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Certain stressful life events have been associated with the onset of depression. This study aims to investigate if 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) is effective against social avoidance induced by social defeat stress model in mice. Furthermore, it was investigated the effects of FDPI in the mouse prefrontal cortical plasticity-related proteins and some parameters of toxicity. Adult Swiss mice were subjected to social defeat stress for 10 days. Two protocols with FDPI were carried out: 1- FDPI (25 mg/kg, intragastric) was administered to mice 24 h after the last social defeat stress episode; 2- FDPI (1–25 mg/kg, intragastric) was administered to mice once a day for 10 days concomitant with the social defeat stress. The mice performed social avoidance and locomotor tests. The prefrontal cortical protein contents of kinase B (Akt), extracellular signal-regulated kinase (ERK), cAMP-response element binding protein (CREB), pro-brain-derived neurotrophic factor (proBDNF), p75 NTR , neuronal nuclear protein (NeuN) and nuclear factor-κB (NF-κB) were determined in mice. A single administration of FDPI (25 mg/kg) partially protected against social avoidance induced by stress in mice. Repeated administration of FDPI (25 mg/kg) protected against social avoidance induced by stress in mice. Social defeat stress decreased the protein contents of p75 NTR , NeuN and the pERK/ERK ratio but increased those of proBDNF and the pCREB/CREB ratio, without changing that of NF-κB. Repeated administration of FDPI modulated signaling pathways altered by social defeat stress in mice. The present findings demonstrate that FDPI promoted resilience to stress in mice. [ABSTRACT FROM AUTHOR]

7-Fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) is a promising isoquinoline that elicits an antidepressant-like action in rodents. In this study, an animal model of stress induced by maternal separation was used to investigate the effects of FDPI in Wistar rats of 30 and 90 days of age. It was investigated the effects of maternal separation in the self-care behavior and the contribution of glutamatergic and gamma-aminobutyric acid (GABA)ergic systems in the FDPI action. Male Wistar rats were separated from their mothers for 3 h/day from postnatal day (PND) 1-10. The rats were treated at different ages (PND-30 and PND-90) with FDPI (5 mg/kg, intragastrically/7 days) and performed the splash test. Maternal separation reduced total grooming time in the splash test, an index of motivational and self-care behavior, and FDPI treatment was effective in reversing this behavior in rats at both ages. The neurochemical parameters were differently affected, dependent on the age of rats, by maternal separation and FDPI. Maternal separation increased the GABA uptake and the excitatory amino acid transporter 1 levels in the prefrontal cortices of rats at PND-30 and FDPI was effective against these alterations. At PND-90, maternal separation decreased the glutamate uptake and increased the GABA uptake and the N-methyl-D-aspartate (NMDA) receptor 2B levels in the prefrontal cortices of rats. FDPI reversed the neurochemical alterations caused by maternal separation in the prefrontal cortices of rats at PND-90. The results of this study demonstrated that FDPI reversed the reduction in self-care behavior induced by maternal separation stress in rats by modulating the glutamatergic/GABAergic systems in rats. [ABSTRACT FROM AUTHOR]

It has been reported that the antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) may result from the modulation of brain monoaminergic systems. However, the mechanisms of FDPI action are not fully understood. The aim of this study was to investigate the contribution of N-methyl- d -aspartate (NMDA) and gamma-aminobutyric acid (GABA) systems as well as l -arginine-nitric oxide-(NO)-cyclic guanosine monophosphate-(cGMP), mitogen-activated protein/extracellular signal-regulated kinase (MEK1/2) and Ca 2+ /calmodulin-dependent protein kinase II (CaMK-II) signaling pathways in the antidepressant-like effect of FDPI in the mouse forced swimming test (FST). The levels of NO and uptake of [ 3 H]glutamate and [ 3 H]GABA were determined in prefrontal cortices of Swiss mice. Pretreatments with NMDA (0.1 pmol/site, i.c.v., a NMDA receptor agonist), bicuculline (1 mg/kg, i.p., a GABA A receptor antagonist), phaclofen (2 mg/kg, i.p., a GABA B receptor antagonist) and l -arginine (750 mg/kg, i.p., a NO precursor), KN-62 (1 μg/site, a CaMK-II inhibitor), U0126 (5 μg/site, a MEK1/2 inhibitor) and PD09058 (5 μg/site, a MEK1/2 inhibitor) blocked the antidepressant-like effect of FDPI, at a dose of 1 mg/kg, in the FST. ODQ (30 pmol/site, i.c.v., a soluble guanylate cyclase (sGC) inhibitor) in combination with a sub-effective dose of FDPI (0.1 mg/kg, i.g.) reduced the immobility time in the FST. The administration of FDPI (50 mg/kg) to mice increased the glutamate uptake and reduced NO levels in the prefrontal cortex of mice. The results suggest a contribution of NMDA, GABA A and GABA B receptors and l -arginine-NO-cGMP pathway in the antidepressant-like action of FDPI in mice, and this effect is related to CaMK-II and MEK 1/2 activation. [ABSTRACT FROM AUTHOR]

