Ursolic acid abrogates depressive-like behavior and hippocampal pro-apoptotic imbalance induced by chronic unpredictable stress.

Emerging evidence has shown that ursolic acid exerts antidepressant-like effects, however, its ability to elicit an antidepressant-like response in rodents subjected to stress model that mimics behavioral and neurochemical alterations found in depression remains to be determined. Thus, this study investigated the possible antidepressant-like effect of ursolic acid in mice subjected to chronic unpredictable stress (CUS) for 14 days, and whether this effect could be associated with the modulation of serum corticosterone levels and hippocampal Bcl-2/Bax mRNA expression. Our results indicated that CUS induced a depressive-like behavior, as demonstrated by an increase in the immobility time and latency to first grooming in the tail suspension test and splash test, respectively. Conversely, the repeated administration of ursolic acid (0.1 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.) in the last 7 days of CUS completely prevented CUS-induced behavioral alterations, suggesting an antidepressant-like effect. Additionally, CUS significantly increased the mRNA expression of Bax (pro-apoptosis marker), but not Bcl-2 (anti-apoptosis marker) in the hippocampus. Moreover, reduced hippocampal mRNA expression of Bcl-2/Bax ratio was detected in CUS-exposed mice. Ursolic acid, but not fluoxetine, prevented CUS-induced increase in the expression of Bax, but both ursolic acid and fluoxetine prevented CUS-induced reduction on Bcl-2/Bax ratio. Furthermore, neither CUS nor treatments with ursolic acid or fluoxetine altered serum corticosterone levels. Our study unveils the ability of ursolic acid to prevent the depressive-like behavior induced by stress and the modulation of Bcl-2/Bax expression could be associated with this response.

Neuroprotective effects of mirtazapine and imipramine and their effect in pro- and anti-apoptotic gene expression in human neuroblastoma cells.

BACKGROUND: Experimental and clinical studies indicate that neuronal death with the presence of high levels of reactive oxygen species are present in depressed patients and antidepressants might display neuroprotective effects against them. However, the mechanisms underlying antidepressant neuroprotection are not completely understood. In our previous study, we showed that mirtazapine modulated the expression of pro- and anti-apoptotic proteins in mouse brain structures, but there are no data in human cells. Thus, this work was designed to study the possible neuroprotective properties of mirtazapine and imipramine, two commercially available antidepressants with different primary mechanisms of action, in human neuroblastoma SH-SY5Y cells against an oxidative insult. METHODS: SH-SY5Y cells were preincubated with mirtazapine and imipramine (1-20 µM) for 24 h, then hydrogen peroxide (H2O2) was added into the medium containing the antidepressants for additional 24 h, and MTT assay was carried out subsequently. Also, to elucidate the molecular mechanism underlying the neuroprotective properties of antidepressants, we investigated the effects of mirtazapine and imipramine (2 µM) in pro- and anti-apoptotic proteins gene expression in SH-SY5Y cells. RESULTS: Mirtazapine (1 and 2 µM) and imipramine (1and 2 µM) protected against hydrogen peroxide-induced cellular viability impairment. Most importantly, both compounds reduced p53 mRNA expression, but only imipramine enhanced the Bcl-2/Bax ratio. CONCLUSIONS: The obtained data indicate that mirtazapine and imipramine have neuroprotective effects against H2O2-induced cell death. Although both antidepressants reduced Bax and p53 mRNA expression, only the protection mediated by imipramine might be due to its ability to enhance Bcl-2/Bax ratio.

Subchronic administration of creatine produces antidepressant-like effect by modulating hippocampal signaling pathway mediated by FNDC5/BDNF/Akt in mice.

