RESUMEN
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. RESULTS AND CONCLUSION: Adenosine, an agonist of A1 adenosine receptors, and hypoxic preconditioning exert a neuroprotective effect on brain cells. The blocker of A1 adenosine receptors aggravates metabolic disturbances in the brain and removes the protective effect of cyclopenyladenosine and ischemic preconditioning.
Asunto(s)
Precondicionamiento Isquémico , Adenosina , Animales , Encéfalo , Hipoxia , Ligandos , Masculino , Ratones , Receptores Purinérgicos P1RESUMEN
Effects of a local compression brain injury and the preventive application of cyclopentyladenosine (CPA) on the behavior of rats in the open field test was investigated. It is established that the local injury of a parietal cortex causes intensification of the orientation--research behavior and an increase in the emotional stress in rats. A protective action of CPA was manifested by a decrease in the expressiveness and duration of disturbances in the emotional and orientation--research behavior of animals in the open field test.
Asunto(s)
Antagonistas del Receptor de Adenosina A1 , Adenosina/análogos & derivados , Conducta Animal/efectos de los fármacos , Lesiones Encefálicas/psicología , Emociones/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Orientación/efectos de los fármacos , Adenosina/farmacología , Animales , Modelos Animales de Enfermedad , Inyecciones Intraventriculares , Masculino , RatasRESUMEN
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. Other A-agonists are much less active.
Asunto(s)
Agonistas del Receptor de Adenosina A1 , Adenosina/análogos & derivados , Encéfalo/efectos de los fármacos , Hipotermia Inducida , Fármacos Neuroprotectores/farmacología , Animales , Femenino , Masculino , RatonesRESUMEN
The neuroprotective properties of N6-cyclohexyladenosine (CHA) and N6-cyclopentyladenosine (CPA), adenosine receptor agonists (A-agonists), were studied on a model of spinal cord ischemia (SCI) in rats (most closely reproducing the analogous clinical pathological process in humans). The SCI model was induced by intravasal occlusion of the abdominal aorta and its branches. CHA and CPA were introduced by intracerebroventricular injections in a dose of 25 micrograms/kg, 60 min before SCI induction. The protective effect was judged by comparing the patterns of neurological and histopathological disturbances in the untreated control (ischemia) and on the CHA or CPA background. The A-agonist CPA produced a pronounced, statistically reliable neuroprotector effect on the minimum invasive SCI model studied. CHA is also a statistically reliable but less effective neuroprotector. The A-agonists may have good prospects in clinics.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Agonistas del Receptor Purinérgico P1 , Isquemia de la Médula Espinal/prevención & control , Animales , Inyecciones Intraventriculares , Dimensión del Dolor , Ratas , Isquemia de la Médula Espinal/patología , Isquemia de la Médula Espinal/fisiopatologíaRESUMEN
Brain function and neuroprotective activity of cyclopentyladenosine in rats with focal cerebral ischemia were evaluated by recording the steady-state potential. Cerebral ischemia was modeled by intravasal occlusion of the left internal carotid and middle cerebral arteries and bilateral occlusion of the common carotid arteries. Recording of the steady-state brain potential during experimental ischemia allowed identifying the development of ischemic depolarization by a negative potential shift. Changes in the steady-state potential after cyclopentyladenosine administration reflected delayed development of ischemic depolarization in the nervous tissue. Cyclopentyladenosine holds much promise for the protection of nerve cells from ischemic injury.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/uso terapéutico , Isquemia Encefálica/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Potenciales de Acción/fisiología , Animales , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Femenino , Infarto de la Arteria Cerebral Media/complicaciones , Masculino , Microelectrodos , Lóbulo Parietal/efectos de los fármacos , Lóbulo Parietal/fisiología , Ratas , Factores de TiempoRESUMEN
We developed a new minimally invasive model of spinal cord ischemia in rats: intravascular occlusion of the abdominal aorta and its branches. This model can be used on small laboratory animals and allows qualitatively and quantitatively evaluating the morphofunctional state of the nervous system during spinal cord ischemia by clinical manifestations and histological changes. Selective intravascular occlusion determines minimal invasiveness and adequacy of the proposed model to in vivo pathological processes. This model of spinal cord ischemia can be used in experimental pharmacology for evaluation of neuroprotective activity of various drugs and bioactive substances.
