RESUMO
Neuropsychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are considered a public health problem since it interferes in personal relationships and at work. The pathophysiological mechanisms of these mental disorders are still not completely understood. The variety and heterogeneity of symptoms, as well as the absence of biomarkers, make the diagnosis, prognosis, and treatment of these disorders difficult. However, oxidative stress appears to play a role in the pathophysiology of these diseases. In this context, advanced oxidation protein products (AOPPs) are considered a biomarker of protein oxidative damage and have been associated with neuroinflammatory diseases. In patients with neuropsychiatric disorders, increased levels of AOPPs were associated with the severity of symptoms and decreased quality of life. Thus, the objective of this integrative review is to investigate and discuss the relationship between AOPPs levels and MDD, BD, and SZ. Different databases were consulted and approximately 112 scientific articles were found relating AOPPs and psychiatric disorders. In the majority of studies, the blood levels of AOPPs were increased in MDD, BD, and SZ and associated with the severity of the disorders. Although the association of this marker with the risk of developing one of these mental disorders is more uncertain, some studies have suggested this relationship. Of the twenty-four studies highlighted, only four did not find significant differences in AOPPs levels in patients with the disorders mentioned. In summary, it may be suggested that the assessment of AOPPs levels can be a useful tool in the evaluation of neuropsychiatric disorders, at least for prognostic evaluation. However, the role of this biomarker in the pathophysiology of mental disorders is still unclear, as well as whether reducing its levels represents a potential therapeutic strategy.
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Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system (CNS) generating neuropathic pain and anxiety. Primary progressive MS (PPMS) is the most disabling clinical form, and the patients present an intense neurodegenerative process. In this context, the advanced oxidation protein products (AOPPs) are oxidized compounds and their accumulation in plasma has been related to clinical disability in MS patients. However, the involvement of AOPPs in neuropathic pain- and anxiety-like symptoms was not previously evaluated. To assess this, female mice C57BL/6J were used to induce progressive experimental autoimmune encephalomyelitis (PMS-EAE). Clinical score, weight, strength of plantar pressure, rotarod test, mechanical allodynia, and cold hypersensitivity were evaluated before induction (baseline) and on days 7th, 10th, and 14th post-immunization. We assessed nest building, open field, and elevated plus-maze tests 13 days post-immunization. Animals were killed at 14 days post-immunization; then, AOPPs levels, NADPH oxidase, and myeloperoxidase (MPO) activity were measured in the prefrontal cortex, hippocampus, and spinal cord samples. The clinical score increased 14th post-immunization without changes in weight and mobility. Reduced paw strength, mechanical allodynia, and cold allodynia increased in the PMS-EAE animals. PMS-EAE mice showed spontaneous nociception and anxiety-like behavior. AOPPs concentration, NADPH oxidase, and MPO activity increase in CNS structures. Multivariate analyses indicated that the rise of AOPPs levels, NADPH oxidase, and MPO activity influenced the clinical score and cold allodynia. Thus, we indicated the association between non-stimuli painful perception, anxiety-like, and CNS oxidative damage in the PMS-EAE model.
Assuntos
Produtos da Oxidação Avançada de Proteínas , Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Animais , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/psicologia , Feminino , Camundongos , Produtos da Oxidação Avançada de Proteínas/metabolismo , Nociceptividade/fisiologia , Hiperalgesia/metabolismo , Medula Espinal/metabolismo , Ansiedade/etiologia , Ansiedade/psicologiaRESUMO
RATIONALE: Major depressive disorder (MDD) is one of the most diagnosed mental disorders. Despite this, its pathophysiology remains poorly understood. In this context, basic research aims to unravel the pathophysiological mechanisms of MDD as well as investigate new targets and substances with therapeutic potential. Transient receptor potential ankyrin 1 (TRPA1) is a transmembrane channel considered a sensor for inflammation and oxidative stress. Importantly, both inflammation and oxidative stress have been suggested as participants in the pathophysiology of MDD. However, the potential participation of TRPA1 in depressive disorder remains poorly investigated. OBJECTIVE: To investigate the involvement of the TRPA1 channel in the behavioral changes induced by chronic corticosterone administration (CCA) in male mice. METHODS: Swiss male mice were exposed to 21 days of CCA protocol and then treated with HC-030031 or A-967079, TRPA1 antagonists. Behavioral tests, analyzes of oxidative parameters and TRPA1 immunocontent were performed in the prefrontal cortex (PFC) and hippocampus (HIP). RESULTS: CCA induced despair-like behavior in mice accompanied by an increase in the levels of hydrogen peroxide (H2O2), a TRPA1 agonist, which was reversed by TRPA1 antagonists and ketamine (positive control). In addition, CCA protocol reduced the immunocontent of this channel in the HIP and showed a tendency to increase the TRPA1 protein expression in the PFC. CONCLUSION: Our work suggests that TRPA1 channel appears crucial to mediate the behavioral impairment induced by CCA in male Swiss mice.