Creatine has been shown to play a significant role in the pathophysiology and treatment of major depressive disorder (MDD) in preclinical and clinical studies. However, the biological mechanisms underlying its antidepressant effect is still not fully elucidated. This study investigated the effect of creatine (p.o.) administered for 21 days in the behavior of mice submitted to tail suspension test (TST), a predictive test of antidepressant activity. Creatine reduced the immobility time in the TST (1-10 mg/kg), without affecting locomotor activity, a finding consistent with an antidepressant profile. Creatine administration increased the ubiquitous creatine kinase (uCK) and creatine kinase brain isoform (CK-B) mRNA in the hippocampus of mice. Taking into account that PGC-1α induces FNDC5/irisin expression mediating BDNF-dependent neuroplasticity, the effect of creatine administration (1 mg/kg, p. o.) on the hippocampal PGC-1α, FNDC5 and BDNF gene expression was investigated. Creatine treatment increased PGC-1α, FNDC5 and BDNF mRNA in the hippocampus as well as BDNF immunocontent. The involvement of BDNF downstream intracellular signaling pathway mediated by Akt, proapoptotic proteins BAX and BAD and antiapoptotic proteins Bcl2 and Bcl-xL was also investigated following creatine treatment. Creatine increased Akt phosphorylation (Ser 473), and Bcl2 mRNA and protein levels, and Bcl-xL mRNA, whereas BAD mRNA was decreased following creatine administration in the hippocampus. Altogether these results indicate that creatine antidepressant-like effect may be dependent on Akt activation and increased expression of the neuroprotective proteins in the hippocampus of mice. The obtained data reinforce the antidepressant property of creatine and highlight the role of these molecular targets in the pathophysiology of MDD.

Central irisin administration affords antidepressant-like effect and modulates neuroplasticity-related genes in the hippocampus and prefrontal cortex of mice.

Evidence has indicated that the practice of physical exercise has antidepressant effects that might be associated with irisin release and BDNF signaling. In this study we investigated the effects of the central administration of irisin or BDNF in predictive tests of antidepressant properties paralleled with the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex of mice. Irisin (0.5-1 ng/mouse, i.c.v.) reduced the immobility time in the tail suspension test (TST) and forced swim test (FST), without altering locomotion in the open field test (OFT). Irisin reduced the immobility time in the TST up to 6 h after its administration. Irisin administration (6 h) increased PGC-1α mRNA in the hippocampus and prefrontal cortex and reduced (1 h) PGC-1α mRNA in the prefrontal cortex. FNDC5 and BDNF mRNA expression was decreased (1 h) in both structures and remained reduced up to 6 h in the prefrontal cortex. Moreover, BDNF administered at 0.25 µg/mouse, i.c.v. (1 and 6 h before the test) reduced the immobility time in the TST. BDNF administration reduced PGC-1α mRNA in the hippocampus (6 h) and prefrontal cortex (1 and 6 h). It also increased FNDC5 mRNA expression in the hippocampus (1 and 6 h), but reduced the expression of this gene and also BDNF mRNA in the prefrontal cortex (1 and 6 h). None of the treatments altered BDNF protein levels in both structures. In conclusion, irisin presents a behavioral antidepressant profile similar to BDNF, an effect associated with the modulation of gene expression of PGC-1α, FNDC5 and BDNF, reinforcing the pivotal role of these genes in mood regulation.

Duloxetine Protects Human Neuroblastoma Cells from Oxidative Stress-Induced Cell Death Through Akt/Nrf-2/HO-1 Pathway.

The contribution of oxidative stress to the pathophysiology of depression has been described in numerous studies. Particularly, an increased production of reactive oxygen species (ROS) caused by mitochondrial dysfunction can lead to neuronal cell death. Human neuroblastoma SH-SY5Y cells were used to investigate the neuroprotective effect of the antidepressant duloxetine against rotenone-induced oxidative stress. SH-SY5Y cells were pretreated with duloxetine (1-5 µM) for 24 h followed by a 24-h rotenone exposure (10 µM). The phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) inhibitor LY294002 (10 µM) and the heme oxygenase 1 (HO-1) inhibitor zinc protoporphyrin IX-ZnPP (5 µM) were added to cultures 1 h prior duloxetine treatments. After treatments cell viability and ROS generation were assessed. NF-E2-related factor-2 (Nrf2) nuclear translocation was assessed by immunofluorescent staining after 4 and 8 h of duloxetine incubation. Furthermore, the Nrf2 and HO-1 mRNA expression was carried out after 4-48 h of duloxetine treatment by qRT-PCR. Duloxetine pretreatment antagonized rotenone-induced overproduction of ROS and cell death in SH-SY5Y cells. In addition, a 1-h pretreatment with LY294002 abolished duloxetine's protective effect. Duloxetine also induced nuclear translocation of the Nrf2 and the expression of its target gene, HO-1. Finally, the HO-1 inhibitor, ZnPP, suppressed the duloxetine protective effect. Overall, these results indicate that the mechanism of duloxetine neuroprotective action against oxidative stress and cell death might rely on the Akt/Nrf2/HO-1 pathways.

Ursolic acid affords antidepressant-like effects in mice through the activation of PKA, PKC, CAMK-II and MEK1/2.