Asunto(s)
Isquemia , Médula Espinal/irrigación sanguínea , Animales , Aorta Abdominal , Enfermedades de la Aorta/complicaciones , Modelos Animales de Enfermedad , Femenino , Isquemia/etiología , Isquemia/patología , Isquemia/fisiopatología , RatasRESUMEN
The neuroprotector properties of cyclopentyladenosine (CPA), an adenosine receptor agonist, were studied on a model of focal brain ischemia in rats (reproducing a clinical pathological process in humans). The model of the focal brain ischemia in rats was induced by intravasal occlusion of left carotid artery, middle cerebral artery, and by bilateral occlusion of both carotid arteries. CPA was introduced by intracerebroventricular injections in a dose of 25 micrograms/kg, 60 min before ischemia induction. The protective effect was judged by comparing the neurological and histopathological disturbances in the control (untreated ischemia) and on the CPA background. CPA injections produced a pronounced neuroprotector effect on the minimum-invasive focal brain ischemia model in rats.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/uso terapéutico , Ataque Isquémico Transitorio/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Agonistas del Receptor Purinérgico P1 , Enfermedad Aguda , Animales , Arteriopatías Oclusivas/complicaciones , Infarto Encefálico/etiología , Infarto Encefálico/patología , Enfermedades de las Arterias Carótidas/complicaciones , Arteria Carótida Común , Arteria Carótida Externa , Enfermedades Arteriales Cerebrales/complicaciones , Femenino , Inyecciones Intraventriculares , Ataque Isquémico Transitorio/etiología , Ataque Isquémico Transitorio/patología , Masculino , Arteria Cerebral Media , RatasRESUMEN
Possibilities of the neuroprotector therapy using adenosine and cyclopentyladenosine (CPA), an adenosine receptor agonist, were studied on a model of spinal cord injury by compression in rats (most closely reproducing the analogous clinical pathological process in humans). The model was induced by slow, graded compression of the spinal cord at the thoracic level. Adenosine and CPA were introduced 60 min before injury by subcutaneous injections in a dose of 300 and 2.5 micrograms/kg, respectively. The protective effect was judged by comparing the neurological, electromyographic, and histopathological changes in animals with the model injury and in the control group (adenosine and CPA background). The A1-agonist CPA injections produced a pronounced, statistically significant neuroprotector effect on the given spinal cord injury model in rats. The neuroprotective effect of adenosine was significant but not as strong. It is concluded that it is expedient to use A-agonists in clinics.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/farmacología , Fármacos Neuroprotectores/farmacología , Agonistas del Receptor Purinérgico P1 , Traumatismos de la Médula Espinal/prevención & control , Animales , Electromiografía , Ratas , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
The problem of brain ischemia damage treatment stimulates the search for new effective methods, which are studied on various experimental models. Most of such models possess significant disadvantages, producing hypoxia in the whole organism, being poorly controlled, involving serious traumas, and still being far from true pathological mechanisms accompanying the ischemia development. A model of focal brain ischemia in rats, induced by middle cerebral artery intravasal occlusion, is free of these disadvantages.
Asunto(s)
Ataque Isquémico Transitorio/etiología , Animales , Arteriopatías Oclusivas/complicaciones , Enfermedades de las Arterias Carótidas/complicaciones , Arteria Carótida Interna , Enfermedades Arteriales Cerebrales/complicaciones , Modelos Animales de Enfermedad , Femenino , Ataque Isquémico Transitorio/patología , Ataque Isquémico Transitorio/fisiopatología , Masculino , Arteria Cerebral Media , RatasRESUMEN
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. The role of A(2B)adenosine receptors in the realization of neuroprotective effects was also demonstrated.
Asunto(s)
Adenosina/análogos & derivados , Isquemia Encefálica/metabolismo , Neuronas/efectos de los fármacos , Receptores Purinérgicos P1/fisiología , Adenosina/farmacología , Animales , Antihipertensivos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Isquemia , Masculino , Ratones , Fenetilaminas/farmacologíaRESUMEN
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). There is a close correlation between the neuroprotective activity of the A1-receptor agonists and their hypothermal effect. It is suggested that the hypothermal action plays an important part in the neuroprotective activity of the A1-receptor agonists.
Asunto(s)
Adenosina/análogos & derivados , Isquemia Encefálica/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Agonistas del Receptor Purinérgico P1 , Adenosina/farmacología , Adenosina/uso terapéutico , Animales , Hipotermia/inducido químicamente , Ratones , Fármacos Neuroprotectores/farmacología , Antagonistas de Receptores Purinérgicos P1RESUMEN
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.
Asunto(s)
Isquemia Encefálica/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Agonistas del Receptor Purinérgico P1 , Animales , Femenino , Masculino , Ratones , Fármacos Neuroprotectores/farmacología , Antagonistas de Receptores Purinérgicos P1 , Receptor de Adenosina A2ARESUMEN
Optimal neuroprotective doses of clonidine and guanobenz considerably reduce the total cerebral blood flow and reduce or do not change arterial pressure. In occlusion of the carotid arteries the alpha 2-agonists fail to reduce the degree of cerebral ischemia and hypotension. The neuroprotective effect of alpha 2-adrenoceptor-agonists is not a result of cerebral blood flow improvement.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/farmacología , Isquemia Encefálica/fisiopatología , Circulación Cerebrovascular/efectos de los fármacos , Clonidina/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Presión Sanguínea/fisiología , Femenino , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
In the total brain ischemia the cerebroprotective effect (CPE) of adenosine was pronounced in the following order: mouse > rat approximately guinea pig (males > females). The sensitizing effect (SE) of theophylline is the same in different species but is more pronounced in females compared to males. Newborn rats are much more tolerant to the total brain ischemia. The adenosine CPE increases and the theophylline SE decreases with age. The adenosine receptor component, evidently, contributes greatly to the natural tolerance of newborn animals to the total brain ischemia.
