Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist.

Numerous reports have implicated theY5 receptor as the 'feeding' receptor mediating the orexigenic action of neuropeptide Y (NPY). This notion is supported by the correlation between the in vitro functional and binding activities of different peptide agonists and their potent stimulation of food intake in rodents. We have discovered a series of small molecule heterocycles with high affinity, selectivity, and functional antagonism for Y5 receptors. Intraperitoneal (i.p.) administration of GW438014A into rodents, resulted in a potent reduction of NPY-induced and normal overnight food intake. Brain levels of GW438014A were detected well in excess of its binding IC(50) for up to 3 h post-dosing. Daily (i.p., BID, 10 mg/kg) administration of this compound to Zucker Fatty rats for a period of 4 days resulted in a marked decrease in the rate of weight gain and a reduction in fat mass. No effect on food intake was observed following oral administration of GW438014A (25-100 mg/kg), consistent with the poor oral bioavailability (<3%) and low brain levels observed.

Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia.

BACKGROUND AND PURPOSE: Elevated glutamate levels are thought to be a primary cause of neuronal death after global cerebral ischemia. The purpose of this study was to investigate the potential neuroprotective effects of lamotrigine, a novel antiepileptic drug that inhibits the release of glutamate in vitro, with both behavioral and histological measures of global ischemia in gerbils. METHODS: The common carotid arteries of gerbils were occluded for either 5, 10, or 15 minutes. Twenty-one days after reperfusion, gerbils were tested for impairments in a spatial memory task (Morris water maze). After water maze testing the animals were killed, and damage to hippocampal pyramidal cells was assessed. The effect of lamotrigine on the behavioral and histological outcome of either 5 or 15 minutes of global ischemia was evaluated. RESULTS: Bilateral occlusion of the common carotid arteries for 5 minutes resulted in severe degeneration of hippocampal CA1 and CA2 pyramidal cells. Lamotrigine significantly prevented loss of hippocampal CA1 neurons when administered acutely (100 mg/kg PO) immediately after reperfusion or when administered in two equal doses of 30 or 50 mg/kg 2 hours before and immediately after reperfusion. Gerbils subjected to 5 minutes of ischemic insult were not impaired in their ability to solve a spatial memory task 21 days after cerebral ischemia. However, gerbils subjected to 10 and 15 minutes of carotid artery occlusion showed significant impairment in their ability to solve a water maze task. Lamotrigine significantly protected against the cognitive deficits associated with 15 minutes of cerebral ischemia. Histologically, increased durations of cerebral ischemia resulted in a progressive loss of CA1, CA2, and CA3 pyramidal cells. Lamotrigine completely protected gerbils exposed to 15 minutes of cerebral ischemia against CA3 cell loss and greatly reduced damage to the CA1 and CA2 cell tracts of the hippocampus. Lamotrigine also reduced the mortality associated with 15 minutes of ischemia. CONCLUSIONS: Lamotrigine had neuroprotective effects in a gerbil model of global cerebral ischemia. Lamotrigine protected gerbils against behavioral deficits resulting from 15 minutes of carotid occlusion and also prevented histological damage resulting from 5 and 15 minutes of global cerebral ischemia.

The effects of an inhibitor of tryptophan 2,3-dioxygenase and a combined inhibitor of tryptophan 2,3-dioxygenase and 5-HT reuptake in the rat.

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3-pyridyl)vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO), and a novel inhibitor 709W92 ((E)-6-fluoro-3-[2-(4-pyridyl)vinyl]-1H-indole), of both TDO and 5-hydroxytryptamine (5-HT) reuptake, were examined on tryptophan catabolism, cerebrospinal fluid (CSF) concentrations of tryptophan and 5-HT and serotonergic-mediated physiology and behaviour in the rat. The catabolism of L-[ring-2-14C]tryptophan in vivo was completely inhibited by prior administration of 709W92. 709W92, but not 680C91, potentiated head-twitch produced by 5-hydroxytryptophan, prevented head-twitch and whole brain 5-HT depletion produced by p-chloroamphetamine and rapidly decreased dorsal raphe firing. Both 709W92 and 680C91 elevated CSF tryptophan by up to 260% of basal concentration. A maximally effective dose of 680C91 elevated a global measure of brain extracellular 5-HT (CSF 5-HT) to concentrations similar to those seen maximally after exogenous tryptophan administration (approx 170% of basal). Maximally effective doses of 709W92 increased CSF 5-HT to concentrations comparable to those seen after tryptophan and 5-HT reuptake inhibitor coadministration (approx 900% of basal) and to concentrations greater than those achieved maximally with serotonergically active antidepressant monotherapy (approx 500% of basal). 709W92 did not elevate CSF 5-HT to concentrations associated with the serotonin syndrome (approx 3000% of basal). The combined TDO inhibitor/5-HT reuptake inhibitor, 709W92, showed anxiolytic activity in the rat-pup vocalization model of anxiety. These results show that 709W92 (a novel inhibitor of both TDO and 5-HT reuptake), can produce an elevation of CSF 5-HT similar to that achieved with a serotonin reuptake inhibitor/tryptophan combination therapy but with a more sustained timecourse; such compounds may therefore have superior antidepressant efficacy in the clinic.

