Tuane Bazanella Sampaio

The antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in the mouse forced swimming test is mediated by serotonergic and dopaminergic systems.

The aim of the present study was to investigate the role of monoaminergic system in the antidepressant-like action of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a derivative of isoquinoline class, in Swiss mice. The antidepressant-like effect of FDPI was characterized in the modified forced swimming test (FST) and the possible mechanism of action was investigated by using serotonergic, dopaminergic and noradrenergic antagonists. Monoamine oxidase (MAO) activity and [(3)H]serotonin (5-HT) uptake were determined in prefrontal cortices of mice. The results showed that FDPI (1, 10 and 20mg/kg, i.g.) reduced the immobility time and increased the swimming time but did not alter climbing time in the modified FST. These effects were similar to those of paroxetine (8mg/kg, i.p.), a positive control. Pretreatments with p-chlorophenylalanine (100mg/kg, i.p., an inhibitor of 5-HT synthesis), WAY100635 (0.1mg/kg, s.c., 5-HT1A antagonist), ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist), haloperidol (0.2mg/kg, i.p., a non-selective D2 receptor antagonist) and SCH23390 (0.05mg/kg, s.c., a D1 receptor antagonist) were effective to block the antidepressant-like effect of FDPI at a dose of 1mg/kg in the FST. Ritanserin (1mg/kg, i.p., a 5-HT2A/2C receptor antagonist), sulpiride (50mg/kg, i.p., a D2 and D3 receptor antagonist), prazosin (1mg/kg, i.p., an α1 receptor antagonist), yohimbine (1mg/kg, i.p., an α2 receptor antagonist) and propranolol (2mg/kg, i.p., a β receptor antagonist) did not modify the effect of FDPI in the FST. FDPI did not change synaptosomal [(3)H]5-HT uptake. At doses of 10 and 20mg/kg FDPI inhibited MAO-A and MAO-B activities. These results suggest that antidepressant-like effect of FDPI is mediated mostly by serotonergic and dopaminergic systems.

m-Trifluoromethyl-diphenyl diselenide, a multi-target selenium compound, prevented mechanical allodynia and depressive-like behavior in a mouse comorbid pain and depression model.

Chronic pain and depression are two complex states that often coexist in the clinical setting and traditional antidepressants and analgesics have shown limited clinical efficacy. There is an intricate communication between the immune system and the central nervous system and inflammation has been considered a common mediator of pain-depression comorbidity. This study evaluated the effect of m-trifluoromethyl diphenyl diselenide [(m-CF3-PhSe)2], an organoselenium compound that has been reported to have both antinociceptive and antidepressant-like actions, in the comorbidity of chronic pain and depression induced by partial sciatic nerve ligation (PSNL) in an inflammatory approach. Mice were submitted to PSNL during 4weeks and treated with (m-CF3-PhSe)2 acutely (0.1-10mg/kg, i.g.) or subchronically (0.1mg/kg, i.g., once a day during the 3rd and 4th weeks). Both treatments prevented PSNL-increased pain sensitivity and depressive-like behavior observed in Von-Frey hair (VFH) and forced swimming (FST) tests, respectively. These effects could be mainly associated with an anti-inflammatory action of (m-CF3-PhSe)2 which reduced the levels of pro-inflammatory cytokines, NF-κB and COX-2, and p38 MAPK activation that were increased by PSNL. (m-CF3-PhSe)2 also increased the BDNF levels and reduced glutamate release and 5-HT uptake altered by PSNL. Although acute and subchronic treatments with (m-CF3-PhSe)2 prevented these alterations induced by PSNL, the best results were found when (m-CF3-PhSe)2 was subchronically administered to mice. Considering the potential common mechanisms involved in the comorbidity of inflammation-induced depression and chronic pain, the results found in this study indicate that (m-CF3-PhSe)2 could become an interesting molecule to treat long-lasting pathological pain associated with depression.

