RESUMO
Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.
Assuntos
Autoantígenos/uso terapêutico , Autoimunidade/imunologia , Fatores Imunológicos/uso terapêutico , Regeneração Nervosa/imunologia , Doenças Neurodegenerativas/terapia , Neuroproteção/imunologia , Peptídeos/uso terapêutico , Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/terapia , Animais , Acetato de Glatiramer/uso terapêutico , Humanos , Imunização Passiva , Imunomodulação , Proteína Básica da Mielina/uso terapêutico , Doenças Neurodegenerativas/imunologia , Doença de Parkinson/imunologia , Doença de Parkinson/terapia , Fragmentos de Peptídeos/uso terapêutico , Deficiências na Proteostase , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/terapia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapiaRESUMO
PURPOSE: Chronic and persistent exposure to negative stress can lead to adverse consequences on health. Particularly, psychosocial factors were found to increase the risk and outcome of respiratory diseases like asthma. Glucocorticoids (GCs) are the most efficient anti-inflammatory therapy for asthma. However, a significant proportion of patients don't respond adequately to GC administration. GC sensitivity is modulated by genetic and acquired disease-related factors. Additionally, it was proposed that endogenous corticosteroids may limit certain actions of synthetic GCs, contributing to insensitivity. Psychological and physiological stresses activate the hypothalamic-pituitary-adrenal axis, increasing cortisol levels. Here, we review the mechanism involved in altered GC sensitivity in asthmatic patients under stressful situations. Strategies for modulation GC sensitivity and improving GC therapy are discussed. METHODS: PubMed was searched for publications on psychological chronic stress and asthma, GC resistance in asthma, biological mechanisms for GC resistance, and drugs for steroid-resistant asthma, including highly potent GCs. FINDINGS: GC resistance in patients with severe disease remains a major clinical problem. In asthma, experimental and clinical evidence suggests that chronic stress induces inflammatory changes, contributing to a worse GC response. GC resistant patients can be treated with other broad-spectrum anti-inflammatory drugs, but these generally have major side effects. Different mechanisms of GC resistance have been described and might be useful for developing new therapeutic strategies against it. Novel drugs, such as highly potent GCs, phosphoinositide 3-kinase-delta inhibitors that reestablish histone deacetylase-2 function, decrease of GC receptor phosphorylation by p38 mitogen-activated protein kinase inhibitors, or phosphatase activators, are currently in clinical development and might be combined with GC therapy in the future. Furthermore, microRNAs (small noncoding RNA molecules) operate as posttranscriptional regulators, providing another level of control of GC receptor levels. Empirical results allow postulating that the detection and study of microRNAs might be a promising approach to better characterize and treat asthmatic patients. IMPLICATIONS: Many molecular and cellular pathobiological mechanisms are responsible of GC resistance. Therefore detecting specific biomarkers to help identify patients who would benefit from new therapies is crucial. Stress consitutes a negative aspect of current lifestyles that increase asthma morbidity and mortality. Adequate stress management could be an important and positive intervention.
Assuntos
Asma/tratamento farmacológico , Resistência a Medicamentos , Glucocorticoides/uso terapêutico , Receptores de Glucocorticoides/imunologia , Estresse Psicológico/complicações , Animais , Asma/imunologia , Doença Crônica , Humanos , Estresse Psicológico/imunologiaRESUMO
Selective serotonin reuptake inhibitors are frequently used antidepressants. In particular, fluoxetine is usually chosen for the treatment of the symptoms of depression, obsessive-compulsive, panic attack and bulimia nervosa. Antidepressant therapy has been associated with immune dysfunction. However, there is contradictory evidence about the effect of fluoxetine on the immune system. Experimental findings indicate that lymphocytes express the serotonin transporter. Moreover it has been shown that fluoxetine is able to modulate the immune function through a serotonin-dependent pathway and through a novel independent mechanism. In addition, several studies have shown that fluoxetine can alter tumor cell viability. Thus, it was recently demonstrated in vivo that chronic fluoxetine treatment inhibits tumor growth by increasing antitumor T-cell activity. Here we briefly review some of the literature referring to how fluoxetine is able to modify, for better or worse, the functionality of the immune system. These results of our analysis point to the relevance of the novel pharmacological action of this drug as an immunomodulator helping to treat several pathologies in which immune deficiency and/or deregulation is present.