BACKGROUND: Ursolic acid has been shown to display antidepressant-like effects in mice through the modulation of monoaminergic systems. In this study, we sought to investigate the involvement of signaling pathways on the antidepressant-like effects of ursolic acid. METHODS: Mice were treated orally with ursolic acid (0.1mg/kg) and, 45min later they received the followings inhibitors by intracerebroventricular route: H-89 (PKA inhibitor, 1µg/mouse), KN-62 (CAMK-II inhibitor, 1µg/mouse), chelerythrine (PKC inhibitor, 1µg/mouse), U0126 (MEK1/2 inhibitor, 5µg/mouse), PD98059 (MEK1/2 inhibitor, 5µg/mouse), wortmannin (PI3K irreversible inhibitor, 0.1µg/mouse) or LY294002 (PI3K inhibitor, 10 nmol/mouse). Immobility time of mice was registered in the tail suspension test (TST). RESULTS: The anti-immobility effect of ursolic acid in the TST was abolished by the treatment of mice with H-89, KN-62, chelerythrine, U0126 or PD98059, but not with wortmannin or LY294002. CONCLUSIONS: These results suggest that activation of PKA, PKC, CAMK-II, MEK1/2 may underlie the antidepressant-like effects of ursolic acid.

Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice.

Experimental autoimmune encephalomyelitis (EAE) is the most used animal model of multiple sclerosis (MS) for the development of new therapies. Dopamine receptors can modulate EAE and MS development, thus highlighting the potential use of dopaminergic agonists in the treatment of MS, which has been poorly explored. Herein, we hypothesized that pramipexole (PPX), a dopamine D2/D3 receptor-preferring agonist commonly used to treat Parkinson's disease (PD), would be a suitable therapeutic drug for EAE. Thus, we report the effects and the underlying mechanisms of action of PPX in the prevention of EAE. PPX (0.1 and 1 mg/kg) was administered intraperitoneally (i.p.) from day 0 to 40 post-immunization (p.i.). Our results showed that PPX 1 mg/kg prevented EAE development, abolishing EAE signs by blocking neuroinflammatory response, demyelination, and astroglial activation in spinal cord. Moreover, PPX inhibited the production of inflammatory cytokines, such as IL-17, IL-1ß, and TNF-α in peripheral lymphoid tissue. PPX was also able to restore basal levels of a number of EAE-induced effects in spinal cord and striatum, such as reactive oxygen species, glutathione peroxidase, parkin, and α-synuclein (α-syn). Thus, our findings highlight the usefulness of PPX in preventing EAE-induced motor symptoms, possibly by modulating immune cell responses, such as those found in MS and other T helper cell-mediated inflammatory diseases.

Inosine, an Endogenous Purine Nucleoside, Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis: a Role for A2A Adenosine Receptor.

Multiple sclerosis (MS) is a T cell autoimmune, inflammatory, and demyelinating disease of the central nervous system (CNS). Currently available therapies have partially effective actions and numerous side reactions. Inosine, an endogenous purine nucleoside, has immunomodulatory, neuroprotective, and analgesic properties. Herein, we evaluated the effect of inosine on the development and progression of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Inosine (1 or 10 mg/kg, i.p.) was administrated twice a day for 40 days. Immunological and inflammatory responses were evaluated by behavioral, histological, immunohistochemical, ELISA, RT-PCR, and Western blotting analysis. The administration of inosine exerted neuroprotective effects against EAE by diminishing clinical signs, including thermal and mechanical hyperalgesia, as well as weight loss typical of the disease. These beneficial effects of inosine seem to be associated with the blockade of inflammatory cell entry into the CNS, especially lymphocytes, thus delaying the demyelinating process and astrocytes activation. In particular, up-regulation of IL-17 levels in the secondary lymphoid tissues, a result of EAE, was prevented by inosine treatment in EAE mice. Additionally, inosine consistently prevented A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. Altogether, these results allow us to propose that this endogenous purine might be a putative novel and helpful tool for the prevention of autoimmune and neurodegenerative diseases, such as MS. Thus, inosine could have considerable implications for future therapies of MS, and this study may represent the starting point for further investigation into the role of inosine and adenosinergic receptors in neuroinflammation processes. Graphical Abstract Preventive treatment with inosine inhibits the development and progression of EAE in C57Bl/6 mice. Furthermore, neuroinflammation and demyelinating processes were blocked by inosine treatment. Additionally, inosine consistently inhibited IL-17 levels in peripheral lymphoid tissue, as well as IL-4 levels and A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. EAE: experimental autoimmune encephalomyelitis; MS: multiple sclerosis; A2AR: adenosine A2A receptor; IL-17: interleukin-17; IL-4: interleukin-4.

