Vitamin D and depression in older adults: lessons learned from observational and clinical studies.

Depression is a mental disorder triggered by the interaction of social, psychological and biological factors that have an important impact on an individual's life. Despite being a well-studied disease with several established forms of treatment, its prevalence is increasing, especially among older adults. New forms of treatment and prevention are encouraged, and some researchers have been discussing the effects of vitamin D (VitD) on depression; however, the exact mechanism by which VitD exerts its effects is not yet conclusive. In this study, we aimed to discuss the possible mechanisms underlying the association between VitD and depression in older adults. Therefore, we conducted a systematic search of databases for indexed articles published until 30 April 2021. The primary focus was on both observational studies documenting the association between VitD and depression/depressive symptoms, and clinical trials documenting the effects of VitD supplementation on depression/depressive symptoms, especially in older adults. Based on pre-clinical, clinical and observational studies, it is suggested that the maintenance of adequate VitD concentrations is an important issue, especially in older adults, which are a risk population for both VitD deficiency and depression. Nevertheless, it is necessary to carry out more studies using longitudinal approaches in low- and middle-income countries to develop a strong source of evidence to formulate guidelines and interventions.

SARS-CoV-2 consequences for mental health: Neuroinflammatory pathways linking COVID-19 to anxiety and depression.

The coronavirus disease 2019 (COVID-19) pandemic has been linked to an increased prevalence of mental health disorders, particularly anxiety and depression. Moreover, the COVID-19 pandemic has caused stress in people worldwide due to several factors, including fear of infection; social isolation; difficulty in adapting to new routines; lack of coping methods; high exposure to social media, misinformation, and fake reports; economic impact of the measures implemented to slow the contagion and concerns regarding the disease pathogenesis. COVID-19 patients have elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α, and other inflammation-related factors. Furthermore, invasion of the central nervous system by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may potentially contribute to neuroinflammatory alterations in infected individuals. Neuroinflammation, a consequence of psychological stress due to the COVID-19 pandemic, may also play a role in the development of anxiety and depressive symptoms in the general population. Considering that neuroinflammation plays a significant role in the pathophysiology of depression and anxiety, this study investigated the effects of SARS-CoV-2 on mental health and focused on the impact of the COVID-19 pandemic on the neuroinflammatory pathways.

Involvement of serotonergic neurotransmission in the antidepressant-like effect elicited by cholecalciferol in the chronic unpredictable stress model in mice.

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.

Functional role of ascorbic acid in the central nervous system: a focus on neurogenic and synaptogenic processes.

Ascorbic acid, a water-soluble vitamin, is highly concentrated in the brain and participates in neuronal modulation and regulation of central nervous system (CNS) homeostasis. Ascorbic acid has emerged as a neuroprotective compound against neurotoxicants and neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Moreover, it improves behavioral and biochemical alterations in psychiatric disorders, including schizophrenia, anxiety, major depressive disorder, and bipolar disorder. Some recent studies have advanced the knowledge on the mechanisms associated with the preventive and therapeutic effects of ascorbic acid by showing that they are linked to improved neurogenesis and synaptic plasticity. This review shows that ascorbic acid has the potential to regulate positively stem cell generation and proliferation. Moreover, it improves neuronal differentiation of precursors cells, promotes adult hippocampal neurogenesis, and has synaptogenic effects that are possibly linked to its protective or therapeutic effects in the brain.

Behavioral and neurochemical effects of folic acid in a mouse model of depression induced by TNF-α.

Folic acid has been reported to exert antidepressant effects, but its ability to abrogate the depressive-like behavior and signaling pathways alterations elicited by an inflammatory model of depression remains to be established. This study examined: a) the efficacy of folic acid in a mouse model of depression induced by tumor necrosis factor (TNF-α); b) whether the administration of subthreshold doses of folic acid and antidepressants (fluoxetine, imipramine, and bupropion), MK-801, or 7-nitroindazole cause antidepressant-like effects; c) the effects of TNF-α and/or folic acid on hippocampal p38MAPK, Akt, ERK, and JNK phosphorylation. Folic acid reduced the immobility time in the tail suspension test (TST) in control mice (10-50 mg/kg, p.o) and abolished the depressive-like behavior elicited by TNF-α (0.001 fg/site, i.c.v.) in this test (1-50 mg/kg, p.o). Coadministration of subthreshold doses of folic acid (1 mg/kg, p.o.) and fluoxetine, imipramine, bupropion, MK-801, or 7-nitroindazole produced an antidepressant-like effect in mice exposed or not to TNF-α. TNF-α-treated mice presented increased p38MAPK phosphorylation and decreased Akt phosphorylation, and the later effect was prevented by folic acid (10 mg/kg, p.o.). Additionally, ERK1 phosphorylation was increased in mice treated with TNF-α + folic acid (1 mg/kg), but no effects on ERK2 or JNK1/2/3 phosphorylation were found in any group. The results indicate the efficacy of folic acid to counteract the depressive-like behavior induced by a pro-inflammatory cytokine, an effect that might be associated with the activation of monoaminergic systems, inhibition of N-methyl-d-aspartate (NMDA) receptors and nitric oxide (NO) synthesis, as well as Akt modulation.

