RESUMO
Modafinil is a psychostimulant drug approved by the FDA primarily for the treatment of sleep disorders such as narcolepsy, excessive daytime sleepiness and sleep apnea. Several documented but not yet approved uses for modafinil have been described over the last 30 years, including alleviating fatigue in neurological and neurodegenerative disorders. Recent evidence has suggested that modafinil may have an immunomodulatory effect. Here, we review the different effects of modafinil treatment in animal models of brain inflammation and peripheral immune function. We conclude that there is unequivocal evidence of an anti-inflammatory effect of modafinil in experimental animal models of brain inflammation and neurodegenerative disorders, including systemic inflammation and methamphetamine-induced neuroinflammation, Parkinson's disease, brain ischemia, and multiple sclerosis. Modafinil acts on resident glial cells and infiltrating immune cells, negatively affecting both innate and adaptive immune responses in the brain. We also review the outcomes of modafinil treatment on peripheral immune function. The results of studies on this subject are still controversial and far from conclusive, but point to a new avenue of research in relation to peripheral inflammation. The data reviewed here raise the possibility of modafinil being used as adjuvant treatment for neurological disorders in which inflammation plays an important role.
Assuntos
Estimulantes do Sistema Nervoso Central , Preparações Farmacêuticas , Promotores da Vigília , Animais , Compostos Benzidrílicos/uso terapêutico , Imunidade , Modafinila , Promotores da Vigília/uso terapêuticoRESUMO
Maternal care is crucial for infants and profoundly affects their responses to different kinds of stressors. Here, we examined how maternal separation affects inflammatory gene expression and the corticosterone response to an acute immune challenge induced by lipopolysaccharide (LPS; 40⯵g/kg ip) in mouse pups, 8-9â¯days old. Maternal separation initially attenuated LPS-induced hypothalamic pro-inflammatory gene expression, but later, at 3â¯h after immune challenge, robustly augmented such gene expression and increased serum corticosterone levels. Providing the pups with a warm and soft object prevented the separation-induced augmented hypothalamic-pituitary-adrenal (HPA)-axis response. It also prevented the potentiated induction of some, but not all, inflammatory genes to a similar extent as did the dam. Our results show that maternal separation potentiates the inflammatory response and the resulting HPA-axis activation, which may have detrimental effects if separation is prolonged or repeated.
Assuntos
Ansiedade de Separação/genética , Inflamação/metabolismo , Privação Materna , Animais , Animais Recém-Nascidos , Ansiedade de Separação/fisiopatologia , Corticosterona/sangue , Corticosterona/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Inflamação/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/metabolismoRESUMO
Multiple sclerosis (MS) is characterized by an autoimmune response against myelin antigens driven by autoreactive T cells. Several lines of evidence indicate that environmental factors, such as previous infection, can influence and trigger autoimmune responses. However, the importance of the gestational period, particularly under inflammatory conditions, on the modulation of MS and related neuroinflammation by the offspring is unknown. This study aimed to evaluate the impact of prenatal exposure to lipopolysaccharide (LPS) during late gestation on the neuroinflammatory response in primary mixed glial cultures and on the progression of experimental autoimmune encephalomyelitis (EAE, an animal model of MS) in the offspring. LPS (Escherichia coli 0127:B8, 120µg/kg) was administered intraperitoneally to pregnant C57BL/6J mice on gestational day 17, and the offspring were assigned to two experiments: (1) mixed glial cultures generated using the brain of neonates, stimulated in vitro with LPS, and (2) adult offspring immunized with MOG35-55. The EAE clinical symptoms were followed for 30days. Different sets of animals were sacrificed either during the onset (7days post-immunization [p.i.]), when spleen and lymph nodes were collected, or the peak of disease (20days p.i.), when CNS were collected for flow cytometry, cytokine production, and protein/mRNA-expression analysis. The primary CNS cultures from the LPS-treated group produced exaggerated amounts of IL-6, IL-1ß and nitrites after in vitro stimulus, while IL-10 production was lowered compared to the data of the control group. Prenatal exposure to LPS worsened EAE disease severity in adult offspring, and this worsening was linked to increased CNS-infiltrating macrophages, Th1 cells and Th17 cells at the peak of EAE severity; additionally, exacerbated gliosis was evidenced in microglia (MHC II) and astrocytes (GFAP protein level and immunoreactivity). The IL-2, IL-6 and IL-17 levels in the spleen and lymph nodes were increased in the offspring of the LPS-exposed dams. Our results indicate that maternal immune activation during late gestation predispose the offspring to increased neuroinflammation and potentiate the autoimmune response and clinical manifestation of EAE.
