receptors in brain vessels in the implementation of anti-ischemic activity of endogenous compounds (melatonin) and well-known pharmacological substances (mexidol, afobazole), and new chemical compounds based on GABA-containing lipid derivatives.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Ácido Glutámico/farmacología , Fármacos Neuroprotectores/farmacología , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Animales no Consanguíneos , Bicuculina/farmacología , Isquemia Encefálica/patología , Arteria Carótida Común/cirugía , Circulación Cerebrovascular/efectos de los fármacos , Oclusión Coronaria/patología , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Masculino , Fármacos Neuroprotectores/antagonistas & inhibidores , Ratas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
The effect of nimodipine, mexidol, melatonin, afobazole, 5-hydroxy-adanamtan-2-one, and GABA conjugates with arachidonic acid and docosahexaenoyl dopamine on the cerebral circulation has been studied in intact rats and those with global transient cerebral ischemia, experimental myocardial infarction, and combined vascular pathology of brain and heart. The most pronounced vasodilation activity in rats with global transient cerebral ischemia is exhibited by nimodipine, mexidol, melatonin, afobazole, 5-hydroxy-adanamtan-2-one, and GABA-containing lipid derivatives. This effect of all these drugs (except for nimodipine) is not manifested on the background of GABA receptor blocker bicuculline. In rats with experimental myocardial infarction and combined vascular pathology of brain and heart not all of the compounds mentioned acbove with GABA-ergic mechanism of action stimulate the cerebral blood flow. Thus, both similarity and differences in cerebrovascular effects of these compounds have been found, which depend on the initial state of organism and the vascular pathology of brain and/or heart. The obtained results show good prospects for this direction of research.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Ataque Isquémico Transitorio/tratamiento farmacológico , Infarto del Miocardio/tratamiento farmacológico , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Adamantano/análogos & derivados , Adamantano/farmacología , Animales , Animales no Consanguíneos , Bencimidazoles/farmacología , Bicuculina/farmacología , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/fisiopatología , Dopamina/análogos & derivados , Dopamina/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Ataque Isquémico Transitorio/complicaciones , Ataque Isquémico Transitorio/fisiopatología , Masculino , Melatonina/farmacología , Morfolinas/farmacología , Infarto del Miocardio/complicaciones , Infarto del Miocardio/fisiopatología , Nimodipina/farmacología , Picolinas/farmacología , Ratas , Receptores de GABA/metabolismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Dynamic changes in serum homeostasis of rats with experimental myocardial infarction evolution using the method of laser correlation spectroscopy were studied. The presence of necrotic myocardial damage was confirmed by electrocardiographic, histological and biochemical methods. Increased contribution of small particles in the acute period of myocardial infarction was detected, which indicates products of catabolism accumulation in serum and changing the level of some proteins. Comparison of subfractional content of sera from rats with varying degrees of extension of myocardial necrosis through the ventricular wall revealed the predominance of particles of low molecular size (up to 10 nm) in animals with transmural infarction and middle-size fraction (50-120 nm) in animals with non-transmural infarction. These results are consistent with the clinical data obtained by this method in patients with Q-wave and non-Q-wave myocardial infarction.
Asunto(s)
Homeostasis , Infarto del Miocardio/sangre , Animales , Masculino , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Necrosis , RatasRESUMEN
Experiments have shown that adamantane derivate - 5-hydroxyadamantan-2-on (100 mg/kg, i.v.) enhances the local blood flow in the cerebral cortex of rats under global transient brain ischemia conditions, while not influencing the brain blood flow in intact rats. In the same dose, adamantane derivate significantly decreases mortality in rats under conditions of hypergravity ischemia. The cerebrovascular effect of adamantane derivate is abolished by bicuculline (GABA-A receptor blocker), which is evidence for a GABAergic component in the mechanism of the cerebrovascular action ofadamantane derivate.
Asunto(s)
Adamantano/uso terapéutico , Antiparkinsonianos/uso terapéutico , Corteza Cerebral/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Ataque Isquémico Transitorio/tratamiento farmacológico , Adamantano/administración & dosificación , Adamantano/análogos & derivados , Animales , Antiparkinsonianos/administración & dosificación , Bicuculina/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/fisiopatología , Antagonistas de Receptores de GABA-A/administración & dosificación , Ataque Isquémico Transitorio/mortalidad , Ataque Isquémico Transitorio/fisiopatología , Flujometría por Láser-Doppler , Masculino , Ratas , Receptores de GABA-A/metabolismo , Tasa de SupervivenciaRESUMEN
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.