Antidepressant-like effect of guanosine involves activation of AMPA receptor and BDNF/TrkB signaling.

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).

mTORC1-dependent signaling pathway underlies the rapid effect of creatine and ketamine in the novelty-suppressed feeding test.

The development of fast-acting antidepressants is crucial considering that conventional antidepressants require a long period to elicit therapeutic effects. Creatine, an ergogenic guanidine-like compound, stands out as a candidate to exert fast antidepressant-like responses. The present study investigated whether a single dose of creatine elicits a fast response in mice submitted to the novelty-suppressed feeding (NSF) test, a paradigm that may assess depression-like and anxiety-like behaviors. Ketamine, an NMDA receptor antagonist that has rapid antidepressant effects, and conventional antidepressants were also tested. The involvement of the mTORC1 signaling pathway in the behavioral responses was also investigated. Biochemical analyses included hippocampal BDNF level (ELISA) and total and phospho-mTORC1 (Ser2448), PSD95 and synapsin immunocontent (Western Blotting). Creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.) reduced the latency to feed in the NSF test. Conversely, fluoxetine (10 mg/kg, p.o.), imipramine (1 mg/kg, p.o.) or bupropion (10 mg/kg, p.o.) did not alter this parameter. The administration of rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the effects of creatine or ketamine in the NSF test. Creatine or ketamine-treated mice presented increased hippocampal BDNF level, an effect abolished by rapamycin. The hippocampal phospho-mTORC1 (Ser2448) immunocontent was increased by creatine, but not by ketamine. However, ketamine, but not creatine, increased PSD95 and synapsin immunocontent. Creatine and ketamine elicit a rapid response in the NSF test by a mechanism dependent on the mTORC1 signaling pathway.

The involvement of PI3K/Akt/mTOR/GSK3ß signaling pathways in the antidepressant-like effect of AZD6765.

AZD6765 (lanicemine) is a non-competitive NMDA receptor antagonist that induces a fast-acting antidepressant effect without presenting psychotomimetic effects. However, the mechanisms underlying its effects remain to be established. In this context, we demonstrated that a single administration of AZD6765 (1 mg/kg, i.p.) was able to induce an antidepressant-like effect in mice submitted to tail suspension test (TST), an effect reversed by LY294002 (a reversible PI3K inhibitor, 10 nmol/site, i.c.v.), wortmannin (an irreversible PI3K inhibitor, 0.1 µg/site, i.c.v.) and rapamycin (a selective mTOR inhibitor, 0.2 nmol/site, i.c.v.). In addition, the administration of sub-effective doses of AZD6765 (0.1 mg/kg, i.p.) in combination with lithium chloride (non-selective GSK-3ß inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3ß inhibitor, (0.01 µg/site, i.c.v.) caused a synergistic antidepressant-like effect. These results suggest the involvement of PI3K/Akt/mTOR/GSK3ß signaling in the AZD6765 antidepressant-like effect. In addition, western blotting analysis showed an increased immunocontent of synapsin in the prefrontal cortex and a tendency to an increased immunocontent of this protein in the hippocampus 30 min after AZD6765 administration, but no significant effect of AZD6765 was observed in P70S6K (Thr389) phosphorylation and GluA1 immunocontent. A single dose of AZD6765 (3 mg/kg, i.p.), similarly to ketamine (1 mg/kg, i.p.), decreased the latency to feed in the novelty suppressed feeding (NSF) test, a behavioral paradigm that evaluates depression/anxiety-related behavior. This effect was reversed by rapamycin administration, suggesting the activation of mTOR signaling in the effect of AZD in the NSF test. In addition, a single administration of AZD6765 (1 mg/kg, i.p.) or ketamine (1 mg/kg, i.p.) reversed the depressive-like behavior induced by chronic unpredictable stress (CUS). Altogether, the results provide evidence for the fast-acting antidepressant profile of AZD6765, by a mechanism likely dependent on PI3K/Akt/mTOR/GSK3ß.