Assuntos
Autoimunidade/imunologia , Encéfalo/imunologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Inflamação/imunologia , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Inflamação/metabolismo , Masculino , Camundongos , Microglia/imunologia , Microglia/metabolismo , Atividade Motora/imunologia , GravidezRESUMO
BACKGROUND/AIMS: Early life experiences are homeostatic determinants for adult organisms. We evaluated the impact of prenatal immune activation during late gestation on the neuroimmune-endocrine function of adult offspring and its interaction with acute stress. METHODS: Pregnant Swiss mice received saline or lipopolysaccharide (LPS) on gestational day 17. Adult male offspring were assigned to the control or restraint stress condition. We analyzed plasmatic corticosterone and catecholamine levels, the monoamine content in the hypothalamus, striatum and frontal cortex, and the sleep-wake cycle before and after acute restraint stress. RESULTS AND CONCLUSION: Offspring from LPS-treated dams had increased baseline norepinephrine levels and potentiated corticosterone secretion after the acute stressor, and no effect was observed on hypothalamic monoamine content or sleep behavior. The offspring of immune-activated dams exhibited impairments in stress-induced serotonergic and dopaminergic alterations in the striatum and frontal cortex. The data demonstrate a distinction between the plasmatic levels of corticosterone in response to acute stress and the hypothalamic monoamine content and sleep patterns. We provide new evidence regarding the influence of immune activation during late gestation on the neuroendocrine homeostasis of offspring.
Assuntos
Monoaminas Biogênicas/metabolismo , Corticosterona/sangue , Hipotálamo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Sono/fisiologia , Estresse Psicológico , Análise de Variância , Animais , Eletromiografia , Feminino , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Caracteres Sexuais , Estresse Psicológico/sangue , Estresse Psicológico/complicações , Estresse Psicológico/patologiaRESUMO
Previous studies have demonstrated that stress or glucocorticoids impair the retrieval of spatial memory in rodents and declarative memory in humans. However, the effects on memory retrieval of stress introduced a long time after learning have not been well studied. We investigated whether a mild, extrinsic stressor (1-s 0.1 or 0.3 mA foot shock) would reactivate low baseline retrieval of an aversive memory [the plus-maze discriminative avoidance task (PM-DAT)] and if it would be modulated by glucocorticoids. In Experiment 1, male Swiss mice received pre-test foot shock (n = 10 mice/group) 7 days after training and just before testing. A time-retrieval curve for low baseline retrieval for the subsequent experiments was also determined (Experiment 2, n = 10 mice/group). We investigated if pre-test foot shock could modify corticosterone release (Experiment 3, n = 8-9 mice/group) and reinstate retrieval in the PM-DAT (Experiment 4, n = 15 mice/group). The effects of metyrapone (100 mg/kg) on retrieval reinstatement (Experiment 5, n = 15 mice/group) and serum corticosterone enhancement (Experiments 6, n = 7-9 mice/group) induced by foot shock were analyzed. Finally, the effects of foot shock itself on PM-DAT exploration were verified (Experiment 7, n = 10 mice/group). We demonstrated here that foot shock reinstated the retrieval of a low baseline, discriminative avoidance task 30 (but not 7) days after training. This facilitative effect was not dependent on corticosterone secretion because metyrapone abolished the enhancement of corticosterone concentration but did not reverse the stress-induced reinstatement of retrieval.