Depressive-like behavior induced by tumor necrosis factor-α is attenuated by m-trifluoromethyl-diphenyl diselenide in mice

A growing body of evidence associates activation of immune system with depressive symptoms. Accordingly, pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), have been shown to play a pivotal role in the pathophysiology of depression. The aim of this study was to evaluate the effectiveness of acute and subchronic treatments with (m-CF3-PhSe)2 to prevent the depressive-like behavior induced by intracerebroventricular injection of TNF-α in mice. TNF-α induced depressive-like behavior in the forced swimming test (FST) and tail suspension test (TST) (0.1 and 0.001 ƒg/5 μL/site, respectively) without changing locomotor activity, performed in the locomotor activity monitor (LAM). Acute (0.01-50 mg/kg; intragastric (i.g.); 30 min) and subchronic (0.01 and 0.1 mg/kg; i.g.; 14 days) treatments with (m-CF3-PhSe)2 at low doses were effective against the effect of TNF-α in the FST and TST. Nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (p38 MAPK), important proteins in TNF-activated signaling, were determined in the prefrontal cortex and hippocampus of mouse. TNF-α (0.1 ƒg/5 μL/site) increased NF-κB levels and p38 MAPK activation in both brain areas and acute (10 mg/kg; i.g.) and subchronic (0.01 mg/kg; i.g.) treatments with (m-CF3-PhSe)2 were effective in attenuating this increase. Although more studies are necessary to indicate this compound as a therapeutic alternative to depression, the antidepressant-like and anti-inflammatory effects of (m-CF3-PhSe)2 demonstrated herein may support it as an interesting molecule in the search for new drugs to treat depressive disorders that have been largely linked to immune process and inflammation.

Synthesis of pharmacologically active 1-amino-isoquinolines prepared via silver triflate-catalyzed cyclization of o-alkynylbenzaldoximes with isocyanates.

The synthesis of a series of 1-amino-isoquinolines prepared via electrophilic cyclization [3+2] cycloaddition/rearrangement reactions of o-alkynylbenzaldoxime 1 with isocyanates 2 in the presence of catalytic amount of AgOTf was demonstrated. The cyclized products were obtained in good yields under an air atmosphere. 1-Amino-isoquinoline derivatives 3a, 3b, 3j and 3t were screened in vitro for the antioxidant potential and efficacy to inhibit cerebral monoamine oxidase (MAO) activity. The antidepressant-like action of some 1-amino-isoquinolines was performed in the mouse forced swimming test (FST). The pharmacological screening of 1-amino-isoquinoline derivatives indicated that 3a, 3b, 3j and 3t were antioxidants and inhibited cerebral MAO-A and B activities at low concentrations. Although at different doses 3a, 3b, 3j and 3t were effective antidepressant-like drugs in the mouse FST. None of 1-amino-isoquinolines tested caused acute cerebral, hepatic or renal toxicity in mice.

Involvement of BDNF/TrkB signaling in the effect of diphenyl diselenide on motor function in a Parkinson's disease rat model.

ABSTRACT Parkinsons disease is a progressive neurodegenerative disorder characterized by degeneration of nigrostriatal dopaminergic neurons. Diphenyl diselenide [(PhSe)2] is a compound with pharmacological proprieties, such as antidepressant and neuroprotective. Therefore, this study investigated whether (PhSe)2 reverses motor impairment and neurochemical alterations in a model of Parkinsons disease induced by 6‐hydroxydopamine (6‐OHDA) in rats. For this, male Wistar rats received 20 &mgr;g/3 &mgr;l of 6‐OHDA or vehicle into the right striatum. Three weeks later, animals were subjected to rotational behavioral test induced by D‐amphetamine and randomly divided into four groups: Sham; (PhSe)2; 6‐OHDA and 6‐OHDA+(PhSe)2. The rats received (PhSe)2 (1 mg/kg/day; i.g.) or vehicle (canola oil) during 30 days. After treatment, behavioral tests were performed in order to evaluate the motor function and the ipsilateral striatal tissue was collected for immunoblotting assay. (PhSe)2 treatment restored the normal motor behavior of 6‐OHDA‐infused rats in the cylinder, stepping and bridge tests, but not in the rotarod test. The 6‐OHDA infusion and/or (PhSe)2 treatment did not alter the muscle strength and spontaneous locomotion in the forelimb support and open‐field tests, respectively. Additionally, striatal brain‐derived neurotrophic factor (BDNF), proBDNF and tyrosine hydroxylase (TH) levels of 6‐OHDA‐lesioned rats were decreased, while the tropomyosin‐related kinase B (TrkB) levels were increased. (PhSe)2 treatment restored striatal proBDNF, TrkB and TH levels. Thus, (PhSe)2 treatment reversed some motor impairment and TH levels in a 6‐OHDA model of Parkinsons disease in rats, demonstrating a potential neurorestorative role. Additionally, the BDNF/TrkB signaling recovery can be involved in its neurorestorative effect.