The involvement of GABAergic system in the antidepressant-like effect of agmatine.

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 GABAA and GABAB receptors in the antidepressant-like effect of agmatine. The administration of muscimol (0.1 mg/kg, i.p., GABAA receptor agonist) or diazepam (0.05 mg/kg, p.o., GABAA 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., GABAB 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 GABAA receptors dependent on NMDA receptor inhibition, similar to ketamine, as well as modulation of GABAB receptors.

Ascorbic acid presents rapid behavioral and hippocampal synaptic plasticity effects.

Growing evidence has suggested that ascorbic acid may exhibit rapid anxiolytic and antidepressant-like effects. In this study the effects of a single administration of ascorbic acid (1 mg/kg, p.o.), ketamine (1 mg/kg, i.p., a fast-acting antidepressant) and fluoxetine (10 mg/kg, p.o., conventional antidepressant) were investigated on: a) behavioral performance in the novelty suppressed feeding (NSF) test; b) hippocampal synaptic protein immunocontent; c) dendritic spine density and morphology in the dorsal and ventral dentate gyrus (DG) of the hippocampus and d) hippocampal dendritic arborization. Ascorbic acid or ketamine, but not fluoxetine, decreased the latency to feed in the NSF test in mice. This effect was accompanied by increased p70S6K (Thr389) phosphorylation 1 h after ascorbic acid or ketamine treatment, although only ascorbic acid increased synapsin I immunocontent. Ketamine administration increased the dendritic spine density in the dorsal DG, but none of the treatments affected the maturation of dendritic spines in this region. In addition, both ascorbic acid and ketamine increased the dendritic spine density in the ventral DG, particularly the mature spines. Sholl analysis demonstrated no effect of any treatment on hippocampal dendritic arborization. Altogether, the results provide evidence that the behavioral and synaptic responses observed following ascorbic acid administration might occur via the upregulation of synaptic proteins, dendritic spine density, and maturation in the ventral DG, similar to ketamine. These findings contribute to understand the cellular targets implicated in its antidepressant/anxiolytic behavioral responses and support the notion that ascorbic acid may share with ketamine the ability to increase synaptic function.

Effects of cholecalciferol on behavior and production of reactive oxygen species in female mice subjected to corticosterone-induced model of depression.

Major depressive disorder (or depression) is one of the most frequent psychiatric illnesses in the population, with chronic stress being one of the main etiological factors. Studies have shown that cholecalciferol supplementation can lead to attenuation of the depressive state; however, the biochemical mechanisms involved in the relationship between cholecalciferol and depression are not very well known. The objective of this study was to investigate the effects of the administration of cholecalciferol on behavioral parameters (tail suspension test (TST), open field test (OFT), splash test (ST)) and redox state (dichlorofluorescein (DCF)) in adult female Swiss mice subjected to a model of depression induced by chronic corticosterone treatment. Corticosterone (20 mg/kg, p.o.) was administered once a day for 21 days. For investigation of the antidepressant-like effect, cholecalciferol (100 IU/kg) or fluoxetine (10 mg/kg, positive control) was administered p.o. within the last 7 days of corticosterone administration. After the treatments, the behavioral tests and biochemical analyses in the hippocampus and prefrontal cortex of the rodent samples were performed. Animals submitted to repeated corticosterone administration showed a depressive-like behavior, evidenced by a significant increase in the immobility time in the TST, which was significantly reduced by the administration of cholecalciferol or fluoxetine. In addition, the groups treated with cholecalciferol and fluoxetine showed a significant decrease in the production of reactive oxygen species (ROS) in the hippocampus. These results show that cholecalciferol, similar to fluoxetine, has a potential antidepressant-like effect, which may be related to the lower ROS production.

The antidepressant-like effect of guanosine is dependent on GSK-3ß inhibition and activation of MAPK/ERK and Nrf2/heme oxygenase-1 signaling pathways.