Assuntos
Aprendizagem da Esquiva , Comportamento Animal , Aprendizagem por Discriminação , Aprendizagem em Labirinto , Rememoração Mental , Estresse Psicológico/psicologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Aprendizagem por Discriminação/efeitos dos fármacos , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Camundongos , Piridinas/farmacologia , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Esteroide 11-beta-Hidroxilase/metabolismo , Estresse Psicológico/sangue , Fatores de TempoRESUMO
BACKGROUND: Although mood-congruent memory (MCM), or the tendency to recall information consistent with one's mood, is a robust phenomenon in human depression, to our knowledge, it has never been demonstrated in animals. METHODS: Mice were subjected to social isolation (SI) or crowding for 12 hours and had their depressive-like behaviour (evaluated by the forced swim, tail suspension, sucrose preference and splash tests) or their serum corticosterone concentrations evaluated. In addition, we determined the temporal forgetting curve of the plus-maze discriminative avoidance task (PM-DAT) and examined the effects of SI or crowding on memory retrieval in the PM-DAT. Finally, we verified the effects of metyrapone pretreatment on reinstatement of memory retrieval or on the increase of corticosterone levels induced by SI. RESULTS: Twelve hours of SI produced depressive-like behaviour, enhanced corticosterone concentration and reinstated retrieval of a forgotten discriminative aversive (i.e., negatively valenced) task. Depressive-like behaviour was critical for this facilitative effect of SI because 12 hours of crowding neither induced depressive-like behaviour nor enhanced retrieval, although it increased corticosterone levels at the same magnitude as SI. However, corticosterone increase was a necessary condition for MCM in mice, in that the corticosterone synthesis inhibitor metyrapone abolished SI-induced retrieval reinstatement. LIMITATIONS: Our study did not investigate the effects of the social manipulations proposed here in a positively valenced task. CONCLUSION: To our knowledge, the present paper provides the first evidence of MCM in animal models.
Assuntos
Afeto , Aprendizagem da Esquiva/efeitos dos fármacos , Depressão/psicologia , Rememoração Mental/efeitos dos fármacos , Isolamento Social/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Aglomeração/psicologia , Depressão/sangue , Discriminação Psicológica , Masculino , Metirapona/farmacologia , Camundongos , Modelos AnimaisRESUMO
OBJECTIVES: Sleep deprivation is a growing public health hazard, yet it is still under-recognized. Sleep disorders and disruption of sleep patterns may compromise the immune function and adversely affect host resistance to infectious diseases. This is a particular risk in cancer patients, who report a high frequency of sleep disturbances. The present study investigated the effects of sleep deprivation on the development of Ehrlich ascitic tumors (EAT) in female BALB/c mice. Our study also evaluated whether EAT would induce alterations in sleep pattern. Spleen lymphocyte cell populations and mortality were also quantified. METHODS: Female BALB/c mice were intraperitoneally inoculated with EAT cells. Immediately after the inoculation procedure, animals were sleep deprived for 72 h. Ten or 15 days after inoculation, the number of tumoral cells was quantified and the lymphocytic cell population in the spleen was characterized by flow cytometry. In addition, the effect of sleep deprivation on EAT-induced mortality was quantified and the influence of EAT on sleep patterns was determined. RESULTS: Sleep deprivation did not potentiate EAT growth, but it significantly increased mortality. Additionally, both EAT and sleep deprivation decreased frequencies of splenic CD4+, CD8+ and CD19+ cells. With respect to sleep patterns, EAT significantly enhanced paradoxical sleep time. CONCLUSIONS: Although sleep deprivation did not potentiate EAT growth, it decreased the survival of female tumor-bearing mice.
Assuntos
Carcinoma de Ehrlich/mortalidade , Privação do Sono/complicações , Análise de Variância , Animais , Antígenos CD/metabolismo , Carcinoma de Ehrlich/imunologia , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Humanos , Linfócitos/imunologia , Linfócitos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias/métodos , Baço/patologiaRESUMO
We investigated the effect of 96 h paradoxical sleep deprivation (PSD) and 21-day sleep restriction (SR) on prostate morphology using stereological assays in male rats. After euthanasia, the rat ventral prostate was removed, weighed, and prepared for conventional light microscopy. Microscopic analysis of the prostate reveals that morphology of this gland was altered after 96 h of PSD and 21 days of SR, with the most important alterations occurring in the epithelium and stroma in the course of both procedures compared with the control group. Both 96 h PSD and 21-day SR rats showed lower serum testosterone and higher corticosterone levels than control rats. The significance of our result referring to the sleep deprivation was responsible for deep morphological alterations in ventral prostate tissue, like to castration microscopic modifications. This result is due to the marked alterations in hormonal status caused by PSD and SR.