Assuntos
Corticosterona , Transtorno Depressivo Maior , Masculino , Animais , Camundongos , Canal de Cátion TRPA1/metabolismo , Peróxido de Hidrogênio/metabolismo , InflamaçãoRESUMO
BACKGROUND: Parkinson's disease (PD) patients experience non-motor symptoms (NMS), which may appear before motor manifestations. The most common NMS is depression, affecting about 30-40% of PD patients. Both PD and depression are associated with an increased inflammatory burden, with studies showing elevation of diverse inflammatory markers in patients with both conditions. METHODS: A systematic review was conducted in PubMed and PsycINFO databases to investigate what inflammatory markers are associated with PD depression (PDD). Only studies in English that measured inflammatory markers and analyzed against depression scores in PD patients were included. RESULTS: A total of 1132 articles were retrieved, and 14 entries were found to be eligible. Twelve were cross-sectional studies, one was a cohort, and one was a non-randomized controlled trial. IL-17A was the only marker strongly associated with PDD, while studies assessing sIL-2R and serum amyloid A found a moderate correlation. C-reactive protein, IL-10, tumor necrosis factor-α, monocyte chemoattractant protein-1, and IL-6 yielded conflicting results. Their possible roles in PDD are discussed. PDD was also related to longer disease duration and other NMS, such as anxiety, fatigue, dementia, REM sleep behavior disorder, and autonomic dysfunction. CONCLUSION: We suggest that these markers may be used for distinguishing isolated depression from that related to neurodegeneration, especially in individuals that concurrently present with other known prodromal symptoms of PD and other α-synucleinopathies. However, future prospective studies are warranted to confirm this hypothesis.
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Doença de Parkinson , Transtorno do Comportamento do Sono REM , Sinucleinopatias , Humanos , Depressão/etiologia , Transtorno do Comportamento do Sono REM/complicações , Ansiedade , BiomarcadoresRESUMO
Major depression is a leading contributor to the global burden of disease. This is mainly related to the disorder chronic and recurrent nature, and to high rates of refractoriness to treatment. Limited efficacy with currently available antidepressants highlights the need for more effective options for treating drug-resistant patients and emphasizes the importance of developing specific preclinical models for treatment-resistant populations. Treatment-resistant depression (TRD) is commonly defined as failure to respond to two or more trials of antidepressants. In this study, we investigated the effect of fluoxetine treatment for fourteen days on the depressive-like behavior and the oxidative and inflammatory parameters of mice submitted to chronic corticosterone administration. After 21 days of subcutaneous corticosterone administration (20 mg/kg/day) and 14 days of oral fluoxetine treatment (10 mg/kg/day, started on day 7 of induction protocol), we separated animals into two groups according to the tail suspension test (TST) results: antidepressant responders (good response to antidepressant, GRA) and non-responders (resistance to antidepressant, AR). Forced swimming test (FST), elevated plus maze test (EPMT), and open field test (OFT) were performed. We found that animals classified as AR (i.e., those with higher immobility values in the TST) demonstrated anxiety-like behavior in the EPMT, increased H2O2 levels, and decreased catalase activity in the hippocampus, as well as increased serum levels of IL-17 and IFN-γ. Our findings suggest that a redox imbalance in the hippocampus, combined with increased levels of peripheral IL-17 and INF-γ, may be involved with an impaired response to fluoxetine.
Assuntos
Corticosterona , Fluoxetina , Animais , Antidepressivos , Ansiedade/tratamento farmacológico , Comportamento Animal , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Fluoxetina/farmacologia , Hipocampo , Humanos , Peróxido de Hidrogênio/farmacologia , Interleucina-17 , Camundongos , Oxirredução , Estresse OxidativoRESUMO
Objectives: This narrative review article provides an overview on the involvement of microglia and the hypothalamic-pituitary-adrenal (HPA) axis in the pathophysiology of depression, as well investigates the mutual relationship between these two entities: how microglial activation can contribute to the dysregulation of the HPA axis, and vice versa.Methods: Relevant studies and reviews already published in the Pubmed electronic database involving the themes microglia, HPA axis and depression were used to meet the objectives.Results: Exposition to stressful events is considered a common factor in the mechanisms proposed to explain the depressive disorder. Stress can activate microglial cells, important immune components of the central nervous system (CNS). Moreover, another system involved in the physiological response to stressors is the hypothalamic-pituitary-adrenal (HPA) axis, the main stress response system responsible for the production of the glucocorticoid hormone (GC). Also, mediators released after microglial activation can stimulate the HPA axis, inducing production of GC. Likewise, high levels of GCs are also capable of activating microglia, generating a vicious cycle.Conclusion: Immune and neuroendocrine systems seems to work in a coordinated manner and that their dysregulation may be involved in the pathophysiology of depression since neuroinflammation and hypercortisolism are often observed in this disorder.
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Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Humanos , Microglia , Glucocorticoides , Depressão , Estresse PsicológicoRESUMO
Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients.
