Neuromodulatory role of serotonin in the anticonvulsant activity of 2-phenylbenzoate of 3-diethylamino-1-propanol.HCl (JAW-669).

The role of serotonin in the mediation of the anticonvulsant activity of JAW-669 was investigated against maximal electric shock (MES)-induced seizures in mice. A dose-dependent protection against seizures was provided by JAW-669 (4, 6 and 8 mg/kg, IP) and the calculated ED50 value was 6.01 mg/kg, IP. Pretreatment of mice with 5-hydroxytryptophan (50 mg/kg, IP) 2 hr before the administration of JAW-669 (6.01 mg/kg, IP) was found to cause a 40% increase in the ability of JAW-669 to provide protection against MES-induced seizures. Similar pretreatment with tryptophan (100 mg/kg, IP, 1 hr) caused a 30% decrease in the anticonvulsant activity of JAW-669. Prior administration of p-chlorophenylalanine (300 mg/kg, IP, 48 hr) and methysergide (10 mg/kg, IP; 0.5 hr) before administration of JAW-699 caused a 66% and 74% decrease, respectively, in the ability of JAW-669 to provide protection against MES-induced seizures. These results suggest a facilitatory role of serotonin in the anticonvulsant activity of JAW-669.

Effects of intracerebroventricular administration of bradykinin on rat brain serotonin and prostaglandins.

Intracerebroventricular (ICV) administration of bradykinin (5, 10 and 20 micrograms) produced a dose-related increase in the concentration of serotonin in rat brain. The maximum increase was observed after 15 min of bradykinin administration. Thereafter, the augmented levels of serotonin declined and tended to come to normal value after 60 min. Bradykinin (20 micrograms) significantly increased the concentrations of serotonin specifically in cortex, hypothalamus, midbrain and pons-medulla but not in cerebellum and spinal cord. The time course of increase and subsequent decline of regional concentrations of serotonin in brain were similar to that noted with bradykinin-induced changes in serotonin levels in whole brain. Bradykinin (5, 10 and 20 mg, ICV) increased the concentration of prostaglandin E2 (PGE2) but not of PGF2 alpha of rat brain. The time course of bradykinin-induced changes in PGE2 concentrations were similar to the effects of bradykinin on the levels of serotonin in rat brain. The inhibitors of PG synthesis, hydrocortisone, diclofenac and paracetamol, antagonized the bradykinin-induced increase of serotonin in rat brain. These results have provided support for the contention that PGs may presumably mediate some of the central actions of bradykinin and that bradykinin-induced augmentation of central serotonergic activity could possibly account for PGE2-induced modulation of rat brain serotonin.

Role of putative neurotransmitters in bradykinin-induced catalepsy in the rat.

Intracerebroventricular administration of bradykinin produced a dose-related cataleptic response in rats. Bradykinin-induced catalepsy was significantly attenuated following pretreatment with pharmacologic agents that decrease central prostaglandin, serotonin, and acetylcholine activity, as well as by the opioid receptor antagonist naloxone. Conversely, pharmacologic treatments that enhance central catecholamine levels and, specifically, central dopaminergic activity also inhibited bradykinin-induced catalepsy. The prostaglandin precursor, arachidonic acid, and prostaglandin E2, as well as met- and leu-enkephalin showed a synergistic effect with bradykinin catalepsy. Much evidence indicates that several actions of bradykinin, in the central nervous system and the periphery, are likely to be prostaglandin mediated. Further, the recent report from this laboratory that centrally administered bradykinin specifically augments rat brain prostaglandin E2 levels, together with the proposed role of central prostaglandins as modulators of central synaptic transmission, suggests that bradykinin-induced catalepsy is mediated and modulated through PGE effects on serotonergic, cholinergic, and dopaminergic neurotransmitter systems. The study also indicates that endogenous opioid peptides may be involved in braydkinin catalepsy.

Testicular growth and functional capability after 4-24 weeks of continuous exposure to 11 ATA He-O2.

A study of testicular developmental and functional capabilities was made of rats continuously exposed for 4, 8, 12, 16, 20, or 24 weeks to 1 ATA He-O2, 11 ATA He-O2, or ambient pressure air environmental conditions. Other groups of rats were exposed for 24 sequential weeks to the same three sets of environmental conditions with brief interruptions for decompression and recompression at the end of each 4 weeks. The rats were comfortably housed and adequately fed in accord with earlier investigations. Visual observations of the testes at the time of slaughter, dry matter content of the testes, and histological examinations--all revealed normal growth and active spermatid formation from healthy germinal epithelia in all semeniferous tubules. The stress of hyperbaria or of helium to 11 ATA did not inhibit or destroy male germinal epithelial functional capabilities.

Anticonvulsant activity and selective inhibition of NAD-dependent oxidations by 1,2,4-trisubstituted-5-imidazolones.

