Summary
In this review, we summarize the involvement of ascorbic acid in neurodegenerative diseases by presenting available evidence on the behavioral and biochemical effects of this compound in ...animal models of neurodegeneration as well as the use of ascorbic acid as a therapeutic approach to alleviate neurodegenerative progression in clinical studies. Ascorbate, a reduced form of vitamin C, has gained interest for its multiple functions and mechanisms of action, contributing to the homeostasis of normal tissues and organs as well as to tissue regeneration. In the brain, ascorbate exerts neuromodulatory functions and scavenges reactive oxygen species generated during synaptic activity and neuronal metabolism. These are important properties as redox imbalance and abnormal protein aggregation constitute central mechanisms implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, multiple sclerosis, and amyotrophic lateral sclerosis. Indeed, several studies have indicated an association between low serum ascorbate concentrations and neurodegeneration. Moreover, ascorbic acid is a suitable candidate for supplying either antioxidant defense or modulation of neuronal and astrocytic metabolism under neurodegenerative conditions. Ascorbic acid acts mainly by decreasing oxidative stress and reducing the formation of protein aggregates, which may contribute to the reduction of cognitive and/or motor impairments observed in neurodegenerative processes. Although several studies support a possible role of ascorbic acid administration against neurodegeneration, more researches are essential to substantiate the existing results and accelerate the knowledge in this field.
Abstract Reactive oxygen species (ROS) have been shown to play a role in the pathophysiology of depression. Taking into account that experimental chronic unpredictable stress (CUS) induces ...depressive-like behavior and that ascorbic acid has antidepressant-like effect in animals, the objective of this study was to investigate the influence of ascorbic acid on depressive-like behavior induced by CUS paradigm, serum corticosterone levels and markers of oxidative stress in cerebral cortex and hippocampus of mice. Animals were submitted to CUS procedure during 14 days. From the 8th to the 14th day mice received ascorbic acid (10 mg/kg) or fluoxetine (10 mg/kg, conventional antidepressant, positive control) once a day by oral route. On 15th day behavioral and biochemical parameters were analyzed. CUS exposure caused a depressive-like behavior evidenced by the increased immobility time in the tail suspension test and decreased time in which mice spent grooming in the splash test. Depressive-like behavior induced by CUS was accompanied by a significant increased lipid peroxidation (cerebral cortex and hippocampus), decreased catalase (CAT) (cerebral cortex and hippocampus) and glutathione reductase (GR) (hippocampus) activities and reduced levels of glutathione (cerebral cortex). Repeated ascorbic acid or fluoxetine administration significantly reversed CUS-induced depressive-like behavior and oxidative damage. No alteration was observed in locomotor activity, corticosterone levels and glutathione peroxidase (GPx) activity. These findings indicate a rapid and robust effect of ascorbic acid in reversing behavioral and biochemical alterations induced by CUS in mice, suggesting that this vitamin may be an alternative approach for the management of depressive symptoms.
Considering the involvement of GABAergic system in the action of the fast-acting antidepressant ketamine, and that agmatine may exert an antidepressant-like effect through mechanisms similar to ...ketamine, the purpose of the present study was to evaluate the involvement of GABA
A
and GABA
B
receptors in the antidepressant-like effect of agmatine. The administration of muscimol (0.1 mg/kg, i.p., GABA
A
receptor agonist) or diazepam (0.05 mg/kg, p.o., GABA
A
receptor positive allosteric modulator) at doses that caused no effect in the tail suspension test (TST) combined with a subeffective dose of agmatine (0.0001 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST. In another set of experiments, the administration of baclofen (1 mg/kg, i.p., GABA
B
receptor agonist) abolished the reduction of immobility time in the TST elicited by agmatine (0.1 mg/kg, p.o., active dose). In another cohort of animals, treatment with NMDA (0.1 pmol/site, i.c.v.) prevented the antidepressant-like effect of the combined administration of agmatine and muscimol as well as ketamine and muscimol in the TST. Results suggest that the effect of agmatine in the TST may involve an activation of GABA
A
receptors dependent on NMDA receptor inhibition, similar to ketamine, as well as modulation of GABA
B
receptors.