Although guanosine is an endogenous nucleoside that displays antidepressant-like properties in several animal models, the mechanism underlying its antidepressant-like effects is not well characterized. The present study aimed at investigating the involvement of ERK/GSK-3ß and Nrf2/HO-1 signaling pathways in the antidepressant-like effect of guanosine in the mouse tail suspension test (TST). The immobility time in the TST was taken as an indicative of antidepressant-like responses and the locomotor activity was assessed in the open-field test. Biochemical analyses were performed by Western blotting in the hippocampus and prefrontal cortex (PFC). The combined treatment with sub-effective doses of guanosine (0.01 mg/kg, p.o.) and lithium chloride (a non-selective GSK-3ß inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3ß inhibitor, 0.01 µg/site, i.c.v.) produced a synergistic antidepressant-like effect in the TST. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) was completely prevented by the treatment with MEK1/2 inhibitors U0126 (5 µg/site, i.c.v.), PD98059 (5 µg/site, i.c.v.), or zinc protoporphyrin IX (ZnPP) (HO-1 inhibitor, 10 µg/site, i.c.v). Guanosine administration (0.05 mg/kg, p.o.) increased the immunocontent of ß-catenin in the nuclear fraction and Nrf2 in the cytosolic fraction in the hippocampus and PFC. The immunocontent of HO-1 was also increased in the hippocampus and PFC. Altogether, the results provide evidence that the antidepressant-like effect of guanosine in the TST involves the inhibition of GSK-3ß, as well as activation of MAPK/ERK and Nrf2/HO-1 signaling pathways, highlighting the relevance of these molecular targets for antidepressant responses.

A single coadministration of subeffective doses of ascorbic acid and ketamine reverses the depressive-like behavior induced by chronic unpredictable stress in mice.

In this study, we investigated the ability of a single coadministration of subeffective doses of ascorbic acid and ketamine to reverse the depressive-like behavior induced by chronic unpredictable stress (CUS) in mice. Moreover, we examined the effect of combined administration of ascorbic acid and ketamine on hippocampal phosphorylation of p70S6K and immunocontents of GLUA1 and PSD-95 in mice submitted to the CUS procedure. CUS procedure was applied for 21 days. Animals received a single coadministration of subeffective doses of ascorbic acid (0.1 mg/kg) and ketamine (0.1 mg/kg) and were subjected to behavioral evaluation 24 h after the treatments. Immediately after the behavioral observations the hippocampi were dissected for Western blotting analyses. Our results revealed that a single administration of subeffective doses of ascorbic acid and ketamine completely reversed the depressive-like behavior induced by CUS, however, this effect was not accompanied by changes in the phosphorylation of p70S6K and immunocontent of GLUA1 or PSD95 in the hippocampus. These findings point to a synergistic antidepressant-like effect of ascorbic acid and ketamine, paving the way for additional studies on the combined use of these compounds for the management of major depressive disorder (MDD).

Augmentation effect of ketamine by guanosine in the novelty-suppressed feeding test is dependent on mTOR signaling pathway.

The ketamine's potential for the treatment of refractory depression and anxiety has been considered one the most important discoveries in the last years, however, repeated use of ketamine is limited due to its side/adverse effects. Therefore, the search for effective augmentation strategies that may reduce ketamine doses is welcome. Therefore, this study sought to augment the effect of ketamine by guanosine in the novelty-suppressed feeding (NSF) test, a behavioral paradigm able to detect depression/anxiety-related behavior. Acute administration of guanosine (0.05 mg/kg, p.o.), similar to ketamine (1 mg/kg, i.p.), produced a rapid behavioral response in mice submitted to NSF test. Moreover, the coadministration of sub-effective doses of guanosine (0.01 mg/kg, p.o.) and ketamine (0.1 mg/kg, i.p.) was effective in mice submitted to NSF test. Subsequently, the intracellular mechanism underpinning the augmentation effect of ketamine by guanosine was investigated. Our results suggest that augmentation response of ketamine by guanosine in the NSF test probably involves the activation of mTOR signaling, since the treatment with rapamycin (0.2 nmol/site, i.c.v., a selective mTOR inhibitor) completely abolished this effect. This augmentation strategy also increased mTOR phosphorylation (Ser2448) in the hippocampus, reinforcing the role of mTOR in this augmentation response. However, no changes in the p70S6K, PSD-95, GluA1, and synapsin immunocontents were found in the hippocampus of ketamine plus guanosine-treated mice. Overall, results provide evidence that guanosine is able to augment the effect of ketamine in the NSF test via mTOR activation, a finding that might have therapeutic implications for the management of depression/anxiety.

Prophylactic effect of physical exercise on Aß1-40-induced depressive-like behavior: Role of BDNF, mTOR signaling, cell proliferation and survival in the hippocampus.