Nine 1-(3,4-dimethoxyphenylethyl)-2-methyl-4-(substituted benzylidene)-5-imidazolones were synthesized, characterized by their sharp melting points, elemental analyses and infrared spectra and evaluated for anticonvulsant activity. All 1,2,4-trisubstituted-5-imidazolones at a dose of 100 mg/kg i.p. possessed anticonvulsant activity and the degree of protection observed against pentylenetetrazol-induced convulsions in mice ranged from 20 to 60%. These 1,2,4-trisubstituted-5-imidazolones selectively inhibited in vitro oxidation of the nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, alpha-ketoglutarate and NADH by rat brain homogenates while the NAD-independent oxidation of succinate remained unaltered. The anti-convulsant activity possessed by 1,2,4-trisubstituted-5-imidazolones was unrelated with their ability to selectively inhibit respiratory activity of rat brain homogenates.

Anti-inflammatory and antiproteolytic properties of 2-[acyl-N-(substituted benzylidene)hydrazino]5-phenyltetrazoles.

Ten 2-[acyl-N-(substituted benzylidene)hydrazino]5-phenyltetrazoles were synthesized, characterized and evaluated for anti-inflammatory and antiproteolytic activity. The protection afforded by these tetrazoles at a dose of 100 mg/kg i.p., against carrageenin-induced edema in rats, ranged from 11 to 46%. Oxyphenbutazone (40 mg/kg i.p.), and hydrocortisone (10 mg/kg i.p.), used as reference drugs, exhibited protection of 54 and 47%, respectively. The antiproteolytic activity of these tetrazoles, as reflected by their ability to inhibit trypsin-induced hydrolysis of bovine serum albumin, ranged from 17 to 57%. The antiproteolytic activity was found to be unrelated to the anti-inflammatory activity possessed by these tetrazoles.

Vitamins limiting for growth of subjects fed a normal diet under hyperbaric He-O2 conditions.

A growth study was conducted of rats continuously exposed for 4 weeks to ambient air, 1 ATA He-O2, or 11 ATA He-O2 conditions and fed one of 16 diets. The diets were the standard diet alone (adequate according to National Research Council standards); the standard diet with additional casein (50%), fat (25%), and all vitamins (25%); or the standard diet with all vitamins (25%), or all vitamins increased (25%) except one, which was supplied at the standard level. The standard diet was inadequate to support a normal rate of growth when fed under 11 ATA He-O2 conditions. Supplemental casein, fat, and vitamins or all vitamins alone adequately provided nutrients necessary for a normal rate of growth by hyperbaric exposed rats. The standard levels of thiamine, pantothenic acid, biotin, and vitamin K were inadequate and the standard levels of niacin, and vitamins A, D, and E were marginal in supporting growth when fed under hyperbaric conditions.

Selective induction of liver drug-metabolizing enzymes in rats exposed to a 21 ATA He-O2 environment.

The effects of prolonged exposure to a hyperbaric environment (21 ATA He-O2, 200 +/- 300 mm Hg O2, 32.5 +/- 1 degrees C) were investigated on the activity of rat liver drug-metabolizing enzyme systems, as monitored by O-dealkylation and N-dealkylation reactions. Continuous exposure of different groups of rats to a hyperbaric environment for 8, 22, 39, 57, or 84 d significantly increased the in vitro activity of drug-metabolizing enzymes in liver preparations obtained from rats subjected to prolonged exposures. The increase in the in vitro O-dealkylation of p-nitroanisole was selective; and the percent increases were 27, 146, 58, 40, 49, and 44 in liver preparations obtained from rats exposed continuously for 8, 22, 39, 57, 72, or 84 d, respectively. On the other hand, no statistically significant increase was observed in the in vitro activity of rat liver drug-metabolizing enzyme preparations during N-dealkylation of morphine and cocaine.

Effects of a hyperbaric environment on respiratory and monoamine oxidase activities.

The effects of a prolonged hyperbaric environment (21 ATA He-O2, 200 +/- 30 mm Hg O2, 32.5 +/- 1 degrees C) were investigated on the respiratory activity of rat liver homogenates and the activity of monoamine oxidase in isolated rat-liver preparations. Exposure to a hyperbaric environment for 84 days caused selective in vitro inhibition of nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, D-isocitrate, and alpha-ketoglutarate by rat-liver homogenates. The addition of NAD to the reaction mixture decreased the degree of such an inhibition. No effects on the in vitro activity of liver monoamine oxidase and its inhibition by pheniprazine were observed during exposure of animals to a prolonged high-pressure environment.

Synthesis of 2-(4-arylthiosemicarbazidocarbonylthio)benzthiazoles and their monoamine oxidase inhibitory and anticonvulsant properties.

Ten 2-(4-arylthiosemicarbazidocarbonylthio)benzthiazoles were synthesized, characterized, and evaluated for their monoamine oxidase inhibitory and anticonvulsant activities. All substituted benzthiazoles inhibited activity of monoamine oxidase in rat brain homogenate where the degree of enzyme inhibition was higher with kynuramine as compared to tyramine and 5-hydroxytryptamine as the substrates. All substituted benzthiazoles possessed measurable anticonvulsant activity against pentylenetetrazol-induced convulsions.