Chronic unpredictable mild stress (CUMS) elicits aspects of cognitive and behavioral alterations that can be used to model comparable aspects of depression in humans. The aim of the present study was to investigate the antidepressant-like potential of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a novel isoquinoline compound, in CUMS, a model that meets face, construct and predictive criteria for validity. Swiss mice were subjected to different stress paradigms daily for a period of 35 days to induce the depressive-like behavior. The animals received concomitant FDPI (0.1 and 1 mg/kg, intragastric) or paroxetine (8 mg/kg, intraperitoneal) and CUMS. The behavioral tests (splash test, tail suspension test, modified forced swimming test and locomotor activity) were performed. The levels of cytokines, corticosterone and adrenocorticotropic (ACTH) hormones were determined in the mouse prefrontal cortex and serum. The synaptosomal [ 3 H] serotonin (5-HT) uptake, nuclear factor (NF)-κB, tyrosine kinase receptor (TrkB) and pro-brain-derived neurotrophic factor (BDNF) levels were determined in the mouse prefrontal cortex. CUMS induced a depressive-like behavior in mice, which was demonstrated in the modified forced swimming, tail suspension and splash tests. FDPI at both doses prevented depressive-like behavior induced by CUMS, without altering the locomotor activity of mice. FDPI at the highest dose prevented the increase in the levels of NF-kB, pro-inflammatory cytokines, corticosterone and ACTH and modulated [ 3 H]5-HT uptake and the proBDNF/TrkB signaling pathway altered by CUMS. The present findings demonstrated that FDPI elicited an antidepressant-like effect in a model of stress-induced depression. [ABSTRACT FROM AUTHOR]

There is a complex relationship between stressful situations and the onset of depression. 7-Fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) has been reported to have an antidepressant-like effect in the forced swimming test (FST). The aim of this study was to investigate the antidepressant-like effect of FDPI administered to mice before or after the acute restraint stress (ARS). The mice were submitted to the ARS for 7 h. Two treatments with FDPI (10 mg/kg) were performed: in the first treatment, the mice received FDPI 30 min before ARS (pre-treatment) and in the second treatment mice received FDPI 10 min after the ARS (post-treatment). Thirty minutes after FDPI administration, the FST and locomotor activity were carried out. ARS induced depressive-like behavior in the FST. Both treatments with FDPI were effective against the increase in immobility time in the FST. Moreover, ARS increased lipid peroxidation and intracellular reactive oxygen species (ROS) levels as well as decreased catalase activity in prefrontal cortical samples of mice. Pre- and post-treatments with FDPI reduced lipid peroxidation and ROS, and post-treatment restored catalase activity. Superoxide dismutase was not altered by stress and/or FDPI. Monoamine oxidase (MAO) activities increased in the prefrontal-cortices of mice submitted to the ARS protocol and treatments with FDPI abolished this increase. Hepatic MAO activities were not altered in the livers of mice submitted to ARS and FDPI treatments. The serotonin uptake was increased in the prefrontal-cortices of mice submitted to the ARS protocol and both treatments with FDPI abolished this increase. The antidepressant-like effect of FDPI appears to involve the modulation of oxidative stress and the monoaminergic system, without inhibiting hepatic MAO activity. [ABSTRACT FROM AUTHOR]

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 [3H]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 [3H]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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

The isoquinoline 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) has been studied due to its multitarget properties, such as modulation of GABAergic and glutamatergic systems, antioxidant, and anti-inflammatory. This study investigated the contribution of oxidative stress, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase (HO-1) signaling, and the cholinergic system to the anti-amnesic action of FDPI in mice. Adult male Swiss mice received FDPI for 5 days (5–25 mg/kg, i.g.); the animals received scopolamine (1 mg/kg, i.p) from day 3–5. The vehicle-control group was carried out. Afterward, mice performed object recognition tests (ORTs). Scopolamine induced amnesia and cholinergic dysfunction by increasing the acetylcholinesterase (AChE) activity and content, decreasing the muscarinic M1 receptor levels in the prefrontal cortex and hippocampus of mice. This study reveals that scopolamine altered oxidative stress parameters differently in the prefrontal cortex and hippocampus of mice. Whereas the prefrontal cortex was susceptible to oxidative stress, none of the parameters evaluated was altered in the hippocampus of scopolamine-treated mice. FDPI at doses of 10 and 25 mg/kg had an anti-amnesic effect in the ORT tests. FDPI 10 mg/kg reversed the increase in the AChE activity and content, oxidative stress parameters, and modulated Nrf2/HO-1 signaling in the prefrontal cortex of scopolamine-exposed mice. Pearson's correlation analyses reinforced the contribution of the prefrontal cortical cholinergic system, oxidative stress as well as Nrf2/HO-1 signaling in the anti-amnesic effect of FDPI. Considering FDPI effects on the hippocampus, it was effective against the cholinergic dysfunction, AChE activity and content, and M1 receptor levels, which collectively could contribute to its anti-amnesic effect. • FDPI treatment was effective against memory impairment induced by scopolamine in mice. • FDPI modulated AChE and M1 receptor contents in mice exposed to scopolamine. • FDPI reversed oxidative stress induced by scopolamine in prefrontal cortex of mice. • Oxidative stress and Nrf2/HO-1 signaling contributed to the action of FDPI. [ABSTRACT FROM AUTHOR]

Parkinson's 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. [ABSTRACT FROM AUTHOR]