Assuntos
Antidepressivos/farmacologia , Fluoxetina/farmacologia , Fatores Imunológicos/farmacologia , Animais , Antidepressivos/uso terapêutico , Fluoxetina/uso terapêutico , Homeostase/efeitos dos fármacos , Humanos , Fatores Imunológicos/uso terapêutico , Serotonina/metabolismoRESUMO
RATIONALE: Oxidative stress and neurotrophins are among the most important factors involved in several pathophysiological brain processes. In addition, long-term exposure to stressful situations has deleterious effects on behaviour. We have previously shown that stressed female BALB/c mice show poor learning performance and that this behaviour is reversed by glatiramer acetate (GA) treatment. OBJECTIVES: We investigated the involvement of the hippocampal oxidative status and neurotrophin levels in cognitive deficit and the improvement of this deficit by GA treatment in chronic stressed BALB/c mice. METHODS: Female BALB/c mice were exposed to a chronic mild stress (CMS) model for 9 weeks. During the last 3 weeks of the stress exposure, one group of mice was subcutaneously injected four times with 100 µg GA/mouse. Following this period, behavioural studies were performed. The mice were then sacrificed, and biochemical studies were performed on the hippocampus. RESULTS: The stressed mice exhibited a significant decline in their performance in the open-field and in object-in-place tasks. This decline was accompanied by an increase in reactive oxygen species (ROS) and a decrease in nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS). Neither antioxidant defences nor neurotrophin protein levels were involved in this process. Interestingly, the administration of GA re-established the normal levels of ROS, restored nNOS activity and improved learning performance. CONCLUSIONS: The GA treatment improved learning and memory in female BALB/c mice under chronic stress through a mechanism that involves the regulation of NO production, which in turn modulates the ROS levels.
Assuntos
Acetato de Glatiramer/farmacologia , Hipocampo/metabolismo , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Óxido Nítrico/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Fatores de Crescimento Neural/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Oxidativo/fisiologia , Estresse Psicológico/complicaçõesRESUMO
It has been demonstrated that a short-duration stress (acute stress) may result in immunopreparatory or immunoenhancing physiological conditions. The aim of the present study was to investigate whether exposure to prenatal restraint stress (PRS) influences the impact of acute stress on the T-cell response in the adult life. We found that female mice exposed to PRS (PS mice) did not exhibit changes in the T-cell-dependent IgG antibody production with respect to prenatally non-stressed mice (no-PS mice). However, no-PS mice exposed to acute stress showed an increase of antibody production after antigen stimulation. In contrast, PS mice exhibited a decreased response after an acute situation. Spleen catecholamines and plasma corticosterone levels were increased in acute stress in both PS and no-PS mice. Nevertheless, lymphocyte response to hormones was altered in PS mice. Particularly, inhibitory effect of corticosterone was higher on lymphocytes from PS mice. In addition, an increase in protein levels and mRNA expression of glucocorticoid receptor was found in lymphoid cells from PS mice. These results show that prenatal stress alters the immune intrinsic regulatory mechanism that in turn induces an increased vulnerability to any stressful situation able to modify immune homeostasis.
Assuntos
Linfócitos/fisiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Receptores de Glucocorticoides/fisiologia , Estresse Psicológico/fisiopatologia , Linfócitos T/fisiologia , Animais , Corticosterona/sangue , Epinefrina/análise , Epinefrina/fisiologia , Feminino , Imunidade Celular/imunologia , Imunidade Celular/fisiologia , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Norepinefrina/análise , Norepinefrina/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Restrição Física/efeitos adversos , Baço/química , Baço/fisiopatologia , Estresse Psicológico/imunologia , Regulação para Cima/imunologia , Regulação para Cima/fisiologiaRESUMO
Long-term exposure to stressful situations has deleterious effects on adult neurogenesis, behavior, and the immune system. We have previously shown that stressed BALB/c mice show poor learning performance, which correlates with an increase in the T helper 1/T helper 2 (Th1/Th2) cytokine balance. Glatiramer acetate (GA) can stimulate autoreactive T cells. In this work we investigated the effects of GA treatment on BALB/c mice exposed to chronic mild stress (CMS). Stressed mice exhibited a significant decline in their performance in the open field and Y-maze tasks, which was accompanied by a reduction in dentate gyrus neurogenesis and an altered Th1/Th2 balance. Interestingly, after 6 weeks of CMS exposure administration of GA reestablished normal levels of adult neurogenesis, restored the Th1/Th2 balance, and improved learning performance. These results demonstrate that GA treatment can reverse the learning impairment induced by stress through a mechanism that likely involves the regulation of the cytokine balance and adult neurogenesis.
