Patient experience and satisfaction with different temporomandibular joint treatments: A retrospective study.

This retrospective study aimed to evaluate patient satisfaction with different temporomandibular joint (TMJ) treatments. Patients were included in the study according to the following inclusion criteria: 1) arthrogenous and/or myogenous temporomandibular disorders (TMD); 2) Dimitroulis classification category between 1-4; 3) conservative treatment without any improvement at least for 3 months; 4) indication for one of the following TMD treatments: injection of botulinum toxin; arthrocentesis; arthroscopy, and open surgery without alloplastic material; and 5) age ≥16 years. An independent satisfaction questionnaire with 11 queries was applied via phone call to all patients, which included 6 questions using a 10-point Likert scale and 5 yes-or-no questions. The principal outcome was the overall satisfaction with the clinical result of the treatment, and the secondary outcomes were specific satisfaction with the following: 1) pain reduction; 2) range of mouth opening; 3) chewing ability; 4) postoperative recovery; 5) the fulfillment of expectations; 6) treatment choice; 7) treatment recommendation to a friend; and 8) the need for another intervention. Anxiety and depression were also included as variables. Data were analyzed using descriptive statistics, non-parametric Kruskal-Wallis and Spearman rank correlation coefficient tests. A total of 120 patients (mean age 41.20 ± 17.78 years) were enrolled, comprising 109 women (90%) and 11 men (10%). The overall clinical satisfaction of all patients was 8.24 ± 2.23 (mean ± SD), and 97 patients (80.8%) stated that they would repeat the treatment. Patients submitted to TMJ arthrocentesis and arthroscopy had higher overall clinical satisfaction (9.09 ± 0.971 and 9.03 ± 1.13, p = 0.021) followed by open surgery (8.38 ± 1.84). The authors observed three statistically significant correlations: 1) overall clinical satisfaction and patient expectations (r = 0.803; p < 0.0001); 2) overall clinical satisfaction and post-treatment pain (r = -0.299; p = 0.003); and (3) the presence of depression and the need for further TMJ treatment (r = 0.186; p = 0.043). Within the limitations of the study it seems that patient expectations should be addressed ad initium, and the presence of a diagnosis of depression with concomitant TMD must alert the clinical team and patient for the possible need of additional treatment.

Impact of the Nutritional Status on Clinical Outcomes of Patients with Coronavirus Disease Undergoing Cancer Treatment.

Coronavirus disease (COVID-19) is a critical and potentially fatal condition. The nutritional status affects the evolution and clinical outcome throughout the disease course among factors influencing the patient prognosis. In patients with cancer, the Patient-Generated Subjective Global Assessment (PG-SGA) is the preferred instrument for assessing the nutritional status. The aim of this retrospective cross-sectional study was to evaluate the impact of the nutritional status on the clinical outcome of patients with COVID-19 undergoing cancer treatment. We enrolled 52 patients with cancer under outpatient follow-up who had been diagnosed with COVID-19 during the cancer treatment course. The PG-SGA instrument revealed age (p = 0.045) and nutritional status (p = 0.042) before infection as the main risk factors of death from COVID-19. In addition, the risk of mortality due to COVID-19 increased with the degree of malnutrition. Twelve (23.1%) of the 52 patients showed no negative effects related to COVID-19, and age below 65 years was considered to be a protective factor.

The antidepressant-like effect of guanosine involves the modulation of adenosine A1 and A2A receptors.