Asunto(s)
Isquemia Encefálica/fisiopatología , Encéfalo/efectos de los fármacos , Receptores Purinérgicos P1/efectos de los fármacos , Adenosina/farmacología , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Animales , Animales Recién Nacidos , Encéfalo/fisiopatología , Femenino , Cobayas , Inmunidad Innata/efectos de los fármacos , Masculino , Ratones , Ratas , Receptores Purinérgicos P1/fisiología , Caracteres Sexuales , Especificidad de la Especie , Teofilina/farmacología , Vasodilatadores/farmacologíaRESUMEN
Nonconformity of arterial pressure (AP) and cerebral blood flow (CBF) to the normal distribution necessitates the use of nonparametric criteria. Cerebroprotective doses of adenosine and cyclohexyladenosine significantly decrease AP and reduce (or virtually do not change) CBF. In conditions of following occlusion of carotid arteries AP is lower and CBF is somewhat better or the same as in the control (ischemia). Changes in CBF can be only an additional contribution to the high cerebroprotective effect of the A-receptor agonists.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Circulación Cerebrovascular/efectos de los fármacos , Agonistas del Receptor Purinérgico P1 , Vasodilatadores/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Isquemia Encefálica/etiología , Isquemia Encefálica/fisiopatología , Evaluación Preclínica de Medicamentos , Femenino , Masculino , Ratas , Estadísticas no Paramétricas , Vasodilatadores/uso terapéuticoAsunto(s)
Adenosina/análogos & derivados , Adenosina/farmacología , Isquemia Encefálica/prevención & control , Receptores Purinérgicos P1/efectos de los fármacos , Vasodilatadores/farmacología , Adenosina/administración & dosificación , Adenosina-5'-(N-etilcarboxamida) , Animales , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraventriculares , Masculino , RatonesRESUMEN
The duration of gasping has no normal distribution, so nonparametric statistic criteria should be used. Three adenosine receptor agonists have a highly cerebro-protective effect which decreases in the order: N-ethylcarboxamide adenosine > > cyclohexyl adenosine > adenosine. Theophylline completely blocks these effects. Thus, they act through adenosine receptors. Adenosine receptor agonist are likely to protect themselves neurons.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Receptores Purinérgicos P1/efectos de los fármacos , Adenosina/farmacología , Adenosina-5'-(N-etilcarboxamida) , Animales , Apnea/tratamiento farmacológico , Apnea/fisiopatología , Isquemia Encefálica/fisiopatología , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Masculino , Ratones , Receptores Purinérgicos P1/fisiología , Teofilina/farmacología , Vasodilatadores/farmacología , Vasodilatadores/uso terapéuticoRESUMEN
Adenosine has prominent cerebro-protective effect at total brain ischemia. Other nucleotides and nucleosides are less active or have no effect at all. It suggests participation of A-receptors. Adenosine is more effective than 8 other drugs that have protective effect in different models of brain ischemia (nimodipine, gamma-hydroxybutyrate etc).
Asunto(s)
Adenosina/uso terapéutico , Isquemia Encefálica/prevención & control , Animales , Masculino , Ratones , Nucleósidos/uso terapéutico , Nucleótidos/uso terapéutico , Receptores Purinérgicos P1/efectos de los fármacosRESUMEN
Curantil intracarotid injection resulted in brain blood supply and in brain oxygen consumption increase as well as in redox processes normalization in 75 cats with main brain arteries occlusion and heart insufficiency induced by chemical necrosis of the myocardium. A single intravenous injection of a higher curantil dose resulted in a significantly less effect. Long-term (3-72 hours) curantil infusion led to the improvement of the functions disturbed (limb movements, speech, vision) in 32 of 42 patients with brain ischemic insult. The greatest therapeutic efficacy was observed in patients with nonobturated brain infarction induced by brain vascular spasm or cardiocerebral vascular insufficiency.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Dipiridamol/administración & dosificación , Insuficiencia Cardíaca/complicaciones , Adulto , Animales , Encéfalo/metabolismo , Arteria Carótida Interna , Cateterismo , Gatos , Infarto Cerebral/tratamiento farmacológico , Circulación Cerebrovascular , Dipiridamol/uso terapéutico , Femenino , Humanos , Infusiones Intraarteriales , Masculino , Persona de Mediana EdadRESUMEN
It has been shown in acute experiments on anesthetized cats that nonachlazine in a dose of 2.5 mg/kg produces a short-term decrease followed by more prolonged elevation of the tone of cerebral vessels, lower extremities and systemic arterial blood pressure. Previous blocking of alpha- and beta-adrenoreceptors decreases or abolishes the development of the above effects. In a dose of 5 mg/kg nonachlazine produces no rise in the tone of intracranial vessels, but increases local and common cerebral blood flow. An increase in PO2 in the brain cortex correlates well with a rise in the blood flow.