A novel gene THSD7A is associated with obesity.

Body mass index (BMI) is a non-invasive measurement of obesity. It is commonly used for assessing adiposity and obesity-related risk prediction. Genetic differences between ethnic groups are important factors, which contribute to the variation in phenotypic effects. India inhabited by the first out-of-Africa human population and the contemporary Indian populations are admixture of two ancestral populations; ancestral north Indians (ANI) and ancestral south Indians (ASI). Although ANI are related to Europeans, ASI are not related to any group outside Indian-subcontinent. Hence, we expect novel genetic loci associated with BMI. In association analysis, we found eight genic SNPs in extreme of distribution (P⩽3.75 × 10(-5)), of which WWOX has already been reported to be associated with obesity-related traits hence excluded from further study. Interestingly, we observed rs1526538, an intronic SNP of THSD7A; a novel gene significantly associated with obesity (P=2.88 × 10(-5), 8.922 × 10(-6) and 2.504 × 10(-9) in discovery, replication and combined stages, respectively). THSD7A is neural N-glycoprotein, which promotes angiogenesis and it is well known that angiogenesis modulates obesity, adipose metabolism and insulin sensitivity, hence our result find a correlation. This information can be used for drug target, early diagnosis of obesity and treatment.

Evaluation of nootropic and neuroprotective effects of low dose aspirin in rats.

OBJECTIVE: To evaluate the nootropic and neuroprotective effects of aspirin in Sprague Dawley rats. MATERIALS AND METHODS: Retention of conditioned avoidance response (CAR) and central 5-HT-mediated behavior (lithium-induced head twitches) were assessed using repeated electroconvulsive shock (ECS) in rats. Rats were divided into eight groups: control (pretreated with distilled water), scopolamine (0.5 mg/kg i.p.), ECS (150 V, 50 Hz sinusoidal with intensity of 210 mA for 0.5 s) pretreated, aspirin (6.75 mg/kg orally) pretreated, combined scopolamine and aspirin pretreated, ondansetron (0.36 mg/kg orally) pretreated, combined ECS and ondansetron pretreated and combined ECS and aspirin pretreated groups. Data was analyzed by the chi-square test and ANOVA. RESULTS: Findings show that administration of single ECS daily for consecutive 8 days results in enhancement of 5-HT-mediated behavior (lithium-induced head twitches) and in disruption of the retention of CAR. Aspirin and ondansetron administration significantly increased the retention of conditioned avoidance response compared to control. Ondansetron and aspirin significantly prevented ECS-induced attenuation of the retention of conditioned avoidance response also. On the other hand, ondansetron and aspirin significantly retarded the ECS-induced enhancement of 5-HT-mediated behavior. CONCLUSION: Inhibition of the serotonergic transmission by aspirin is responsible for its nootropic and neuroprotective actions.

Some aspects of activity profile of sodium lawsonate in mice and rats.

Sodium lawsonate (SL: derivative of lawsone, hydroxy-1,4-naphthaquinone) was studied for its activity profile in mice and rats, with emphasis on actions on the central nervous system. The drug produced a cataleptic state, hypothermia and loss of active avoidance behaviour, but it did not augment barbiturate sleep. The catalepsy was prevented by hyoscine (mice) or by sodium salicylate (rats). SL did not affect apomorphine-sterotypy (a dopamine-mediated behaviour) but blocked the lithium-induced head twitches (a serotonin-mediated behavioural response). SL did not produce excitation, analgesia or exhibit anti-MES activity. All actions of SL were rapid in onset and brief in duration. In view of effective dose range (40-80 mg/kg, i.p.) and MLD 50 values (76 mg/kg, i.p., in mice; 122 mg/kg, i.p., in rats), safety index of SL appears to be low.

The effect of estradiol on the alterations in monoamine-mediated behavioural responses induced by administration of electroconvulsive shocks or imipramine to female rats.