Cognitive effects of diphenyl diselenide and estradiol treatments in ovariectomized mice.

This study investigated the effects of co-administration of diphenyl diselenide [(PhSe)(2)] and 17β-estradiol (E(2)) on spatial reference, recognition, and working memories in ovariectomized (OVX) female mice. Sixty-day-old female adult Swiss mice were submitted to ovariectomy. From the 30th until 32nd day after ovariectomy, different doses of (PhSe)(2) (0.5-10mg/kg p.o.) were administrated to OVX mice 30min before each training of Morris Water Maze (MWM) test in order to find the highest subeffective dose for this drug. After that, OVX mice were divided into four groups: Oil, (PhSe)(2), E(2), and (PhSe)(2)+E(2). (PhSe)(2) (0.5mg/kg) and E(2) (0.1mg/kg) were administered to OVX mice from 30th to 32nd day after surgery, 30min before the training phases of behavioral tests (Open Field, MWM, Object Recognition, and T-maze). Our results demonstrated that 0.5mg/kg (PhSe)(2) plus 0.1mg/kg E(2) combined treatment improved spatial memory in the MWM test. By contrast, this same co-administration therapy was not effective in ameliorating neither delayed spontaneous alternation in the T-maze test nor object recognition memory deficits in OVX mice, although the dose of 0.5mg/kg (PhSe)(2) enhanced per se the object recognition memory in OVX mice. In conclusion, the current behavioral data suggest that a combination of (PhSe)(2) plus E(2) treatment seems to be a promising alternative to treat the cognitive decline related to menopause. Further studies should be conducted in order to determine an effective dose for (PhSe)(2) plus E(2) therapy on Object Recognition and T-maze tests.

Involvement of the serotonergic system in the anxiolytic-like effect of 2-phenylethynyl butyltellurium in mice

Anxiety is a serious disorder with symptoms manifested at the psychological, behavioral, and physiological levels, accompanied by alterations in the serotonergic system and monoaminergic signaling. In this study, the anxiolytic-like effect of 2-phenylethynyl butyltellurium (PEBT), in three well-consolidated anxiety mouse models (light-dark test, novelty suppressed-feeding, elevated plus-maze), was investigated. The involvement of the serotonergic system, synaptosomal [(3)H] serotonin (5-HT) uptake and monoamine oxidase (MAO A and B) activities on cerebral cortices of mice, was examined. Mice received PEBT (1mg/kg, by intragastric route, i.g.) or canola oil (10 ml/kg, i.g.) 30 min before behavioral tests. The results showed that PEBT was effective in increasing the time spent by mice in the illuminated side on the light-dark box and in the open arms on the elevated plus-maze. PEBT decreased the latency to begin eating on the novelty suppressed-feeding test, indicating an anxiolytic-like effect of PEBT. Furthermore, PEBT reduced [(3)H] 5-HT uptake and selectively inhibited MAO-A activity in cerebral cortex, suggesting the involvement of the serotonergic system in the mechanism of action of this tellurium compound.