MPP+-Lesioned Mice: an Experimental Model of Motor, Emotional, Memory/Learning, and Striatal Neurochemical Dysfunctions.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces motor and nonmotor dysfunctions resembling Parkinson's disease (PD); however, studies investigating the effects of 1-methyl-4-phenylpyridinium (MPP+), an active oxidative product of MPTP, are scarce. This study investigated the behavioral and striatal neurochemical changes (related to oxidative damage, glial markers, and neurotrophic factors) 24 h after intracerebroventricular administration of MPP+ (1.8-18 µg/mouse) in C57BL6 mice. MPP+ administration at high dose (18 µg/mouse) altered motor parameters, since it increased the latency to leave the first quadrant and reduced crossing, rearing, and grooming responses in the open-field test and decreased rotarod latency time. MPP+ administration at low dose (1.8 µg/mouse) caused specific nonmotor dysfunctions as it produced a depressive-like effect in the forced swim test and tail suspension test, loss of motivational and self-care behavior in the splash test, anxiety-like effect in the elevated plus maze test, and short-term memory deficit in the step-down inhibitory avoidance task, without altering ambulation. MPP+ at doses of 1.8-18 µg/mouse increased tyrosine hydroxylase (TH) immunocontent and at 18 µg/mouse increased α-synuclein and decreased parkin immunocontent. The astrocytic calcium-binding protein S100B and glial fibrillary acidic protein (GFAP)/S100B ratio was decreased following MPP+ administration (18 µg/mouse). At this highest dose, MPP+ increased the ionized calcium-binding adapter molecule 1 (Iba-1) immunocontent, suggesting microglial activation. Also, MPP+ at a dose of 18 µg/mouse increased thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and increased glutathione peroxidase (GPx) and hemeoxygenase-1 (HO-1) immunocontent, suggesting a significant role for oxidative stress in the MPP+-induced striatal damage. MPP+ (18 µg/mouse) also increased striatal fibroblast growth factor 2 (FGF-2) and brain-derived neurotrophic factor (BDNF) levels. Moreover, MPP+ decreased tropomyosin receptor kinase B (TrkB) immunocontent. Finally, MPP+ (1.8-18 µg/mouse) increased serum corticosterone levels and did not alter acetylcholinesterase (AChE) activity in the striatum but increased it in cerebral cortex and hippocampus. Collectively, these results indicate that MPP+ administration at low doses may be used as a model of emotional and memory/learning behavioral deficit related to PD and that MPP+ administration at high dose could be useful for analysis of striatal dysfunctions associated with motor deficits in PD.

Antidepressant-like effect of pramipexole in an inflammatory model of depression.

Pramipexole (PPX), a dopamine D2/3 receptor preferring agonist, is currently in use for the treatment of Parkinson's disease symptoms and restless legs syndrome. Recently, anti-inflammatory properties of PPX have been shown in an autoimmune model of multiple sclerosis, and case reports indicate PPX ameliorates depressive symptoms. Since peripheral inflammation is known to induce depression-like behavior in rodents, we assessed the potential antidepressant effect of PPX in an inflammatory model of depression induced by LPS. Repeated (daily for 7days, 1mg/kg, i.p.), but not acute (1h before LPS) treatment with PPX abolished the depression-like behavior induced by LPS (0.1mg/kg, i.p.) in the forced swim test, and the anhedonic behavior in the splash test. Interestingly, PPX per se decreased interleukin 1ß levels and reversed LPS-induced increase in its content in mice hippocampus⋅ Repeated PPX treatment also prevented the increase in hippocampal levels of the 3-nitrotyrosine protein adducts induced by LPS. Haloperidol (0.2mg/kg, i.p.) and sulpiride (50mg/kg, i.p.) were unable to prevent the antidepressant-like effect of PPX in LPS-treated mice. Altogether, these results suggest that the observed antidepressant-like effect of PPX in LPS-treated mice may be dependent on its anti-inflammatory properties and may not be related to dopamine D2 receptor activation.

Creatine affords protection against glutamate-induced nitrosative and oxidative stress.

