CL 218-872 pretreatment and intervention block kainate-induced convulsions and neuropathology.

Two experiments were conducted to test the antiepileptic properties of CL 218-872, a triazolopyridizine reported to have anxiolytic and anticonvulsant effects without accompanying sedative and ataxic effects. In Experiment 1 pretreatment with CL 218-872, a recently synthesized and potent triazolopyridizine, reduced kainic acid-induced convulsions and subsequent neuropathology in rats given ip doses of 25 mg/kg or greater. CL 218-872 at doses of 50 mg/kg or greater was more effective than a high dose of diazepam (20 mg/kg) in blocking status epilepticus-like convulsions and the associated widespread neuropathological sequelae. Moreover, diazepam pretreatment was associated with a higher mortality rate than CL 218-872. In Experiment 2 the efficacy of intervention with 20 mg/kg diazepam was compared with that of 50 mg/kg CL 218-872 in suppressing ongoing convulsions and reducing subsequent brain damage following a convulsant dose of kainic acid. Although CL 218-872 and diazepam were equally effective behaviorally (i.e., in suppressing kainic acid-induced convulsions), CL 218-872 was superior in its ability to reduce subsequent neuropathology, especially in the hippocampus and neocortex. Because kainic acid has been suggested as a model for human status epilepticus, CL 218-872 may be a potentially therapeutic treatment for this disorder.

Dopamine-beta-hydroxylase inhibitors modulate the concentration of functional estrogen receptors in female rat hypothalamus and pituitary gland.

In order to study further the regulation of steroid hormone receptors in the brain and anterior pituitary gland of ovariectomized rats by catecholamines, the influence of two dopamine-beta-hydroxylase inhibitors on the estrogen receptor system was studied. The two inhibitors, FLA 63 and diethyldithiocarbamate (DDC) both caused a biphasic effect on the concentration of cytosol estrogen receptors in the mediobasal hypothalamus without influencing the concentration of cell nuclear estrogen receptors in the absence of estradiol; the concentration of cytosol estrogen receptors first increased and then decreased after treatment. In a study of the neuroanatomical areas in which inhibition of dopamine-beta-hydroxylase decreases the concentration of cytosol estrogen receptors, it was found that the concentration of cytosol estrogen receptors decreased after drug treatment in the mediobasal hypothalamus and preoptic area-septum, but not in the amygdala. This suggests that the decrease in concentration of hypothalamic cytosol estrogen receptors caused by dopamine-beta-hydroxylase inhibitors is not a nonspecific effect on all cytosol estrogen receptors. Finally, an injection of estradiol-17 beta in animals that had been pretreated with either DDC or FLA 63 resulted in less accumulation of cell nuclear estrogen receptors in those tissues in which the drug first caused a decrease in the concentration of cytosol estrogen receptors than in vehicle-injected controls. Therefore, under some conditions, pretreatment with a dopamine-beta-hydroxylase inhibitor decreased the concentration of functional cytosol estrogen receptors resulting in decreased nuclear estrogen receptor accumulation in response to an estradiol injection.(ABSTRACT TRUNCATED AT 250 WORDS)