Alzheimer's disease (AD) is characterized by progressive cognitive impairments as well as non-cognitive symptoms such as depressed mood. Physical exercise has been proposed as a preventive strategy against AD and depression, an effect that may be related, at least partially, to its ability to prevent impairments on cell proliferation and neuronal survival in the hippocampus, a structure implicated in both cognition and affective behavior. Here, we investigated the ability of treadmill exercise (4 weeks) to counteract amyloid ß1-40 peptide-induced depressive-like and anxiety-like behavior in mice. Moreover, we addressed the role of the BDNF/mTOR intracellular signaling pathway as well as hippocampal cell proliferation and survival in the effects of physical exercise and/or Aß1-40. Aß1-40 administration (400 pmol/mouse, i.c.v.) increased immobility time and reduced the latency to immobility in the forced swim test, a finding indicative of depressive-like behavior. In addition, Aß1-40 administration also decreased time spent in the center of the open field and increased grooming and defecation, alterations indicative of anxiety-like behavior. These behavioral alterations were accompanied by a reduction in the levels of mature BDNF and mTOR (Ser2448) phosphorylation in the hippocampus. In addition, Aß1-40 administration reduced cell proliferation and survival in the ventral, dorsal and entire dentate gyrus of the hippocampus. Importantly, most of these behavioral, neurochemical and structural impairments induced by Aß1-40 were not observed in mice subjected to 4 weeks of treadmill exercise. These findings indicate that physical exercise has the potential to prevent the occurrence of early emotional disturbances associated with AD and this appears to be mediated, at least in part, by modulation of hippocampal BDNF and mTOR signaling as well as through promotion of cell proliferation and survival in the hippocampal DG.

Single administration of agmatine reverses the depressive-like behavior induced by corticosterone in mice: Comparison with ketamine and fluoxetine.

Agmatine is a neuromodulator that has been proposed as a therapeutic strategy for the treatment of major depressive disorder (MDD). A previous study reported that agmatine caused a fast-acting effect in mice subjected to chronic mild stress without causing changes in the levels of synaptic proteins in the prefrontal cortex. We examined whether a single administration of agmatine is able to counteract the depressive-like behavior induced by chronic administration of corticosterone, a pharmacological model of stress, paralleled with the modulation of synaptic protein levels in the prefrontal cortex and hippocampus. Female mice received corticosterone (20 mg/kg, p.o.) for 21 days and, in the last day of treatment, were administered with a single dose of agmatine (0.1 mg/kg, p.o.), fluoxetine (10 mg/kg, p.o.; control for a conventional antidepressant) or ketamine (1 mg/kg, i.p.; control for a fast-acting antidepressant). Agmatine, similar to ketamine, reversed the depressive-like behavior induced by corticosterone in the tail suspension test (TST), an effect that was not observed in mice treated with fluoxetine. The immunocontent of GluA1 was increased by all the treatments in the hippocampus of control mice, whereas PSD95 was not significantly altered by treatments in any brain structure. Although the levels of synaptic proteins do not seem to account for the behavioral findings reported here, the present study provides clear evidence for the fast-acting antidepressant profile of agmatine in the TST, similar to ketamine.

Involvement of Heme Oxygenase-1 in Neuropsychiatric and Neurodegenerative Diseases.

Heme oxygenase (HO) family catalyzes the conversion of heme into free iron, carbon monoxide and biliverdin. It possesses two well-characterized isoforms: HO-1 and HO-2. Under brain physiological conditions, the expression of HO-2 is constitutive, abundant and ubiquitous, whereas HO-1 mRNA and protein are restricted to small populations of neurons and neuroglia. HO-1 is an inducible enzyme that has been shown to participate as an essential defensive mechanism for neurons exposed to oxidant challenges, being related to antioxidant defenses in certain neuropathological conditions. Considering that neurodegenerative diseases (Alzheimer's Disease (AD), Parkinson's Disease (PD) and Multiple Sclerosis (MS)) and neuropsychiatric disorders (depression, anxiety, Bipolar Disorder (BD) and schizophrenia) are associated with increased inflammatory markers, impaired redox homeostasis and oxidative stress, conditions that may be associated with alterations in HO-levels/activity, the purpose of this review is to present evidence on the possible role of HO-1 in these Central Nervous System (CNS) diseases. In addition, the possible therapeutic potential of targeting brain HO-1 is explored in this review.

The Gender-Biased Effects of Intranasal MPTP Administration on Anhedonic- and Depressive-Like Behaviors in C57BL/6 Mice: the Role of Neurotrophic Factors.

