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1.
Cell Mol Neurobiol ; 42(4): 1225-1240, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33259004

RESUMO

One of the most substantial and established environmental risk factors for neurological and psychiatric disorders is stress exposure, whose detrimental consequences hinge on several variables including time. In this regard the gestational period is known to present an intrinsic vulnerability to environmental insults and thus stressful events during pregnancy can lead to severe consequences on the offspring's brain development with long-term repercussions throughout adulthood. On this basis, we investigated the long-lasting impact of prenatal stress exposure on the susceptibility to the experimental autoimmune encephalomyelitis (EAE), a well-established murine model of multiple sclerosis. Although stress is considered a triggering factor for this chronic, progressive, autoimmune disease, little is known about the underlying mechanisms. To this end, EAE was induced by immunization with MOG35-55/CFA and pertussis toxin administration in adult female C57BL/6 mice born from control or stressed dams exposed to restraint stress during the last days of gestation. Our results demonstrate that gestational stress induces a marked increase in the severity of EAE symptoms in adulthood. Further, we highlight an altered maturation of oligodendrocytes in the spinal cord of prenatally stressed EAE mice, as indicated by the higher levels of GPR17, a marker of immature oligodendrocyte precursor cells. These behavioral and molecular alterations are paralleled by changes in the expression and signaling of the neurotrophin BDNF, an important mediator of neural plasticity that may contribute to stress-induced impaired remyelination. Since several already marketed drugs are able to modulate BDNF levels, these results pave the way to the possibility of repositioning these drugs in multiple sclerosis.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Medula Espinal/metabolismo
2.
Int J Mol Sci ; 23(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36293308

RESUMO

Neuroinflammation has emerged as an important factor in the molecular underpinnings of major depressive disorder (MDD) pathophysiology and in the mechanism of action of antidepressants. Among the inflammatory mediators dysregulated in depressed patients, interleukin (IL)-6 has recently been proposed to play a crucial role. IL-6 activates a signaling pathway comprising the JAK/STAT proteins and characterized by a specific negative feedback loop exerted by the cytoplasmic protein suppressor of cytokine signalling-3 (SOCS3). On these bases, here, we explored the potential involvement of IL-6 signaling in the ability of the antidepressant drug agomelatine to normalize the anhedonic-like phenotype induced in the rat by chronic stress exposure. To this aim, adult male Wistar rats were subjected to the chronic mild stress (CMS) paradigm and chronically treated with vehicle or agomelatine. The behavioral evaluation was assessed by the sucrose consumption test, whereas molecular analyses were performed in the prefrontal cortex. We found that CMS was able to stimulate IL-6 production and signaling, including SOCS3 gene and protein expression, but the SOCS3-mediated feedback-loop inhibition failed to suppress the IL-6 cascade in stressed animals. Conversely, agomelatine treatment normalized the stress-induced decrease in sucrose consumption and restored the negative modulation of the IL-6 signaling via SOCS3 expression and activity. Our results provide additional information about the pleiotropic mechanisms that contribute to agomelatine's therapeutic effects.


Assuntos
Transtorno Depressivo Maior , Interleucina-6 , Animais , Ratos , Masculino , Interleucina-6/genética , Interleucina-6/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/metabolismo , Ratos Wistar , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transdução de Sinais , Mediadores da Inflamação/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Sacarose
3.
Pharmacol Res ; 163: 105330, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33276101

RESUMO

Psychiatric disorders represent a critical challenge to our society, given their high global prevalence, complex symptomatology, elusive etiology and the variable effectiveness of pharmacological therapies. Recently, there has been a shift in investigating and redefining these diseases by integrating behavioral observations and multilevel neurobiological measures. Accordingly, endophenotype-oriented studies are needed to develop new therapeutic strategies, with the idea of targeting shared symptoms instead of one defined disease. With these premises, here we investigated the therapeutic properties of chronic treatment with the second-generation antipsychotic blonanserin in counteracting the alterations caused by 7 weeks of Chronic Mild Stress (CMS) in the rat. CMS is a well-established preclinical model able to induce depressive and anxiety-like alterations, which are shared by different psychiatric disorders. Our results demonstrated that the antipsychotic treatment normalizes the CMS-induced emotionality deficits, an effect that may be due to its ability in modulating, within the prefrontal cortex, redox mechanisms, a molecular dysfunction associated with several psychiatric disorders. These evidences provide new insights into the therapeutic properties and potential use of blonanserin as well as in its mechanisms of action and provide further support for the role of oxidative stress in the pathophysiology of psychiatric disorders.