7-Fluoro-1,3-diphenylisoquinoline reverses motor and non-motor symptoms induced by MPTP in mice: Role of striatal neuroinflammation

ABSTRACT Parkinsons disease (PD) is a dopaminergic neurodegenerative disorder, which presents motor and non‐motor symptoms. 7‐Fluoro‐1,3‐diphenylisoquinoline (FDPI) is an isoquinoline compound with antioxidant and antidepressant properties. This study investigated whether FDPI reverses motor and non‐motor symptoms in an acute mouse model of PD induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). It was also assessed the anti‐inflammatory mechanisms in FDPI pharmacological action. C57Bl/6 male adult mice received four MPTP (20 mg/kg, intraperitoneal) or saline (vehicle) injections to induce an acute PD model. FDPI (10 mg/kg, intragastric) was daily administered to mice from the 2nd to 9th day after the induction and mice performed the behavioral tests on the 8th and 9th days. Striatum samples were collected for biochemical and molecular analyses. The results of the rotarod and challenging beam tests demonstrated that the administration of FDPI attenuated the impairments in balance and coordination of mice induced by MPTP. The FDPI reversed the short‐term memory deficit and depressive‐like behavior induced by MPTP in mice. FDPI attenuated the reduction in the striatal tyrosine hydroxylase levels, and it reversed the increase in the cyclooxygenase‐2 levels and myeloperoxidase activity caused by MPTP in mice. Therefore, FDPI reversed motor and non‐motor symptoms induced by an acute PD model and its restorative effects seem to be mediated by an anti‐inflammatory action associated with a modulation of the striatal cyclooxygenase‐2 levels and myeloperoxidase activity.

Sulfhydryl‐Based Inhibition of δ‐ALA‐D and Na+, K+‐ATPase Activities Depends on the Organoselenium Group Bonded to the Isoquinoline

Organoselenium compounds and isoquinoline derivatives have their toxicity linked to induction of pro‐oxidant situations. δ‐Aminolevulinate dehydratase (δ‐ALA‐D) and Na+, K+‐ATPase have sulfhydryl groups susceptible to oxidation. Thus, we investigated toxicological effects of 4‐organoseleno‐isoquinoline derivatives, cerebral monoamine oxidase B inhibitors, on rat cerebral δ‐ALA‐D and Na+, K+‐ATPase activities and the involvement of sulfhydryl groups in vitro. Compounds substituted with fluoro (4‐(4‐fluorophenylseleno)‐3‐phenylisoquinoline), chloro (4‐(4‐chlorophenylseleno)‐3‐phenylisoquinoline) and trifluoro (4‐(3‐trifluoromethylphenylseleno)‐3‐phenylisoquinoline) at the selenium‐bonded aromatic ring inhibited δ‐ALA‐D (IC50 values: 78.42, 92.27, 44.98 µM) and Na+, K+‐ATPase (IC50 values: 41.36, 89.43, 50.66 µM) activities, possibly due to electronic effects induced by these groups. 3‐Phenyl‐4‐(phenylseleno) isoquinoline (without substitution at the selenium‐bonded aromatic ring) and 4‐(4‐methylphenylseleno)‐3‐phenylisoquinoline (with a methyl group substituted at the selenium‐bonded aromatic ring) did not alter the activity of these enzymes. Dithiothreitol, a reducing agent, restored the enzymatic activities inhibited by 4‐(4‐fluorophenylseleno)‐3‐phenylisoquinoline, 4‐(4‐chlorophenylseleno)‐3‐phenylisoquinoline and 4‐(3‐trifluoromethylphenylseleno)‐3‐phenylisoquinoline, suggesting the involvement of sulfhydryl residues in this effect. However, the release of essential zinc seems not to be related to the δ‐ALA‐D inhibition by these compounds. According to these data, the effect of oral administration (300 mg/kg, intragastric) of 3‐phenyl‐4‐(phenylseleno) isoquinoline on markers of systemic toxicity in Wistar rats was evaluated. None signs of toxicity was observed during or after treatment. This study suggests that the insertion of electron‐withdrawing groups in the aromatic ring bonded to the selenium atom of isoquinolines tested increased its inhibitory effect on sulfhydryl enzymes in vitro. 3‐Phenyl‐4‐(phenylseleno) isoquinoline, which has documented pharmacological properties, had no toxicological effects on the parameters evaluated in this study. J. Cell. Biochem. 118: 1144–1150, 2017.