Studies have demonstrated an association between stressful conditions and the onset of clinical depression. Considering the antidepressant-like properties of ascorbic acid in both experimental and ...clinical approaches, we evaluated the beneficial effect of this vitamin on restraint stress-induced behavioral and neurochemical alterations. Acute restraint stress caused a depressive-like behavior in the forced swimming test, accompanied by increased lipid peroxidation (cerebral cortex and hippocampus); increased superoxide dismutase (cerebral cortex and hippocampus), glutathione reductase (cerebral cortex), and glutathione peroxidase (cerebral cortex and hippocampus) activities; and elevated expression of Bcl-2 (hippocampus). Oral administration of ascorbic acid (1 mg/kg) or fluoxetine (10 mg/kg) 1 h before restraint stress prevented the stress-induced increase on immobility time in the forced swimming test. Moreover, this vitamin reduced lipid peroxidation to control levels and restored the activity of superoxide dismutase, glutathione reductase, and glutathione peroxidase. Ascorbic acid had no effect on the increased level of Bcl-2 induced by stress. Glutathione levels, glycogen synthase kinase-3β phosphorylation, and Bax expression were not altered by stress or ascorbic acid administration. Besides reinforcing the antioxidant potential of ascorbic acid, our results support the notion that oxidative stress plays a role in the pathogenesis and treatment of stress-induced depression.
Considering that intracellular signaling pathways that modulate brain BDNF are implicated in antidepressant responses, this study investigated whether signaling pathway inhibitors upstream to BDNF ...might influence the antidepressant-like effect of zinc, a metal that has been shown to display antidepressant properties. To this end, the influence of i.c.v. administration of H-89 (1μg/site, PKA inhibitor), KN-62 (1μg/site, CAMKII inhibitor), chelerythrine (1μg/site, PKC inhibitor), PD98059 (5μg/site, MEK1/2 inhibitor), U0126 (5μg/site, MEK1/2 inhibitor), LY294002 (10nmol/site, PI3K inhibitor) on the reduction of immobility time in the tail suspension test (TST) elicited by ZnCl2 (10mg/kg, p.o.) was investigated. Moreover, the effect of the combination of sub-effective doses of ZnCl2 (1mg/kg, p.o.) and AR-A014418 (0.001μg/site, GSK-3β inhibitor) was evaluated. The occurrence of changes in CREB phosphorylation and BDNF immunocontent in the hippocampus and prefrontal cortex of mice following ZnCl2 treatment was also investigated. The anti-immobility effect of ZnCl2 in the TST was prevented by treatment with PKA, PKC, CAMKII, MEK1/2 or PI3K inhibitors. Furthermore, ZnCl2 in combination with AR-A014418 caused a synergistic anti-immobility effect in the TST. None of the treatments altered locomotor activity of mice. ZnCl2 treatment caused no alteration in CREB phosphorylation and BDNF immunocontent. The results extend literature data regarding the mechanisms underlying the antidepressant-like action of zinc by indicating that its antidepressant-like effect may be dependent on the activation of PKA, CAMKII, PKC, ERK, and PI3K/GSK-3β pathways. However, zinc is not able to acutely increase BDNF in the hippocampus and prefrontal cortex.
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•The anti-immobility effect of zinc was prevented by PKA and PKC inhibitors.•The anti-immobility effect of zinc was prevented by CAMKII and MEK1/2 inhibitors.•The antidepressant-like effect of zinc may be dependent on the PI3K/GSK-3β pathway.•Zinc did not alter hippocampal and cortical CREB phosphorylation or BDNF levels.
Guanosine is a purine nucleoside that has been shown to exhibit antidepressant effects, but the mechanisms underlying its effect are not well established. We investigated if the antidepressant-like ...effect induced by guanosine in the tail suspension test (TST) in mice involves the modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-dependent calcium channel (VDCC), and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway. We also evaluated if the antidepressant-like effect of guanosine is accompanied by an acute increase in hippocampal and prefrontocortical BDNF levels. Additionally, we investigated if the ability of guanosine to elicit a fast behavioral response in the novelty suppressed feeding (NSF) test is associated with morphological changes related to hippocampal synaptogenesis. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) in the TST was prevented by DNQX (AMPA receptor antagonist), verapamil (VDCC blocker), K-252a (TrkBantagonist), or BDNF antibody. Increased P70S6K phosphorylation and higher synapsin I immunocontent in the hippocampus, but not in the prefrontal cortex, were observed 1 h after guanosine administration. Guanosine exerted an antidepressant-like effect 1, 6, and 24 h after its administration, an effect accompanied by increased hippocampal BDNF level. In the prefrontal cortex, BDNF level was increased only 1 h after guanosine treatment. Finally, guanosine was effective in the NSF test (after 1 h) but caused no alterations in dendritic spine density and remodeling in the ventral dentate gyrus (DG). Altogether, the results indicate that guanosine modulates targets known to be implicated in fast antidepressant behavioral responses (AMPA receptor, VDCC, and TrkB/BDNF pathway).