Depression is a highly prevalent and debilitating non-motor symptom observed during the early stages of Parkinson's disease (PD). Although PD prevalence is higher in men, the depressive symptoms in PD are more common in women. Therefore, the aim of this study was to investigate the development of anhedonic- and depressive-like behaviors in male and female mice and the potential mechanisms related to depressive symptoms in an experimental model of PD. Young adult male and female C57BL/6 mice (3 months old) received a single intranasal (i.n.) administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and were submitted to a battery of behavioral tasks (sucrose consumption, splash test, tail suspension, forced swimming and open field tests) to assess their emotional and motor profiles. Considering the role of sexual hormones in emotional behaviors, the same protocol of i.n. MPTP administration and the splash, tail suspension, and open field tests were conducted in ovariectomized (OVX) and aged C57BL/6 female (20 months old) mice. We also investigated the immunocontent of neurotrophins (BDNF, GDNF, and VEGF) in the hippocampus and prefrontal cortex by western blot. I.n.  MPTP administration induced more pronounced anhedonic- and selective depressive-like behaviors in female adult mice, also observed in OVX and aged female mice, with the absence of motor impairments. Furthermore, MPTP induced a more pronounced depletion of neurotrophins in the prefrontal cortex and hippocampus in female than male mice. This study provides new evidence of increased susceptibility of female mice to anhedonic- and depressive-like behaviors following i.n. MPTP administration. The observed gender-related effects of MPTP on emotional parameters seem to be linked to increased depletion of neurotrophins (particularly BDNF and GDNF) in the hippocampus and prefrontal cortex of female mice.

Anxiolytic effects of ascorbic acid and ketamine in mice.

Some studies have demonstrated that ascorbic acid, similarly to ketamine, exhibits antidepressant-like effects mediated, at least in part, by modulation of the glutamatergic system. Despite the involvement of glutamatergic system in the pathophysiology of anxiety disorders, the ability of ascorbic acid and ketamine to elicit anxiolytic effects in animal models remains to be established. Therefore, this study investigated the effects of a single administration of ascorbic acid, ketamine or diazepam (positive control) in different animal models of anxiety. Mice were treated with ascorbic acid (1, 3 and 10 mg∕kg, p.o.), ketamine (1 and 10 mg∕kg, i.p.) or diazepam (2 mg∕kg, p.o) and their behavioral responses were assessed in the elevated plus maze, open field test (OFT), ligh∕dark preference test and marble burying test. Ascorbic acid increased total time spent in the open arms of elevated plus maze, increased total time in the center of the OFT, decreased rearing responses, increased the latency to grooming, decreased the rostral grooming, but did not affect body grooming. Furthermore, ascorbic acid increased the latency time and total time in light area in the ligh∕dark preference test, but did not affect the performance of mice in the marble burying test. Ketamine demonstrated an anxiolytic-like effect in elevated plus maze, OFT, and ligh∕dark preference test. Diazepam exhibited an anxiolytic-like effect in all the behavioral tests. Altogether, the results indicate the potential anxiolytic effect of ascorbic acid and ketamine, providing a possible new avenue for the management of anxiety-related disorders.

Evidence for the involvement of opioid system in the antidepressant-like effect of ascorbic acid.

Considering the involvement of the opioid system in major depressive disorder (MDD), mainly concerning refractory MDD, and the evidence that ascorbic acid may exert a beneficial effect for the treatment of this disorder, this study investigated the involvement of the opioid system in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST). Treatment of Swiss mice with the non-selective opioid receptor antagonist naloxone (1 mg/kg, i.p.) prevented the reduced immobility time caused by ascorbic acid (1 mg/kg, p.o.) in the TST. Additionally, administration of the selective µ1-opioid receptor antagonist, naloxonazine (10 mg/kg, i.p.), also abolished the antidepressant-like action of the same dose of ascorbic acid in the TST. We also investigated the possible relationship between the opioid system and NMDA receptors in the mechanism of action of ascorbic acid or ketamine (0.1 mg/kg, i.p.) in the TST. Treatment of mice with naloxone (1 mg/kg, i.p.) blocked the synergistic antidepressant-like effect of ascorbic acid (0.1 mg/kg. p.o.) and MK-801 (0.001 mg/kg, p.o., a non-competitive NMDA receptor antagonist) in the TST. Combined administration of ketamine and MK-801 induced a synergistic antidepressant-like action, and naloxone partially abolished this effect. Our results indicate that the antidepressant-like effect of ascorbic acid in the TST appears to be dependent on the activation of the opioid system, especially µ1-opioid receptors, which might be an indirect consequence of NMDA receptor inhibition elicited by ascorbic acid administration.