Female rats were treated daily with electroconvulsive shocks (ECS) or imipramine (10 mg/kg) for 10 days. Both types of treatment enhanced behavioural responses mediated by 5-hydroxytryptamine (5-HT) and noradrenaline (NA). A behavioural response mediated by dopamine (DA) was enhanced by electroconvulsive shock-treatment alone. On the other hand, rats treated only once with imipramine exhibited reduced DA-mediated behaviour. Priming the rats with estradiol valerate before starting electroconvulsive shock- or imipramine- treatment did not produce any significant effect on the enhancement in the behavioural response mediated by 5-HT. The enhancement in behaviour mediated by NA caused by electroconvulsive shock was also not altered, but that caused by treatment with imipramine was abolished. Enhancement of behaviour mediated by DA following electroconvulsive shock-treatment was also attenuated, while there was a positive reduction in behaviour mediated by DA in imipramine-treated rats. The two therapeutic approaches to depression, viz., electroconvulsive shock and imipramine, thus produced somewhat different effects on the central functions mediated by monoamines. Furthermore, an estrogen given prior to the treatments differentially altered the influence exerted by electroconvulsive shock and imipramine on monoamine functions in brain. The results may be pertinent to the clinical impression that estrogens produce a partial resistance to the antidepressant efficacy of imipramine-like drugs.

The effect of some anti-epilepsy drugs on enhancement of the monoamine-mediated behavioural responses following the administration of electroconvulsive shocks to rats.

Daily administration of electroconvulsive shocks (ECS) to rats for 10 days resulted in enhanced 5-hydroxytryptamine (5-HT), dopamine (DA) and noradrenaline (NA)-mediated behavioural responses. 5-HT and NA-mediated responses were still enhanced after 21 shock-free days. The three types of behavioural responses were also studied in rats given phenytoin sodium, carbamazepine and diazepam every day, alone, or 1 h after ECS administration. Phenytoin did not alter the ECS-induced enhancement of any of the three behaviours. Carbamazepine and diazepam significantly retarded the enhancement in 5-HT and DA-mediated behaviours, although they did not alter the enhancement in NA-mediated behaviour.

Antagonism of some central effects of d-tubocurarine by gamma-aminobutyric acid.

d-Tubocurarine (dtc) administered intracerebroventricularly (icv) to rats produced seizures. Gamma-aminobutyric acid (GABA) administered icv or hydroxylamine administered intraperitoneally (ip) protected the rats from dtc-induced seizures. GABA administered (ip) was ineffective. Local application of dtc to the spinal cord in decerebrate dogs produced facilitation of the scratch reflex. Application of GABA to the spinal cord inhibition the scratch reflex. It is thus concluded that the excitatory effects of dtc on the CNS may be through inhibition of naturally occurring inhibitory substances such as GABA or a closely related compound.

PGF2 alpha on drug-induced contractile responses of frog rectus abdominis muscle.

In the present study, augmentation of contractile responses to acetylcholine, potassium chloride and caffeine by prostaglandin F2 alpha on frog rectus abdominis muscle is documented. The PG-induced responses to ACh was restricted to brief exposure of the tissue to PG. Prolonged exposure resulted in disappearance of the enhancing effect and depression of ACh responses. The augmentation of ACh response was unaltered in presence of physostigmine and the pA2-value of d-tubocurarine was not changed by PGF2 alpha ruling out the involvement of a cholinergic mechanism. In potassium depolarized muscle, PGF2 alpha abolished the contractile response to caffeine, indicating an action at the trigger calcium site. PGF2 alpha also permitted reactivation contracture during repolarization.

Antagonism of some contractile responses to prostaglandins by cyproheptadine.

In the present study antagonism of the contractile responses to PGE1 and PGF2 alpha, by cyproheptadine on isolated rat stomach strip, rabbit uterus, guinea-pig ileum and rabbit jejunum is documented. Cyproheptadine blocks the responses to PGE1, PGF2 alpha, acetylcholine, 5-hydroxytryptamine in extremely small concentrations varying from 10 ng to 1 microgram/ml. The blockade is persistant, provided the exposure is prolonged. However, it does not antagonise the responses of adrenaline on guinea-pig seminal vesicle. Polyphloretine phosphate was used in the concentration of 2.5 to 100 micrograms/ml on the rat stomach strip, rabbit jejunum and rabbit uterus; it failed to produce any blockade of contractile responses to prostaglandins. It is concluded that cyproheptadine nonspecifically antagonised the responses to acetylcholine, 5-hydroxytryptamine, PGE1 and PGF2 alpha in extremely small concentrations.