Creatine has been reported to exert beneficial effects in several neurodegenerative diseases in which glutamatergic excitotoxicity and oxidative stress play an etiological role. The purpose of this study was to investigate the protective effects of creatine, as compared to the N-Methyl-d-Aspartate (NMDA) receptor antagonist dizocilpine (MK-801), against glutamate or hydrogen peroxide (H2O2)-induced injury in human neuroblastoma SH-SY5Y cells. Exposure of cells to glutamate (60-80 mM) or H2O2 (200-300 µM) for 24 h decreased cellular viability and increased dichlorofluorescein (DCF) fluorescence (indicative of increased reactive oxygen species, ROS) and nitric oxide (NO) production (assessed by mono-nitrogen oxides, NOx, levels). Creatine (1-10 mM) or MK-801 (0.1-10 µM) reduced glutamate- and H2O2-induced toxicity. The protective effect of creatine against glutamate-induced toxicity involves its antioxidant effect, since creatine, similar to MK-801, prevented the increase on DCF fluorescence induced by glutamate or H2O2. Furthermore, creatine or MK-801 blocked glutamate- and H2O2-induced increases in NOx levels. In another set of experiments, the repeated, but not acute, administration of creatine (300 mg/kg, po) in mice prevented the decreases on cellular viability and mitochondrial membrane potential (assessed by tetramethylrhodamine ethyl ester, TMRE, probe) of hippocampal slices incubated with glutamate (10 mM). Creatine concentration-dependent decreased the amount of nitrite formed in the reaction of oxygen with NO produced from sodium nitroprusside solution, suggesting that its protective effect against glutamate or H2O2-induced toxicity might be due to its scavenger activity. Overall, the results suggest that creatine may be useful as adjuvant therapy for neurodegenerative disease treatments.

Low-level laser therapy ameliorates disease progression in a mouse model of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating inflammatory disease characterized by recurrent episodes of T cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. The existing therapies for MS are only partially effective and are associated with undesirable side effects. Low-level laser therapy (LLLT) has been clinically used to treat inflammation, and to induce tissue healing and repair processes. However, there are no reports about the effects and mechanisms of LLLT in experimental autoimmune encephalomyelitis (EAE), an established model of MS. Here, we report the effects and underlying mechanisms of action of LLLT (AlGaInP, 660 nm and GaAs, 904 nm) irradiated on the spinal cord during EAE development. EAE was induced in female C57BL/6 mice by immunization with MOG35-55 peptide emulsified in complete Freund's adjuvant. Our results showed that LLLT consistently reduced the clinical score of EAE and delayed the disease onset, and also prevented weight loss induced by immunization. Furthermore, these beneficial effects of LLLT seem to be associated with the down-regulation of NO levels in the CNS, although the treatment with LLLT failed to inhibit lipid peroxidation and restore antioxidant defense during EAE. Finally, histological analysis showed that LLLT blocked neuroinflammation through a reduction of inflammatory cells in the CNS, especially lymphocytes, as well as preventing demyelination in the spinal cord after EAE induction. Together, our results suggest the use of LLLT as a therapeutic application during autoimmune neuroinflammatory responses, such as MS.

Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway.

Ketamine has emerged as a novel strategy to treat refractory depression, producing rapid remission, but elicits some side effects that limit its use. In an attempt to investigate a safer compound that may afford an antidepressant effect similar to ketamine, this study examined the effects of the ergogenic compound creatine in a model of depression, and the involvement of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) for 21 days. This treatment increased immobility time in the tail suspension test (TST), an effect abolished by a single administration of creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 0.1 µg/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and ketamine. None of the treatments affected locomotor activity of mice. The immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 protein (PSD95) were increased by creatine and ketamine in corticosterone or vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished by creatine or ketamine. Altogether, the results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders. Moreover, we suggest that creatine should be further investigated as a possible fast-acting antidepressant.

The modulation of NMDA receptors and L-arginine/nitric oxide pathway is implicated in the anti-immobility effect of creatine in the tail suspension test.