Guanosine has been considered a promising candidate for antidepressant responses, but if this nucleoside could modulate adenosine A1 (A1R) and A2A (A2AR) receptors to exert antidepressant-like actions remains to be elucidated. This study investigated the role of A1R and A2AR in the antidepressant-like response of guanosine in the mouse tail suspension test and molecular interactions between guanosine and A1R and A2AR by docking analysis. The acute (60 min) administration of guanosine (0.05 mg/kg, p.o.) significantly decreased the immobility time in the tail suspension test, without affecting the locomotor performance in the open-field test, suggesting an antidepressant-like effect. This behavioral response was paralleled with increased A1R and reduced A2AR immunocontent in the hippocampus, but not in the prefrontal cortex, of mice. Guanosine-mediated antidepressant-like effect was not altered by the pretreatment with caffeine (3 mg/kg, i.p., a non-selective adenosine A1R/A2AR antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX - 2 mg/kg, i.p., a selective adenosine A1R antagonist), or 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)-phenol (ZM241385 - 1 mg/kg, i.p., a selective adenosine A2AR antagonist). However, the antidepressant-like response of guanosine was completely abolished by adenosine (0.5 mg/kg, i.p., a non-selective adenosine A1R/A2AR agonist), N-6-cyclohexyladenosine (CHA - 0.05 mg/kg, i.p., a selective adenosine A1 receptor agonist), and N-6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine (DPMA - 0.1 mg/kg, i.p., a selective adenosine A2A receptor agonist). Finally, docking analysis also indicated that guanosine might interact with A1R and A2AR at the adenosine binding site. Overall, this study reinforces the antidepressant-like of guanosine and unveils a previously unexplored modulation of the modulation of A1R and A2AR in its antidepressant-like effect.

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.

Vitamin E for the management of major depressive disorder: possible role of the anti-inflammatory and antioxidant systems.

OBJECTIVES: Vitamin E has various functions in humans, including antioxidant, anti-inflammatory, anti-cancer, and anti-atherogenic actions, as well as direct effects on enzymatic activities and modulation of gene transcription. In addition to these functions, vitamin E is also important for the central nervous system, and its role in the prevention and/or treatment of some neurological diseases has been suggested. In particular, the role of vitamin E in the modulation of major depressive disorder (MDD) is an issue that has emerged in recent studies. Many factors have been implicated in the pathophysiology of this disorder, including inflammation, oxidative, and nitrosative stress. METHODS: This narrative review discusses the involvement of inflammation, oxidative, and nitrosative stress in the pathophysiology of MDD and presents clinical and preclinical studies that correlate vitamin E with this psychiatric disorder. RESULTS: We gathered evidence from clinical studies that demonstrated the relationship between low vitamin E status and MDD symptoms. Vitamin E has been reported to exert a beneficial influence on the oxidative and inflammatory status of individuals, factors that may account for the attenuation of depressive symptoms. Preclinical studies have reinforced the antidepressant-like response of vitamin E, and the mechanisms underlying its effect seem to be related to the modulation of oxidative stress and neuroinflammation. CONCLUSION: We suggest that vitamin E has potential to be used as an adjuvant for the management of MDD, but more studies are clearly needed to ascertain the efficacy of vitamin E for alleviating depressive symptoms.

The resilient phenotype elicited by ketamine against inflammatory stressors-induced depressive-like behavior is associated with NLRP3-driven signaling pathway.

Ketamine has emerged as a prophylactic agent against depressive-like behavior induced by stress. However, the possible pro-resilience effects of ketamine against inflammatory stressors-induced depressive-like behavior and the signaling pathways associated with this response remain to be determined. Therefore, this study investigated the ability of prophylactic ketamine administration to produce a pro-resilience effect against the depressive-like behavior induced by lipopolysaccharide (LPS - 0.83 mg/kg, i.p.) and tumor necrosis factor-alpha (TNF-α - 0.1 fg/site, i.c.v.) administration in mice. The possible contribution of the NLRP3 inflammasome-driven signaling pathway to this effect was evaluated in the ventral hippocampus. A single administration of ketamine (5 mg/kg, i.p.) given 1 week before the LPS or TNF-α administration prevented the depressive-like behavior induced by these inflammatory stressors in the tail suspension test (TST) and splash test (SPT). On the other hand, a lower dose of ketamine (1 mg/kg, i.p.) failed to produce a similar effect. The administration of LPS, but not TNF-α, increased the immunocontent of the microglial marker Iba-1 in the ventral hippocampus. LPS increased the immunocontent of all proteins related to NLRP3 signaling, namely ASC, NLRP3, TXNIP, cleaved caspase-1, and IL-1ß in this brain region, while TNF-α only increased ASC and NLRP3 immunocontent. Ketamine administered at the dose of 5 mg/kg, but not at 1 mg/kg, prevented the increase on the immunocontent of NLRP3 inflammasome complex components and regulators induced by LPS or TNF-α administration. Collectively, these findings suggest that ketamine elicits a pro-resilient phenotype against inflammatory stressors-induced depressive-like behavior, an effect associated with the suppression of the NLRP3 inflammasome-driven signaling pathway.