Graphical abstract
Cholecalciferol deficiency has been associated with stress-related psychiatric disorders, particularly depression. Therefore, the present study investigated the antidepressant-like effect of ...cholecalciferol in female mice and the possible role of the serotonergic system in this response. The ability of cholecalciferol to elicit an antidepressant-like effect and to modulate serotonin levels in the hippocampus and prefrontal cortex of mice subjected to chronic unpredictable stress (CUS) was also investigated. The administration of cholecalciferol (2.5, 7.5, and 25 µg/kg, p.o.) for 7 days, similar to fluoxetine (10 mg/kg, p.o., serotonin reuptake inhibitor), reduced the immobility time in the tail suspension test, without altering the locomotor performance in the open-field test. Moreover, the administration of
p-
chlorophenylalanine methyl ester (PCPA – 100 mg/kg, i.p., for 4 days, a selective inhibitor of tryptophan hydroxylase, involved in the serotonin synthesis) abolished the antidepressant-like effect of cholecalciferol and fluoxetine in the tail suspension test, demonstrating the involvement of serotonergic system. Additionally, CUS protocol (21 days) induced depressive-like behavior in the tail suspension test and decreased serotonin levels in the prefrontal cortex and hippocampus of mice. Conversely, the administration of cholecalciferol and fluoxetine in the last 7 days of CUS protocol completely abolished the stress-induced depressive-like phenotype. Cholecalciferol was also effective to abrogate CUS-induced reduction on serotonin levels in the prefrontal cortex, but not in the hippocampus. Our results indicate that cholecalciferol has an antidepressant-like effect in mice by modulating the serotonergic system and support the assumption that cholecalciferol may have beneficial effects for the management of depression.
Considering that depression is a common non-motor comorbidity of Parkinson’s disease and that agmatine is an endogenous neuromodulator that emerges as a potential agent to manage diverse central ...nervous system disorders, this study investigated the antidepressant-like effect of agmatine in mice intracerebroventricularly (i.c.v.) injected with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP
+
). Male C57BL6 mice were treated with agmatine (0.0001, 0.1 or 1 mg/kg) and 60 min later the animals received an i.c.v. injection of MPP
+
(1.8 µg/site). Twenty-four hours after MPP
+
administration, immobility time, anhedonic behavior, and locomotor activity were evaluated in the tail suspension test (TST), splash test, and open field test, respectively. Using Western blot analysis, we investigated the putative modulation of MPP
+
and agmatine on striatal and frontal cortex levels of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF). MPP
+
increased the immobility time of mice in the TST, as well as induced an anhedonic-like behavior in the splash test, effects which were prevented by pre-treatment with agmatine at the three tested doses. Neither drug, alone or in combination, altered the locomotor activity of mice. I.c.v. administration of MPP
+
increased the striatal immunocontent of TH, an effect prevented by the three tested doses of agmatine. MPP
+
and agmatine did not alter the immunocontent of BDNF in striatum and frontal cortex. These results demonstrate for the first time the antidepressant-like effects of agmatine in an animal model of depressive-like behavior induced by the dopaminergic neurotoxin MPP
+
.
Abstract In this study, we assessed the oxidative stress parameters in rats submitted to an animal model of mania induced by ouabain (OUA), which included the use of lithium (Li) and valproate (VPA). ...Li and VPA treatment reversed and prevented the OUA-induced damage in these structures, however, this effect varies depending on the brain region and treatment regimen. Moreover, the activity of the antioxidant enzymes, namely, superoxide dismutase (SOD) and catalase (CAT) was found to be increased and decreased, respectively, in the brain of OUA-administered rats. Li and VPA modulated SOD and CAT activities in OUA-subjected rats in both experimental models. Our results support the notion that Li and VPA exert antioxidant-like properties in the brain of rats submitted to animal model of mania induced by ouabain.
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