The modulation of N-methyl-D-aspartate receptor (NMDAR) and L-arginine/nitric oxide (NO) pathway is a therapeutic strategy for treating depression and neurologic disorders that involves excitotoxicity. Literature data have reported that creatine exhibits antidepressant and neuroprotective effects, but the implication of NMDAR and L-arginine/nitric oxide (NO) pathway in these effects is not established. This study evaluated the influence of pharmacological agents that modulate NMDAR/L-arginine-NO pathway in the anti-immobility effect of creatine in the tail suspension test (TST) in mice. The NOx levels and cellular viability in hippocampal and cerebrocortical slices of creatine-treated mice were also evaluated. The anti-immobility effect of creatine (10 mg/kg, po) in the TST was abolished by NMDA (0.1 pmol/mouse, icv), D-serine (30 µg/mouse, icv, glycine-site NMDAR agonist), arcaine (1 mg/kg, ip, polyamine site NMDAR antagonist), L-arginine (750 mg/kg, ip, NO precursor), SNAP (25 µg/mouse, icv, NO donor), L-NAME (175 mg/kg, ip, non-selective NOS inhibitor) or 7-nitroindazole (50 mg/kg, ip, neuronal NOS inhibitor), but not by DNQX (2.5 µg/mouse, icv, AMPA receptor antagonist). The combined administration of sub-effective doses of creatine (0.01 mg/kg, po) and NMDAR antagonists MK-801 (0.001 mg/kg, po) or ketamine (0.1 mg/kg, ip) reduced immobility time in the TST. Creatine (10 mg/kg, po) increased cellular viability in hippocampal and cerebrocortical slices and enhanced hippocampal and cerebrocortical NO x levels, an effect potentiated by L-arginine or SNAP and abolished by 7-nitroindazole or L-NAME. In conclusion, the anti-immobility effect of creatine in the TST involves NMDAR inhibition and enhancement of NO levels accompanied by an increase in neural viability.

Folic acid prevents depressive-like behavior induced by chronic corticosterone treatment in mice.

The objective of this study was to investigate the effects of folic acid on depressive-like behavior induced by chronic administration of corticosterone in mice. Corticosterone (20mg/kg, p.o.) was administered once a day for 21days. Folic acid (30mg/kg, p.o.) or fluoxetine (10mg/kg, positive control, p.o.) was administered immediately after corticosterone injection during the last 7days of corticosterone treatment. On the 22nd day, animals were submitted to tail suspension test, open-field test and splash test. Corticosterone treatment caused a depressive-like behavior, evidenced by increased immobility time in the tail suspension test and decreased time in which mice spent grooming in the splash test. Repeated folic acid or fluoxetine administration significantly abolished corticosterone-induced depressive-like behavior. Chronic administration of corticosterone decreased levels of serum corticosterone in mice. Neither folic acid, nor fluoxetine treatment reversed this impairment. These findings indicate a robust effect of folic acid in reversing behavioral alterations induced by corticosterone model of depression in mice, suggesting that this vitamin may be an alternative approach for the management of depressive symptoms.

Chronic administration of duloxetine and mirtazapine downregulates proapoptotic proteins and upregulates neurotrophin gene expression in the hippocampus and cerebral cortex of mice.

Structural alterations in the limbic system, neuronal cell loss, and low levels of neurotrophins have been implicated in the pathogenesis of depression. While it is generally accepted that increasing monoamine levels in the brain can effectively alleviate depression, the precise neurobiological mechanisms involved are unclear. In the present study, we examined the effects of two antidepressants, duloxetine and mirtazapine, on the expression of apoptotic and neurotrophic proteins in the cerebral cortex and hippocampus of mice. Duloxetine (10 mg/kg) and mirtazapine (3 mg/kg) were chronically administered for 21 days, and qRT-PCR analysis was carried for the following: neurotrophins (BDNF, NGF, FGF-2, and NT-3); anti-apoptotic proteins (Bcl-2 and Bcl-xL) and pro-apoptotic proteins (Bax, Bad, and p53). Both duloxetine and mirtazapine produced antidepressant activity in the forced swimming test and induced increased cortical and hippocampal mRNA expression of BDNF. Duloxetine also increased Bcl-2, Bcl-xL, FGF-2, and NT-3 expression in the cerebral cortex, and FGF-2 expression in the hippocampus. Moreover, duloxetine reduced Bax and p53 expression in the hippocampus, and Bad expression in the cerebral cortex. Mirtazapine decreased Bcl-xL and Bax expression in the hippocampus, and Bad and p53 expression in both the hippocampus and cerebral cortex. Mirtazapine also increased the expression of neurotrophins, NGF and NT-3, in the cerebral cortex. These results suggest that duloxetine and mirtazapine could elicit their therapeutic effect by modulating the activity of apoptotic and neurotrophic pathways, thus enhancing plasticity and cell survival in depressive patients.