Chemical structure and selected biological properties of a glucomannan from the lichenized fungus Heterodermia obscurata.

Successive aqueous and alkaline extraction of the thallus of the lichenized fungus Heterodermia obscurata provided a highly branched glucomannan fraction (GM), whose chemical structure was determined. This was based on monosaccharide composition, methylation, partial acid hydrolysis, and NMR spectroscopic analysis. It consisted of a main chain of (1→6)-linked α-D-mannopyranosyl units, almost all being substituted at O-2 with α-D-glucopyranosyl, α-D-mannopyranosyl, and 4-O-substituted α-D-mannopyranosyl groups. Intra-peritoneal administration of this GM induced a marked and dose-dependent inhibition of acetic acid-induced visceral pain with an ID(50) of 0.6 (0.2-2.0) mg/kg and inhibition of 88±4%. It also reduced leukocyte migration by 58±4%, but did not alter plasmatic extravasation to the peritoneal cavity. The results suggest that the glucomannan from the H. obscurata might have potential for antinociceptive and anti-inflammatory utilization.

Antidepressant-like effect of scopoletin, a coumarin isolated from Polygala sabulosa (Polygalaceae) in mice: evidence for the involvement of monoaminergic systems.

The relationship between depression and monoaminergic systems has been hypothesized for many years. In this study, we have investigated the possible antidepressant-like effect of scopoletin, a coumarin from Polygala sabulosa in the tail suspension test and forced swimming test. Moreover, the ability of scopoletin to reverse the depression-like behavior in the forced swimming test induced by immobility stress in mice was evaluated. Scopoletin reduced the immobility time in the tail suspension test (10-100mg/kg, p.o.), but not in the forced swimming test. Fluoxetine (positive control) decreased the immobility time in the forced swimming and tail suspension tests (20mg/kg, p.o. and 10mg/kg. p.o., respectively). Immobility stress caused an increase in the immobility time in the forced swimming test (depression-like behavior), which was reversed by scopoletin (1-100mg/kg, p.o.) and fluoxetine (10mg/kg, p.o.). Scopoletin produced no psychostimulant effect in the open-field test. The pretreatment of mice with ketanserin (5mg/kg, i.p., a preferential 5-HT(2A) receptor antagonist), prazosin (1mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), haloperidol (0.2mg/kg, i.p., a dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist), but not WAY100635 (0.1mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) prevented the antidepressant-like effect of scopoletin (10mg/kg, p.o.) in the tail suspension test. The results indicate that its antidepressant-like effect is dependent on the serotonergic (5-HT(2A) receptors), noradrenergic (alpha(1)- and alpha(2)-adrenoceptors) and dopaminergic (dopamine D(1) and D(2) receptors) systems.

Involvement of dopamine receptors in the antidepressant-like effect of melatonin in the tail suspension test.

Melatonin was previously shown to produce an antidepressant-like effect in the tail suspension test. In this work the mechanisms underlying its antidepressant-like effect were further studied by investigating the involvement of the dopaminergic system in its antidepressant-like effect in the tail suspension test. The effect of melatonin (1mg/kg, i.p.) was prevented by the pretreatment of mice with haloperidol (0.2mg/kg, i.p., a nonselective dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a selective dopamine D1 receptor antagonist), and sulpiride (50mg/kg, i.p., a selective dopamine D2 receptor antagonist). The i.p. administration of melatonin (0.01 mg/kg) or fluoxetine (1mg/kg, a serotonin reuptake inhibitor) in combination with SFK38393 (0.1mg/kg, s.c., a dopamine D1 receptor agonist) reduced the immobility time in the tail suspension test as compared with either drug alone. Moreover, the pretreatment with melatonin (0.01 mg/kg, i.p.) produced a synergistic effect with apomorphine (0.5 microg/kg, i.p., a dopamine D2 receptor agonist), but the pretreatment with fluoxetine (1mg/kg, i.p.) was ineffective to potentiate the effect of apomorphine. Dopamine receptor antagonists or agonists alone or in combination with melatonin did not affect locomotor activity. These results indicate that the antidepressant-like effect of melatonin in the tail suspension test is likely mediated by an interaction with the dopaminergic system, through an activation of dopamine D1 and D2 receptors. Our data confirm the previous notion on the role exerted by melatonin in depression, suggesting that it might be further investigated as an alternative for the management of depression associated with anhedonia.

Synergistic neurotoxicity induced by methylmercury and quercetin in mice.