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.

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.

Agmatine potentiates antidepressant and synaptic actions of ketamine: Effects on dendritic arbors and spines architecture and Akt/S6 kinase signaling.

We investigated the ability of agmatine to potentiate the antidepressant-like and synaptic effects of ketamine in mice. Agmatine (0.1 and 1 mg/kg, p.o.) and ketamine (1 and 10 mg/kg, i.p.) produced an antidepressant-like effect in the tail suspension test. The combination of agmatine (0.01 mg/kg, p.o.) and ketamine (0.1 mg/kg, i.p.), at subthreshold doses, produced an antidepressant-like effect 1 h, 24 h and 7d after treatment. Western blot analysis from prefrontal cortex tissue showed that the combined treatment, after 1 h, increased p70S6K and GluA1, and reduced synapsin 1 phosphorylation. Additionally, after 24 h, Akt, p70S6K, GluA1, and synapsin 1 phosphorylation; and PSD95 immunocontent increased (which persisted for up to 7d). Dendritic architecture analysis of the prefrontal cortex revealed that the combined treatment improved dendritic arbor complexity (after 24 h, up to 7d), and increased spine density (after 1 h, up to 24 h). Morphometric analysis revealed a filopodia-shaped dendrite spine upregulation after 1 h. A predominance of stubby, mushroom, branched and filopodia; and a reduction in thin protrusions were observed after 24 h. Finally, mushroom-shaped dendritic spines predominance increased after 7d. Agmatine potentiated ketamine's antidepressant, and dendritic arbors and spines remodeling effects in a time-dependent manner. Our data indicate Akt/p70S6K signaling as a likely target for these effects.

Multiple cellular targets involved in the antidepressant-like effect of glutathione.

A previous study demonstrated that glutathione (GSH) produces specific antidepressant-like effect in the forced swimming test (FST), a predictive test of antidepressant activity. The present study investigated the involvement of multiple cellular targets implicated in the antidepressant-like effect of GSH in the FST. The antidepressant-like effect of GSH (300 nmol/site, icv) lasted up to 3 h when mice were submitted to FST. The central administration of oxidized GSH (GSSG, 3-300 nmol/site) did not alter the behavior of mice submitted to the FST. Furthermore, the combined treatment of sub-effective doses of GSH (100 nmol/site, icv) with a sub-effective dose of classical antidepressants (fluoxetine 10 mg/kg, and imipramine 5 mg/kg, ip) presented synergistic effect by decreasing the immobility time in the FST. The antidepressant-like effect of GSH was abolished by prazosin (1 mg/kg, ip, α1-adrenoceptor antagonist), baclofen (1 mg/kg, ip, GABAB receptor agonist), bicuculline (1 mg/kg, ip, GABAA receptor antagonist), l-arginine (750 mg/kg, ip, NO precursor), SNAP (25 µg/site, icv, NO donor), but not by yohimbine (1 mg/kg, ip, α2-adrenoceptor antagonist). The NMDA receptor antagonists, MK-801(0.001 mg/kg, ip) or GMP (0.5 mg/kg, ip), potentiated the effect of a sub-effective dose of GSH in the FST. These results suggest that the antidepressant-like effect induced by GSH is connected to the activation of α1 adrenergic and GABAA receptors, as well as the inhibition of GABAB and NMDA receptors and NO biosyntesis. We speculate that redox-mediated signaling on the extracelular portion of cell membrane receptors would be a common mechanism of action of GSH.

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.