Effects on rectal temperature in rats of gamma-aminobutyric acid; possible mediation through putative transmitters.

The rectal temperature of male rats was measured in a thermoneutral environment (25 degrees C) and at ambient temperatures of 15 and 35 degrees C. Unless otherwise specified all drugs were administered intracerebroventricularly (i.c.v.) and all results are reported for the thermoneutral environment. Exposure to 15 degrees C did not affect the rectal temperature but exposure to 35 degrees C produced hyperthermia. At 15 and 25 degrees C, 20 mug GABA produced hyperthermia which was longer lasting at the former ambient temperature. GABA (20 mug) prevented the hyperthermic effect of exposure to 35 degrees C and produced hypothermia in animals maintained at this temperature for 1 hr. A low dose (1 mug) of NA produced hyperthermia and a higher dose (mug) hypothermia. In rats pretreated with sodium salicylate (i.p.), 20 mug GABA and 1 mug NA produced hypothermia instead of hyperthermia, suggesting the release of PGE in mediating hyperthermia. The hypothermic effect of 10 mug NA and of GABA observed at 35 degrees C was blocked by phentolamine, an indication of the possibility of alpha-adrenoceptor mediation.

Analysis of the effects on body temperature of intracerebroventricular injection in anaesthetized dogs of gamma-aminobutyric acid.

1 The cerebral ventricles of dogs under intravenous pentobarbitone sodium anaesthesia, were perfused with artificial cerebro-spinal fluid (CSF) at a rate of 0.4-0.5 ml/min from the ventricular to the aqueductal cannulae. The effluent was collected from the aqueductal cannula in 20 min samples. The animals' temperatures were recorded from the rectum.2 gamma-Aminobutyric acid (GABA) 0.1-5 mg when injected into the ventricles produced variable temperature effects. Doses of 0.1 and 0.5 mg always produced hyperthermia and 1 and 5 mg doses sometimes produced hyperthermia and sometimes hypothermia.3 Intraventricular perfusion with 2-bromolysergic acid diethylamide (BOL) and hyoscine did not block hyperthermia. Tests on the rat isolated stomach strip or the guinea-pig isolated superfused ileum for the possible release, respectively, of 5-hydroxytryptamine or acetylcholine by GABA were negative.4 When tested for the presence of prostaglandin E(PGE)-like substances on the isolated rat stomach strip, both the control effluent and the GABA effluent showed activity, the latter being much more potent. There was a temporal correlation between this effect and hyperthermia. Intraventricularly administered sodium salicylate converted the GABA-induced hyperthermia to hypothermia and blocked the release of PGE-like substances.5 Hypothermia induced by GABA alone or in the presence of sodium salicylate was associated with the release of noradrenaline into the effluent.6 Intraventricular administration of GABA in reserpinized dogs produced hyperthermia and not hypothermia. Similar results were obtained with phentolamine perfusion in normal dogs.7 Perfusion with calcium-free solution blocked both the noradrenaline-releasing and hypothermic actions of GABA.8 It is concluded that hyperthermia associated with intraventricular injections of GABA is due to the release of PGE-like substance and hypothermia is due to the release of noradrenaline.

Effect on body temperature in dogs of perfusion of cerebral ventricles with artificiaL CSF deficient in calcium or containing excess of sodium or calcium.

In anaesthetized dogs at room temperatures of 28-33 degrees C, the cerebral ventricles were perfused with artificial CSF from the left lateral ventricular to the aqueductal cannulae. The animals' temperatures were recorded from the rectum. Addition of Ca(++) in excess to the artificial CSF perfusing the ventricles produced hyperthermia and addition of Na+ in excess produced hypothermia. Perfusion with medium deficient in Ca(++) and containing sodium edetate produced hypothermia. The temperature effects of Na(+) or Ca(++) in excess were mutually antagonistic.