Methylmercury (MeHg) is a highly neurotoxic pollutant, whose mechanisms of toxicity are related to its pro-oxidative properties. A previous report showed under in vivo conditions the neuroprotective effects of plants of the genus Polygala against MeHg-induced neurotoxicity. Moreover, the flavonoid quercetin, isolated from Polygala sabulosa, displayed beneficial effects against MeHg-induced oxidative damage under in vitro conditions. In this study, we sought for potential beneficial effects of quercetin against the neurotoxicity induced by MeHg in Swiss female mice. Animals were divided into six experimental groups: control, quercetin low dose (5 mg/kg), quercetin high dose (50 mg/kg), MeHg (40 mg/L, in tap water), MeHg+quercetin low dose, and MeHg+quercetin high dose. After the treatment (21 days), a significant motor deficit was observed in MeHg+quercetin groups. Biochemical parameters related to oxidative stress showed that the simultaneous treatment with quercetin and MeHg caused a higher cerebellar oxidative damage when compared to the individual exposures. MeHg plus quercetin elicited a higher cerebellar lipid peroxidation than MeHg or quercetin alone. The present results indicate that under in vivo conditions quercetin and MeHg cause additive pro-oxidative effects toward the mice cerebellum and that such phenomenon is associated with the observed motor deficit.

Evidence for the involvement of the opioid system in the antidepressant-like effect of folic acid in the mouse forced swimming test.

The opioid system has been implicated in major depression and in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of the water-soluble B-vitamin folic acid in the forced swimming test (FST). The effect of folic acid (10 nmol/site, i.c.v.) was prevented by the pretreatment of mice with naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist), naltrindole (3 mg/kg, i.p., a selective delta-opioid receptor antagonist), naloxonazine (10 mg/kg, i.p., a selective mu(1)-opioid receptor antagonist, 24 h before), but not with naloxone methiodide (1 mg/kg, s.c., a peripherally acting opioid receptor antagonist). In addition, a sub-effective dose of folic acid (1 nmol/site, i.c.v.) produced a synergistic antidepressant-like effect in the FST with a sub-effective dose of morphine (1 mg/kg, s.c.). A further approach was designed to investigate the possible relationship between the opioid system and NMDA receptors in the mechanism of action of folic acid in the FST. Pretreatment of the animals with naloxone (1 mg/kg, i.p.) prevented the synergistic antidepressant-like effect of folic acid (1 nmol/site, i.c.v.) and MK-801 (0.001 mg/kg, i.p., a non-competitive NMDA receptor antagonist). Together the results firstly indicate that the anti-immobility effect of folic acid in the FST is mediated by an interaction with the opioid system (mu(1) and delta), likely dependent on the inhibition of NMDA receptors elicited by folic acid.

Evidence for the involvement of the monoaminergic system in the antidepressant-like effect of magnesium.

Literature data has shown that acute administration of magnesium reduces immobility time in the mouse forced swimming test (FST), which suggests potential antidepressant activity in humans. However, its mechanism of action is not completely understood. Thus, this study is aimed at investigating the antidepressant-like action of magnesium and the possible involvement of the monoaminergic system in its effect in the FST. The immobility time in the FST was significantly reduced by magnesium chloride administration (30-100 mg/kg, i.p.) without accompanying changes in ambulation when assessed in an open-field test. The pre-treatment of mice with NAN-190 (0.5 mg/kg, i.p. a 5-HT(1A) receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), ketanserin (5 mg/kg, a preferential 5-HT(2A) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), haloperidol (0.2 mg/kg, i.p., a non selective dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist) 30 min before the administration of magnesium chloride (30 mg/kg, i.p.) significantly prevented its anti-immobility effect in the FST. Moreover, the administration of sub-effective doses of fluoxetine (10 mg/kg, i.p., serotonin reuptake inhibitor), imipramine (5 mg/kg, i.p., a mixed serotonergic noradrenergic reuptake inhibitor), bupropion (1 mg/kg, i.p., dopamine reuptake inhibitor) was able to potentiate the action of sub-effective doses of magnesium chloride. In conclusion, the present study provides evidence indicating that the antidepressant-like effect of magnesium in the FST is dependent on its interaction with the serotonergic (5-HT(1A) and 5-HT(2A/2C) receptors), noradrenergic (alpha(1)- and alpha(2)- receptors) and dopaminergic (dopamine D(1) and D(2) receptors) systems.

Involvement of the adenosine A1 and A2A receptors in the antidepressant-like effect of zinc in the forced swimming test.