Homeless population: characterization and contextualization by census research / Población en situación de calle: caracterización y contextualización por investigación censal / Pessoas em situação de rua: caracterização e contextualização por pesquisa censitária

ABSTRACT Objectives: to analyze characteristics of homeless people and factors associated with living on the streets. Methods: a census-type sectional survey carried out between 2015 and 2018, in the municipality of Maringá-Paraná. A total of 701 homeless answered a structured questionnaire with sociodemographic data, living conditions, and drug use. We used Pearson's correlation test for the association analysis of the variables at a 95% confidence level. Results: men (90.7%) the average age of 37.7 years had been homeless for an average of 5.39 years. Most had little education (54.2%), and homelessness was due to drug use (47.2%) and family disagreements (38.9%). Conclusions: drug use and family disagreements were the main reasons for homelessness. Time on the street, gender, and drugs were associated with a negative correlation to be homeless; and age, mean daily income, the number of daily meals, having been in prison, and having an income source were associated with positive correlation.

RESUMEN Objetivos: analizar las características de las personas en situación de calle y factores asociados a la vida en las calles. Métodos: investigación seccional del tipo censal, realizada entre 2015 y 2018, en el municipio de Maringá-Paraná. Un total de 701 personas en situación de calle ha respondido a un cuestionario estructurado con datos sociodemográficos y condiciones de vida y uso de drogas. El test de correlación de Pearson ha sido utilizado para el análisis de asociación de las variables con nivel de confianza de 95%. Resultados: hombres (90,7%), con edad media de 37,7 años, estaban en situación de calle hace 5,39 años. La mayoría tenía escasa escolaridad (54,2%), y la situación de calle se debía al uso de drogas (47,2%) y a los desentendimientos familiares (38,9%). Conclusiones: el uso de drogas y los desentendimientos familiares han sido los principales motivos para la situación de calle. El tiempo en la calle, sexo y drogas han sido asociados a una correlación negativa para la situación de calle; y edad, renta media diaria, número de comidas diarias, tener sido preso y tener una fuente de renta han sido asociados a la correlación positiva.

RESUMO Objetivos: analisar características das pessoas em situação de rua e fatores associados à vida nas ruas. Métodos: pesquisa seccional do tipo censitário, realizada entre 2015 e 2018, no município de Maringá-Paraná. Um total de 701 pessoas em situação de rua respondeu a um questionário estruturado com dados sociodemográficos e condições de vida e uso de drogas. O teste de correlação de Pearson foi utilizado para a análise de associação das variáveis com nível de confiança de 95%. Resultados: homens (90,7%), com idade média de 37,7 anos, estavam em situação de rua há 5,39 anos. A maioria possuía pouca escolaridade (54,2%), e a situação de rua se devia ao uso de drogas (47,2%) e a desentendimentos familiares (38,9%). Conclusões: o uso de drogas e os desentendimentos familiares foram os principais motivos para a situação de rua. O tempo na rua, sexo e drogas foram associados a uma correlação negativa para a situação de rua; e idade, renda média diária, número de refeições diárias, ter sido preso e ter uma fonte de renda foram associados a correlação positiva.

Involvement of PI3K/Akt/GSK-3ß signaling pathway in the antidepressant-like and neuroprotective effects of Morus nigra and its major phenolic, syringic acid.

Depression is a common neuropsychiatric disorder whose pathophysiology has been associated with glutamatergic excitotoxicity. Thus, the research for new antidepressant strategies with the ability to mitigate glutamate toxicity has received growing attention. Given this background, the present study sought to investigate the antidepressant-like and neuroprotective effects of Morus nigra (MN) and its major phenolic, syringic acid (SA), against glutamate-induced damage, as well as, the role of the PI3K/Akt/GSK-3ß signaling pathway in these effects. Treatment with MN (3 mg/kg) and SA (1 mg/kg) for 7 days, similar to fluoxetine (10 mg/kg), triggered an antidepressant-like effect. Moreover, the treatments evoked neuroprotection against glutamatergic excitotoxicity in hippocampal slices, and MN treatment also afforded protection in cerebrocortical slices. Notably, ex vivo neuroprotective effect of MN and SA was mediated, at least in part, by PI3K/Akt/GSK-3ß signaling pathway. Furthermore, the ability of MN and SA to counteract the glutamate-induced damage were evaluated in three different in vitro experiments. The hippocampal slices pretreated with MN (0.05 and 0.1 µg/mL) or SA (0.01-0.1 µg/mL) as well as the concomitant treatment with MN (0.01 and 0.05 µg/mL) or SA (0.05 and 0.1 µg/mL) exhibited protection against glutamate toxicity. Interestingly, post-treatment with MN in all doses (0.01-0.1 µg/mL) and SA at dose of 0.1 µg/mL were capable of preventing glutamate-induced cell death. In vitro neuroprotective effect of SA, but not MN, involves the activation of Akt, since the pretreatment with LY294002 completely abolished the protective effect. Overall, MN and SA presented antidepressant-like and neuroprotective effects against glutamatergic excitotoxicity via PI3K/Akt/GSK-3ß.