Assuntos
Antipsicóticos/uso terapêutico , Piperazinas/uso terapêutico , Piperidinas/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Animais , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Oxirredutases/genética , Piperazinas/farmacologia , Piperidinas/farmacologia , Ratos Wistar , Estresse Psicológico/genética
4.
Psychopharmacology (Berl) ; 239(8): 2547-2557, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35459959

RESUMO

RATIONALE: Although the occurrence of stressful events is very common during life, their impact may be different depending on the experience severity and duration. Specifically, acute challenges may trigger adaptive responses and even improve the individual's performance. However, such a physiological positive coping can only take place if the underlying molecular mechanisms are properly functioning. Indeed, if these systems are compromised by genetic factors or previous adverse conditions, the response set in motion by an acute challenge may be maladaptive and even cause the insurgence or the relapse of stress-related psychiatric disorders. OBJECTIVES: On these bases, we evaluated in the rat brain the role of the antioxidant component of the redox machinery on the acute stress responsiveness and its modulation by potential detrimental or beneficial events. METHODS: The expression of several antioxidant enzymes was assessed in different brain areas of adult male rats exposed to acute stress 3 weeks after a chronic immobilization paradigm with or without a concomitant treatment with the antipsychotic lurasidone. RESULTS: The acute challenge was able to trigger a marked antioxidant response that, despite the washout period, was impaired by the previous adverse experience and restored by lurasidone in an anatomical-specific manner. CONCLUSIONS: We found that a working antioxidant machinery takes part in acute stress response and may be differentially affected by other experiences. Given the essential role of stress responsiveness in almost every life process, the identification of the underlying mechanisms and their potential pharmacological modulation add further translational value to our data.


Assuntos
Antipsicóticos , Cloridrato de Lurasidona , Animais , Antioxidantes/farmacologia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Cloridrato de Lurasidona/farmacologia , Masculino , Ratos
5.
Psychopharmacology (Berl) ; 237(6): 1783-1793, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32296859

RESUMO

RATIONALE: Patients diagnosed with schizophrenia typically receive life-long treatments with antipsychotic drugs (APDs). However, the impact of chronic APDs treatment on neuroplastic mechanisms in the brain remains largely elusive. OBJECTIVE: Here, we focused on blonanserin, a second-generation antipsychotic (SGA) that acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors, and represents an important tool for the treatment of schizophrenia. METHODS: We used rats to investigate the ability of chronic treatment blonanserin to modulate the activity of brain structures relevant for schizophrenia, under baseline conditions or in response to an acute forced swim session (FSS). We measured the expression of different immediate early genes (IEGs), including c-Fos, Arc/Arg 3.1, Zif268 and Npas4. RESULTS: Blonanserin per se produced limited changes in the expression of these genes under basal conditions, while, as expected, FSS produced a significant elevation of IEGs transcription in different brain regions. The response of blonanserin-treated rats to FSS show anatomical and gene-selective differences. Indeed, the upregulation of IEGs was greatly reduced in the striatum, a brain structure enriched in dopamine receptors, whereas the upregulation of some genes (Zif268, Npas4) was largely preserved in other regions, such as the prefrontal cortex and the ventral hippocampus. CONCLUSIONS: Taken together, our findings show that chronic exposure to blonanserin modulates selective IEGs with a specific anatomical profile. Moreover, the differential activation of specific brain regions under challenging conditions may contribute to specific clinical features of the drug.


Assuntos
Antipsicóticos/administração & dosagem , Encéfalo/efeitos dos fármacos , Genes Precoces/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Estresse Psicológico/tratamento farmacológico , Animais , Encéfalo/fisiologia , Esquema de Medicação , Genes Precoces/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Dopaminérgicos/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Estresse Psicológico/genética , Estresse Psicológico/psicologia
6.
Oxid Med Cell Longev ; 2020: 8363245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32832006

RESUMO

Neurodegenerative disease is an umbrella term for different conditions which primarily affect the neurons in the human brain. In the last century, significant research has been focused on mechanisms and risk factors relevant to the multifaceted etiopathogenesis of neurodegenerative diseases. Currently, neurodegenerative diseases are incurable, and the treatments available only control the symptoms or delay the progression of the disease. This review is aimed at characterizing the complex network of molecular mechanisms underpinning acute and chronic neurodegeneration, focusing on the disturbance in redox homeostasis, as a common mechanism behind five pivotal risk factors: aging, oxidative stress, inflammation, glycation, and vascular injury. Considering the complex multifactorial nature of neurodegenerative diseases, a preventive strategy able to simultaneously target multiple risk factors and disease mechanisms at an early stage is most likely to be effective to slow/halt the progression of neurodegenerative diseases.


Assuntos
Doenças Neurodegenerativas/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Humanos , Pessoa de Meia-Idade , Oxirredução , Fatores de Risco , Adulto Jovem
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