It was previously shown that the acute administration of zinc chloride elicits an antidepressant-like effect in the mouse forced swimming test (FST). We have also shown that the activation of adenosine A(1) and A(2A) receptors produces an antidepressant-like effect in FST. Thus, this study investigated the involvement of adenosine receptors in the antidepressant-like effect of zinc in the FST. The antidepressant-like effect of ZnCl(2) (30 mg/kg, i.p.) in the FST was prevented by the pretreatment of animals with caffeine (3 mg/kg, i.p., a non-selective adenosine receptor antagonist), DPCPX (2 mg/kg, i.p., a selective adenosine A(1) receptor antagonist) or ZM241385 (1 mg/kg, i.p., a selective adenosine A(2A) receptor antagonist), administered at doses that per se produced no anti-immobility effect. Moreover, the treatment of mice with CHA (0.05 mg/kg, i.p., a selective adenosine A(1) receptor agonist), DPMA (0.1 mg/kg, i.p., a selective adenosine A(2A) receptor agonist) or dipyridamole (0.1 microg/site, i.c.v., an adenosine transporter inhibitor) was able to potentiate the action of sub-effective doses of ZnCl(2). Taken together, the results suggest that the antidepressant-like effect of zinc in the mouse FST might involve a direct or indirect activation of adenosine A(1) and A(2A) receptors.

Putrescine produces antidepressant-like effects in the forced swimming test and in the tail suspension test in mice.

Putrescine, a polyamine present at high concentrations in the mammalian brain, was suggested to play a role in the modulation of depression. Thus, this study investigated the effect of putrescine in the mouse forced swimming test (FST) and in the tail suspension test (TST), two models predictive of antidepressant activity. Putrescine significantly reduced the immobility time both in the FST and in the TST (dose range of 1-10 mg/kg, i.p.), without changing locomotion in an open-field. I.c.v. injection of putrescine (0.1-10 nmol/site) also reduced the immobility time in the FST and in the TST. The pretreatment of mice with arcaine (1 mg/kg, i.p., an antagonist of the polyamine-site of NMDA receptor) completely blocked the anti-immobility effect of putrescine (10 mg/kg, i.p.). A subeffective dose of putrescine (0.1 mg/kg, i.p.) produced a synergistic antidepressant-like effect with agmatine (0.001 mg/kg, i.p.) in the FST. Moreover, a subeffective dose of putrescine (0.01 nmol/site, i.c.v.) produced a synergistic antidepressant-like effect with arcaine (50 microg/site, i.c.v.). The results indicate that putrescine produces antidepressant-like effects in the FST that seems to be mediated through its interaction with the polyamine-site of NMDA receptors.

Involvement of NMDA receptors and L-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice.

This study investigated the involvement of NMDA receptors and the L-arginine-nitric oxide (NO) pathway in the antidepressant-like effects of zinc in the forced swimming test (FST). The immobility times in the FST and in the tail suspension test (TST) were reduced by zinc chloride (ZnCl(2), 30 and 10-30 mg/kg intraperitoneal (i.p.), respectively). The doses active in the FST and TST reduced locomotor activity in an open-field. The antidepressant-like effect of ZnCl(2) in the FST was prevented by pre-treatment of animals with guanosine 5'-monophosphate (GMP), ascorbic acid, L-arginine, or S-nitroso-N-acetyl-penicillamine (SNAP), but not with D-arginine, administered at doses that per se produced no anti-immobility effect. The immobility time of mice treated with ZnCl(2)+MK-801 was not different from the result obtained with ZnCl(2) or MK-801 alone, but ZnCl(2)+imipramine had a greater effect in the FST than administration of either drug alone. Pre-treatment of animals with a sub-threshold dose of ZnCl(2) prevented the anti-immobility effect of MK-801, ketamine, GMP, L-arginine or N(G)-nitro-L-arginine (L-NNA), but did not alter the effect of imipramine or fluoxetine. Taken together, the results demonstrate that zinc produced an antidepressant-like effect that seems to be mediated through its interaction with NMDA receptors and the L-arginine-NO pathway.

Agmatine produces antidepressant-like effects in two models of depression in mice.

Agmatine produces an antidepressant-like effect when assessed in the forced swimming test (FST) and in the tail suspension test (TST) in mice (dose range 0.01-50 mg/kg, i.p.), without accompanying changes in ambulation in an open-field. I.c.v. injection of agmatine (1-100 nmol/site) also reduced the immobility time in the FST. Agmatine significantly enhanced the anti-immobility effect of imipramine, but did not affect that of MK-801. The anti-immobility effect of agmatine assessed in the FST was not affected by pre-treatment with prazosin. In contrast, agmatine's antidepressant-like effect was completely prevented by pre-treatment of animals with yohimbine, GMP or L-arginine. Taken together these data demonstrate that agmatine elicited a significant antidepressant-like effect through a mechanism that seems to involve an interaction with NMDA receptors, the L-arginine-nitric oxide pathway and alpha2-adrenoceptors.