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.

Antidepressant effects of creatine on amyloid ß1-40-treated mice: The role of GSK-3ß/Nrf2 pathway.

Alzheimer's disease (AD) is characterized by progressive synaptic dysfunction and neuronal lost in specific brain areas including hippocampus, resulting in memory/learning deficits and cognitive impairments. In addition, non-cognitive symptoms are reported in AD patients, such as anxiety, apathy and depressed mood. The current antidepressant drugs present reduced efficacy to improve depressive symptoms in AD patients. Here, we investigated the ability of creatine, a compound with neuroprotective and antidepressant properties, to counteract amyloid ß1-40 peptide-induced depressive-like behavior in mice. Moreover, we addressed the participation of the intracellular signaling pathway mediated by glycogen synthase kinase-3ß (GSK-3ß)/nuclear factor erythroid-2-related factor 2 (Nrf2) in the creatine effects. Aß1-40 administration (400 pmol/mouse, i.c.v.) increased the immobility time in the tail suspension test and decreased the grooming time and increased latency to grooming in the splash test, indicative of depressive-like behavior. These impairments were attenuated by creatine (0.01 and 10 mg/kg, p.o.) and fluoxetine (10 mg/kg, p.o., positive control). No significant alterations on locomotor performance were observed in the open field. Aß1-40 administration did not alter hippocampal phospho-GSK-3ß (Ser9)/total GSK-3ß, total GSK-3ß and heme oxygenase-1 (HO-1) immunocontents. However, Aß1-40-infused mice treated with creatine (0.01 mg/kg) presented increased phosphorylation of GSK-3ß(Ser9) and HO-1 immunocontent in the hippocampus. Fluoxetine per se increased GSK-3ß(Ser9) phosphorylation, but did not alter HO-1 levels. In addition, Aß1-40 administration increased hippocampal glutathione (GSH) levels as well as glutathione reductase (GR) and thioredoxin reductase (TrxR) activities, and these effects were abolished by creatine and fluoxetine. This study provides the first evidence of the antidepressive-like effects of creatine in Aß1-40-treated mice, which were accompanied by hippocampal inhibition of GSK-3ß and modulation of antioxidant defenses. These findings indicate the potential of creatine for the treatment of depression associated with AD.

Depression and peripheral inflammatory profile of patients with obesity.

This narrative review will present and discuss clinical data from 16 cross-sectional and 6 longitudinal studies examining the relationship between body mass index (BMI), symptoms of depression and peripheral inflammation. Our aim is to determine which of obesity and depression contributes best to the peripheral low-grade inflammation frequently associated to both conditions. Studies including a complete evaluation of inflammatory markers are scarce and high levels of interleukin-6 (IL-6) and C-reactive protein (CRP) are the most consistent findings associated with obesity and symptoms of depression. Among the cross-sectional studies, seven studies, including a total of 9421 individuals, pointed to BMI as the major factor associated with systemic low-grade inflammation. However, in four studies, including 16,837 individuals, CRP levels remained associated with the symptoms of depression even after correction for BMI, suggestion that in the absence of overweight or obesity other sources of peripheral inflammation might contribute to presence of depressive symptoms. Additionally, another five studies, including 5569 individuals failed to find an association between depression and peripheral inflammation, reinforcing the heterogeneity of this condition. In the longitudinal data, changes in BMI were associated with a reduction in depressive scores at follow-up, after bariatric surgery or after diet. In four longitudinal studies, high levels of CRP were found to be associated with depression even after adjustment for BMI and weight loss, further corroborating the idea that other sources of peripheral inflammation might contribute to depressive symptoms. Thus it seems that both obesity and depressive symptoms can contribute to peripheral inflammation, and once installed the presence of inflammation can contribute to several behavioral alterations that reinforce the cyclic pattern of co-occurrence observed in patients with obesity and MDD. Future clinical studies should focus on strategic efforts to collect new data and to improve or standardize methods for the evaluation of depression, body composition and a more complete inflammatory profile. These approaches are essential for the development of pharmacological and/or non-pharmacological strategies designed to break this cyclic pattern of co-occurrence.