Exposure of Japanese quail embryos to o,p'-DDT has long-term effects on reproductive behaviors, hematology, and feather morphology.

Japanese quail eggs were injected with 1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2,2-trichloroethane o,p'-DDT(1-10 mg),1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane p,p'-DDT (1-10 mg), or, in one study, 0.5 mg chlordecone dissolved in 50 microliters of corn oil on day 1 of incubation. Hatchability was not decreased by o,p'-DDT or p,p'-DDT, as compared to corn-oil-injected controls, but was reduced in progeny of parents injected in ovo with either isomer. Tremor was observed for up to 4 days posthatching only in birds injected with 1.75-10 mg p,p'-DDT or chlordecone. Survivability to 5 weeks posthatch was reduced (less than or equal to 50%) in birds injected in ovo with 6.25-7.5 mg, o,p'-DDT or 1.75-5 mg p,p'-DDT as compared to corn oil (96%). Reproductive behaviors were attenuated in birds injected during development with o,p'-DDT, both DDT isomers decreased the total number of ovipositions, and o,p'-DDT increased the total number of eggshell malformations. Neither body weights nor reproductive organ weights at 12 weeks were affected by injection of either isomer. Exposure to DDT did not affect acquisition of a matched-to-sample food-reinforced response or subsequent responding on a random interval schedule of reinforcement. In another experiment, total circulating erythrocyte numbers were reduced in females after injection in ovo with o,p'-DDT but not after injection with p,p'-DDT. A primary humoral immune response was not affected by in ovo exposure to either isomer of DDT. In ovo exposure to o,p'-DDT but not to p,p'-DDT had long-term and estrogen-like effects on behavior and hematology in Japanese quail. Posthatch primary feather morphology was also altered by embryonic exposure to o,p'-DDT, p,p'-DDT, and chlordecone.

Direct administration of chlordecone into Japanese quail eggs has persistent effects on conditioned behavior of adults.

Chlordecone (0.1 to 10 mg) or corn oil vehicle was injected into Japanese quail eggs on day 1 of incubation. Higher doses (0.5-10 mg per egg) produced tremor and ataxia at hatching and dose-related decreases in hatchability and survivability. Doses lower than 0.25 mg per egg had no effects. Gonad weights were not affected at 12 weeks of age. A second study examined the effect of injecting 0.5 mg of chlordecone into the egg on day 1, 3, 7 or 14 of incubation. Chlordecone-induced tremor was present at hatching regardless of the day of injection. Significant decreases in hatchability and increases in embryonic mortality were seen when chlordecone was injected on day 1 of incubation. Survivability to 5 weeks of age was decreased in birds receiving chlordecone on day 1 or 3 of incubation. At 75 to 84 days of age, egg production was decreased only in birds injected on day 1 of incubation. The offspring from these studies were mated and the hatchability and reproductive capability of these birds was studied at 75 to 84 days of age and found to be not significantly affected. In a third study, birds exposed to 0.5 mg of chlordecone or vehicle on day 1 of incubation were trained as adults in a food reinforced operant task. Exposure to chlordecone affected performance during the first 3 of 15 days of a match-to-sample task. The baseline response rate of these animals on a food reinforced random interval 60 sec schedule was then determined. During the last two weeks of asymptotic performance, chlordecone-exposed birds had a significantly lower rate of responding than controls. These data indicate that in ovo exposure to chlordecone can have significant long-term effects on conditioned behavior and egg production, particularly if exposure occurs on day 1 of incubation.