Assuntos
Adjuvantes Imunológicos/farmacologia , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Peptídeos/farmacologia , Estresse Psicológico/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Feminino , Acetato de Glatiramer , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Nitric oxide (NO) has been involved in many pathophysiological brain processes. Recently, we showed that neuronal nitric oxide synthase (nNOS)-mediated decrease in NO production is involved in memory impairment induced by chronic mild stress (CMS) in BALB/c mice. Two genetically different inbred murine strains, C57BL/6 and BALB/c, show distinct behavioral responses, neurodevelopmental and neurochemical parameters. Here, we perform a comparative study on CMS effects upon learning and memory in both strains, analyzing the role of NO production and its regulation by protein kinase C (PKC). Stressed BALB/c, but not C57Bl/6 mice, showed a poor learning performance in both the open field and passive avoidance inhibitory tasks. Also, CMS induced a diminished NO production by nNOS, associated with an increment in gamma and zeta PKC isoenzymes in BALB/c mice. In C57BL/6 mice, CMS had no effect on NO production, but increased delta and decreased betaI PKC isoforms. In vivo administration of a NOS inhibitor induced behavioral alterations in both strains. These results suggest a differential effect of stress, with BALB/c being more vulnerable to stress than C57BL/6 mice. This effect could be related to a differential regulation of NOS and PKC isoenzymes, pointing to an important role of NO in learning and memory.
Assuntos
Comportamento Animal/efeitos dos fármacos , Aprendizagem , Memória , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico/biossíntese , Proteína Quinase C/metabolismo , Estresse Psicológico/psicologia , Animais , Aprendizagem da Esquiva , Comportamento Exploratório/efeitos dos fármacos , Feminino , Hipocampo/enzimologia , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Estresse Psicológico/fisiopatologiaRESUMO
Fluoxetine, a selective serotonin reuptake inhibitor, is widely used for the treatment of depressive symptoms of cancer patients. However, there are contradictory evidences about its effects on immunity and cancer. Thus, we studied the effects of fluoxetine on tumor growth and on antitumoral T-cell-mediated immunity. In vivo chronic fluoxetine treatment inhibited tumor growth, and increased latency of appearance of solid tumors and survival of mice. Fluoxetine administration also increased mitogen-induced T-cell proliferation and Tumor Necrosis Factor-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) expression, without altering CD4(+)/CD8(+) ratio. In vitro, fluoxetine did not affect tumor cells proliferation, but it exerted a direct effect on T lymphocytes. Both fluoxetine and serotonin stimulated proliferation induced by a suboptimal mitogen concentration but inhibited proliferation at the optimal one. When both drugs were combined the results indicated that the effects of fluoxetine are in part independent of its ability to elevate serotonin extracellular levels. Finally, continue fluoxetine administration in nude mice - devoid of T lymphocytes - did not modify tumor progression, thus supporting the hypothesis of an immuno-modulatory effect of this drug on T cells that drives tumor growth control. These findings indicate, for the first time, that fluoxetine inhibits tumor growth through modulation of T-cell-mediated immunity by the already known serotonin-dependent pathway and by a novel independent mechanism.
Assuntos
Proliferação de Células/efeitos dos fármacos , Fluoxetina/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Serotonina/metabolismo , Linfócitos T/efeitos dos fármacos , Animais , Relação CD4-CD8 , Linhagem Celular Tumoral , Citocinas/biossíntese , Feminino , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Imunidade Celular/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/metabolismo , Linfoma de Células T/imunologia , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Nitric oxide (NO) has been involved in many pathophysiological brain processes. However, the exact role of NO in the cognitive deficit associated to chronic stress exposure has not been elucidated. In this study, we investigated the participation of hippocampal NO production and their regulation by protein kinase C (PKC) in the memory impairment induced in mice subjected to chronic mild stress model (CMS). CMS mice showed a poor learning performance in both open field and passive avoidance inhibitory task respect to control mice. Histological studies showed a morphological alteration in the hippocampus of CMS mice. On the other hand, chronic stress induced a diminished NO production by neuronal nitric oxide synthase (nNOS) correlated with an increment in gamma and zeta PKC isoenzymes. Partial restoration of nNOS activity was obtained after PKC activity blockade. NO production by inducible nitric oxide synthase isoform was not detected. The magnitude of oxidative stress, evaluated by reactive oxygen species production, after excitotoxic levels of NMDA was increased in hippocampus of CMS mice. Moreover, ROS formation was higher in the presence of nNOS inhibitor in both control and CMS mice. Finally, treatment of mice with nNOS inhibitors results in behavioural alterations similar to those observed in CMS animals. These findings suggest a novel role for nNOS showing protective activity against insults that trigger tissue toxicity leading to memory impairments.