Screening for cerebroprotective agents using an in vivo model of cerebral reversible depolarization in awake rats.

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.

Melanocortins and fast axonal transport in intact and regenerating sciatic nerve.

The effect of ACTH/MSH peptides on fast axonal transport along intact or regenerating sciatic nerve was examined following injection of tritiated leucine into the rat lumbar spinal cord. The rate of fast axonal transport was not significantly changed by treatment with ACTH/MSH(4-10), the ACTH(4-9) analog ORG 2766, hypophysectomy, or adrenalectomy. Fast axonal transport was unchanged in regenerating nerves and in regenerating, ACTH(4-10)-treated nerves. However, treatment with ORG 2766 in dosages of either 1 or 10 micrograms/kg/day IP for seven days significantly reduced (62% and 64%, respectively) the crest height of the fast axonal transport curve of intact sciatic nerve. The results suggest that the reported peptide-induced enhancement of nerve regeneration is not due to changes in the rate of fast axonal transport.

Vinpocetine: nootropic effects on scopolamine-induced and hypoxia-induced retrieval deficits of a step-through passive avoidance response in rats.

Vinpocetine, vincamine, aniracetam, and Hydergine, compounds with purported cognition activating activity, were evaluated for their ability to prevent scopolamine-induced and hypoxia-induced impairment of passive avoidance retention (24 hr) in rats. Vinpocetine (peak effect dose [PED]= 200 mg/kg PO), aniracetam (PED = 100 mg/kg PO), vincamine (PED = 30 mg/kg PO), and Hydergine (PED = 1 mg/kg PO) prevented memory disruption by scopolamine. Vinpocetine (PED = 3 mg/kg PO) and aniracetam (PED = 30 mg/kg PO) were also effective in preventing disruption of passive avoidance retention impaired by 7% oxygen hypoxia. In contrast, Hydergine (0.05 to 3 mg/kg PO) and vincamine (0.3 to 100 mg/kg PO) were not effective against hypoxia-induced impairment. Hydergine at doses greater than 10 mg/kg PO markedly impaired motor function. In both tests the protection was dose-related for all test substances in an inverted U-shaped manner. Mecamylamine (1, 3, 10 mg/kg SC), (-)-nicotine (0.1 to 0.4 mg/kg SC), apovincaminic acid (1-400 mg/kg PO) and pemoline (1-100 mg/kg PO) did not protect against memory impairment induced by either procedure. These data support the view that vinpocetine, a compound chemically distinct from the pyrrolidinones, has a cognitive activating ability as defined in models of both scopolamine-induced and hypoxia-induced memory impairment in rats.

On the mechanism of renin release by restraint stress in rats.

Restraint causes an increase in plasma renin activity (PRA) which is not affected by pretreatment with dl-propranolo (1 mg/kg IP) or sotalol (15 mg/kg IP). These doses of beta-adrenergic blocking agents are effective in suppressing the stimulation of PRA by isoproterenol. Large doses of dl-propranolol (10 mg/kg IP) and d-propranolol (5 mg/kg IP) attenuate the restraint-induced PRA increase. Adrenal demedullectomy does not affect the PRA response to restraint. Renal denervation blunts the PRA rise due to restraint, but not to direct stimulation by the beta-adrenergic agonist, isoproterenol. It is concluded that the increase in PRA during restraint stress in rats is not solely dependent on an intact renal sympathetic innervation. A significant portion of this stress-induced PRA increase appears to involve a non-adrenergic mechanism.

Plasma corticosterone and brain catecholamines in stress: effect of psychotropic drugs.

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.

Physiological and biochemical concomitants of restraint stress in rats.

Restraint stress of 30 min increases plasma CS and lowers hypothalamic NE. Restraints of longer durations are associated with an attenuation of these changes. Daily repetitive restraint enhances the CS response on the second day and progressively diminishes it on subsequent days. Whole brain NE increases on the first day and decreases on Day 2 to 5. The CS response to acute restraint is similar in 5 different normotensive rat strains, but is enhanced in the genetically hypertensive SH rat, its normotensive backbreed WKY, and the DOCA hypertensive Sprague-Dawley rat. Comparison with other stressors (electric foot shock and novel environment) indicate that the responses to restraint are different at least in time course, if not qualitatively.

Plasma corticosterone following alterations of hypothalamic catecholamines in rats.

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.