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.

Therapeutic Potential of Ursolic Acid to Manage Neurodegenerative and Psychiatric Diseases.

Ursolic acid is a pentacyclic triterpenoid found in several plants. Despite its initial use as a pharmacologically inactive emulsifier in pharmaceutical, cosmetic and food industries, several biological activities have been reported for this compound so far, including anti-tumoural, anti-diabetic, cardioprotective and hepatoprotective properties. The biological effects of ursolic acid have been evaluated in vitro, in different cell types and against several toxic insults (i.e. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, amyloid-ß peptides, kainic acid and others); in animal models of brain-related disorders (Alzheimer disease, Parkinson disease, depression, traumatic brain injury) and ageing; and in clinical studies with cancer patients and for muscle atrophy. Most of the protective effects of ursolic acid are related to its ability to prevent oxidative damage and excessive inflammation, common mechanisms associated with multiple brain disorders. Additionally, ursolic acid is capable of modulating the monoaminergic system, an effect that might be involved in its ability to prevent mood and cognitive dysfunctions associated with neurodegenerative and psychiatric conditions. This review presents and discusses the available evidence of the possible beneficial effects of ursolic acid for the management of neurodegenerative and psychiatric disorders. We also discuss the chemical features, major sources and potential limitations of the use of ursolic acid as a pharmacological treatment for brain-related diseases.

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.

Signaling pathways underlying the antidepressant-like effect of inosine in mice.

Inosine is a purine nucleoside formed by the breakdown of adenosine that elicits an antidepressant-like effect in mice through activation of adenosine A1 and A2A receptors. However, the signaling pathways underlying this effect are largely unknown. To address this issue, the present study investigated the influence of extracellular-regulated protein kinase (ERK)1/2, Ca2+/calmoduline-dependent protein kinase (CaMKII), protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase 3beta (GSK-3ß) modulation in the antiimmobility effect of inosine in the tail suspension test (TST) in mice. In addition, we attempted to verify if inosine treatment was capable of altering the immunocontent and phosphorylation of the transcription factor cyclic adenosine monophosphatate (cAMP) response-binding element protein (CREB) in mouse prefrontal cortex and hippocampus. Intracerebroventricular administration of U0126 (5 µg/mouse, MEK1/2 inhibitor), KN-62 (1 µg/mouse, CaMKII inhibitor), H-89 (1 µg/mouse, PKA inhibitor), and wortmannin (0.1 µg/mouse, PI3K inhibitor) prevented the antiimmobility effect of inosine (10 mg/kg, intraperitoneal (i.p.)) in the TST. Also, administration of a sub-effective dose of inosine (0.1 mg/kg, i.p.) in combination with a sub-effective dose of AR-A014418 (0.001 µg/mouse, GSK-3ß inhibitor) induced a synergic antidepressant-like effect. None of the treatments altered locomotor activity of mice. Moreover, 24 h after a single administration of inosine (10 mg/kg, i.p.), CREB phosphorylation was increased in the hippocampus. Our findings provided new evidence that the antidepressant-like effect of inosine in the TST involves the activation of PKA, PI3K/Akt, ERK1/2, and CaMKII and the inhibition of GSK-3ß. These results contribute to the comprehension of the mechanisms underlying the purinergic system modulation and indicate the intracellular signaling pathways involved in the antidepressant-like effect of inosine in a preclinical test of depression.