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Multiple sclerosis (MS) is an autoimmune-mediated disease that damages the central nervous system. MS pathophysiological features are not entirely understood, but the increase of reactive oxygen species (ROS) possibly causes myelin and oligodendrocyte degeneration. ROS-increased production generates new compounds through oxidative modifications, including advanced oxidative protein products (AOPPs). The AOPPs are oxidative stress biomarkers and inflammatory mediators commonly formed by hypochlorous acid oxidative action on albumin. Considering that AOPPs accumulation produces ROS and induces neuronal apoptosis, these may represent a new target for drug development to MS treatment and a possible biomarker to monitor the severity of the disease. Thus, this review aims to investigate if there is an alteration in the AOPPs levels in MS and its possible involvement in patient disability. The second objective is to analyze whether drugs or compounds used in MS treatment could modify the AOPPs levels. The protocol was registered in PROSPERO (CRD42020203268). The databases' search yielded 327 articles. We excluded 259 duplicated articles and evaluated 68 articles by the title and abstract. We full-text analyzed 17 articles and included 13 articles. The AOPPs levels were increased in not-treated MS patients. Furthermore, the increase in disability status was associated with AOPPs accumulation in not-treated MS patients. Additionally, the AOPPs levels were reduced in MS patients after treatment. Therefore, AOPPs seem to play a role in MS pathophysiology and may become a new target for drug development and help MS diagnosis or treatment follow-up.
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Produtos da Oxidação Avançada de Proteínas/sangue , Esclerose Múltipla/sangue , Apoptose , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Estudos Transversais , Desenvolvimento de Medicamentos , Humanos , Inflamação , Esclerose Múltipla/tratamento farmacológico , Estresse Oxidativo , Espécies Reativas de OxigênioRESUMO
Progressive multiple sclerosis (PMS) is a neurological disease associated with the development of depression and anxiety, but treatments available are unsatisfactory. The transient receptor potential ankyrin 1 (TRPA1) is a cationic channel activated by reactive compounds, and the blockage of this receptor can reduce depression- and anxiety-like behaviors in naive mice. Thus, we investigated the role of TRPA1 in depression- and anxiety-like behaviors in a PMS model in mice. PMS model was induced in C57BL/6 female mice by the experimental autoimmune encephalomyelitis (EAE). Nine days after the PMS-EAE induction, behavioral tests (tail suspension and elevated plus maze tests) were performed to verify the effects of sertraline (positive control), selective TRPA1 antagonist (A-967,079), and antioxidants (α-lipoic acid and apocynin). The prefrontal cortex and hippocampus were collected to evaluate biochemical and inflammatory markers. PMS-EAE induction did not cause locomotor changes but triggered depression- and anxiety-like behaviors, which were reversed by sertraline, A-967,079, α-lipoic acid, or apocynin treatments. The neuroinflammatory markers (AIF1, GFAP, IL-1ß, IL-17, and TNF-α) were increased in mice's hippocampus. Moreover, this model did not alter TRPA1 RNA expression levels in the hippocampus but decrease TRPA1 levels in the prefrontal cortex. Moreover, PMS-EAE induced an increase in NADPH oxidase and superoxide dismutase activities and TRPA1 endogenous agonist levels (hydrogen peroxide and 4-hydroxynonenal). TRPA1 plays a fundamental role in depression- and anxiety-like behaviors in a PMS-EAE model; thus, it could be a possible pharmacological target for treating these symptoms in PMS.
Assuntos
Ansiedade/genética , Ansiedade/psicologia , Comportamento Animal , Depressão/genética , Depressão/psicologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/psicologia , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Crônica Progressiva/psicologia , Canal de Cátion TRPA1/genética , Animais , Antioxidantes/farmacologia , Feminino , Elevação dos Membros Posteriores , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oximas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sertralina/farmacologia , Canal de Cátion TRPA1/antagonistas & inibidoresRESUMO
Depression is one of the most common mood disorders, which affects one in six people at some point in life. However, the treatment of this disease is still a challenge. Chronic corticosterone administration (CCA) is a widely used animal model to study the mechanisms involved, as well as possible therapeutic strategies for the treatment of depression. Moreover, elevated oxidative stress has been observed in psychiatric disorders, including major depression and, in this context, antioxidant therapy may be a potential therapeutic alternative. In this study, we investigated the effect of seven days of treatment with apocynin, an antioxidant of natural origin, on depressive-like behavior and oxidative parameters in mice submitted to CCA. After 21 days of corticosterone administration (20 mg/Kg/day, subcutaneously, s.c.), we observed the development of depressive-like behavior with an increase in immobility time on tail suspension test and forced swimming test and reduction in total grooming time on splash test. Also, we found high superoxide dismutase activity and hydrogen peroxide levels whereas catalase activity was reduced in the prefrontal cortex, hippocampus and striatum. Seven days of treatment with apocynin (100 mg/Kg/day orally, p.o), performed immediately after corticosterone administration in the last week of protocol, was able to reverse the most of these changes, revealing its antidepressant-like effect. In conclusion, our results suggest apocynin as an antidepressant-like agent with a mechanism of action based on the attenuation of oxidative changes induced by CCA.