RESUMEN
The need to screen cerebroprotective compounds without anesthetic interference prompted the development of a model using hypoxic rats. In this model two outcome measures were used: (1) the time to reach isoelectric electroencephalogram (iEEG), caused by nitrogen gas inhalation in the test chamber, and (2) the time for behavioral recovery measuring the latency of restoration of the head-withdrawal reflex upon vibrissae stimulation. We report here data of blood chemistry, cerebral tissue oxygen measurements, a definition of a proposed scoring system, and the pharmacological results of RGH-2202. The findings with RGH-2202 are used here to show the utility of the screening method. Events during hypoxia: Arterial and venous pO(2), pCO(2), and pH, and brain tissue pO(2)significantly declined. Significant correlations were established among the pO(2)of cerebral tissue, blood, and the test chamber. RGH-2202 significantly and dose-dependently shortened the iEEG time; the compound's Effective Dose(30)was 227.8 mg kg(-1). Events during recovery: Immediately after the iEEG, when the atmosphere in the chamber was replaced with room air, the arterial, venous and brain tissue pO(2)increased above the control level and subsequently recovered to baseline levels. Behavioral recovery occurred before blood chemistry was otherwise normalized. RGH-2202 significantly and dose-dependently shortened the recovery time; the Effective Dose(30)was 8.71 mg kg(-1). The available data define and support the physiological basis of this practicable rat-screening model.
Asunto(s)
Evaluación Preclínica de Medicamentos/instrumentación , Evaluación Preclínica de Medicamentos/métodos , Fármacos Neuroprotectores/administración & dosificación , Hormona Liberadora de Tirotropina/análogos & derivados , Administración Oral , Animales , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Modelos Animales de Enfermedad , Electroencefalografía/efectos de los fármacos , Electroencefalografía/instrumentación , Electroencefalografía/métodos , Hipoxia Encefálica/sangre , Hipoxia Encefálica/inducido químicamente , Hipoxia Encefálica/tratamiento farmacológico , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Wistar , Hormona Liberadora de Tirotropina/farmacología , Hormona Liberadora de Tirotropina/uso terapéuticoRESUMEN
In nonstressed rats, subcutaneous administration of haloperidol (HAL) and large doses of diazepam (DZ) increased plasma corticosterone (CS). Hypothalamic norepinephrine (NE) was lowered significantly by desmethylimipramine (DMI), HAL and, to a lesser extent, by DZ and phenobarbital (PHB). In rats pretreated with either DZ, DMI, HAL or PHB the restraint-induced rise of CS was diminished, DZ being most potent. CPZ had a variable effect, slightly increasing or decreasing the CS response. Pretreatment (16 hr) with pargyline (PA) did not affect the CS rise to stress. The reduction of hypothalamic NE evoked by restraint was attenuated by DZ, and to a lesser extent, by PHB and HAL. Restraint of PA-treated rats did not lower the PA-elevated hypothalamic NE. The stress-induced increase in hypothalamic dopamine was prevented by CPZ and, partially, by PHB. It is emphasized that the net plasma CS and brain catecholamine changes in response to stress are dependent on the drug-induced neuroendocrine feedback state prevalent immediately before commencement of the stress procedure.
Asunto(s)
Química Encefálica/efectos de los fármacos , Catecolaminas/metabolismo , Corticosterona/sangre , Psicotrópicos/farmacología , Estrés Fisiológico/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/farmacología , Animales , Clorpromazina/farmacología , Desipramina/farmacología , Diazepam/farmacología , Dopamina/metabolismo , Haloperidol/farmacología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Técnicas In Vitro , Masculino , Norepinefrina/metabolismo , Pargilina/farmacología , Fenobarbital/farmacología , Prohibitinas , Ratas , Telencéfalo/efectos de los fármacos , Telencéfalo/metabolismoRESUMEN
The role of central catecholamines in the regulation of resting ACTH secretion has been investigated by relating plasma corticosterone to changes in hypothalamic catecholamines after treating rats with various amine depleting agents. The hypothesis of a noradrenergic inhibitory control is not supported by the data since a correlation between hypothalamic catecholamine content and plasma corticosterone levels could not be established.