Assuntos
Bioensaio , Corticosterona/sangue , Próstata/patologia , Privação do Sono/sangue , Privação do Sono/patologia , Testosterona/sangue , Animais , Atrofia , Masculino , Próstata/metabolismo , Ratos , Ratos Wistar , Sono REM , Coloração e RotulagemRESUMO
BACKGROUND/AIMS: Several lines of evidence indicate that sleep loss imposes significant consequences on the host defense system, including changes in cell number, activity and distribution. However, it is not clear whether cellular alterations after sleep deprivation are caused by redistribution to immune organs or by death of these cells or how the response to a nonspecific immune activator would be affected. Therefore, the aim of this study was to assess the leukocyte distribution after paradoxical sleep deprivation (PSD) in saline- and lipopolysaccharide-treated mice. METHODS: Adult inbred mice were paradoxical sleep deprived (72 h), whereas the controls were kept in their home cages. After PSD, both groups received an injection of either saline or lipopolysaccharide (LPS; 1 or 5 µg/animal, intraperitoneally), 2 h prior to the collection of blood, spleen, lymph nodes and peritoneal wash. Isolated cells were then designated to differential leukocyte count (blood) and flow cytometry analysis of immune cell subsets (immune sites). RESULTS: The data revealed that PSD caused a significant reduction of circulating lymphocytes and a general decrease in all cellular subsets of spleen, mainly T and B cells. However, no alteration in response of PSD was found on other immune sites, such as lymph nodes and peritoneum. Of note, immune cell distribution in response to in vivo LPS stimulation remained unchanged after PSD. CONCLUSIONS: Our study provided original evidence concerning the immune outcomes of PSD, indicating that cellular decrease caused by PSD is not restricted to circulation, but also to immune sites. Taken together, our results could help shed light on the physiological mechanisms of leukocyte trafficking.
Assuntos
Imunidade Celular/imunologia , Leucócitos/imunologia , Lipopolissacarídeos/toxicidade , Privação do Sono/imunologia , Sono REM/imunologia , Animais , Imunidade Celular/efeitos dos fármacos , Contagem de Leucócitos/métodos , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Privação do Sono/patologiaRESUMO
The aim of this investigation was to evaluate overall DNA damage induced by experimental paradoxical sleep deprivation (PSD) in estrous-cycling and ovariectomized female rats to examine possible hormonal involvement during DNA damage. Intact rats in different phases of the estrous cycle (proestrus, estrus, and diestrus) or ovariectomized female Wistar rats were subjected to PSD by the single platform technique for 96 h or were maintained for the equivalent period as controls in home-cages. After this period, peripheral blood and tissues (brain, liver, and heart) were collected to evaluate genetic damage using the single cell gel (comet) assay. The results showed that PSD caused extensive genotoxic effects in brain cells, as evident by increased DNA migration rates in rats exposed to PSD for 96 h when compared to negative control. This was observed for all phases of the estrous cycle indistinctly. In ovariectomized rats, PSD also led to DNA damage in brain cells. No significant statistically differences were detected in peripheral blood, the liver or heart for all groups analyzed. In conclusion, our data are consistent with the notion that genetic damage in the form of DNA breakage in brain cells induced by sleep deprivation overrides the effects related to endogenous female sex hormones.
Assuntos
Dano ao DNA , Hormônios Esteroides Gonadais/metabolismo , Privação do Sono/genética , Privação do Sono/metabolismo , Sono REM , Animais , Sangue/metabolismo , Encéfalo/metabolismo , Corticosterona/metabolismo , Diestro/genética , Diestro/fisiologia , Estro/genética , Estro/fisiologia , Feminino , Fígado/metabolismo , Miocárdio/metabolismo , Ovariectomia , Proestro/genética , Proestro/fisiologia , Progesterona/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Testosterona/metabolismoRESUMO
OBJECTIVES: Infections, cancer, and systemic inflammation elicit anorexia. Despite the medical significance of this phenomenon, the question of how peripheral inflammatory mediators affect the central regulation of food intake is incompletely understood. Therefore, we have investigated the sickness behavior induced by the prototypical inflammatory mediator IL-1ß. METHODS: IL-1ß was injected intravenously. To interfere with IL-1ß signaling, we deleted the essential modulator of NF-κB signaling (Nemo) in astrocytes and tanycytes. RESULTS: Systemic IL-1ß increased the activity of the transcription factor NF-κB in tanycytes of the mediobasal hypothalamus (MBH). By activating NF-κB signaling, IL-1ß induced the expression of cyclooxygenase-2 (Cox-2) and stimulated the release of the anorexigenic prostaglandin E2 (PGE2) from tanycytes. When we deleted Nemo in astrocytes and tanycytes, the IL-1ß-induced anorexia was alleviated whereas the fever response and lethargy response were unchanged. Similar results were obtained after the selective deletion of Nemo exclusively in tanycytes. CONCLUSIONS: Tanycytes form the brain barrier that mediates the anorexic effect of systemic inflammation in the hypothalamus.
Assuntos
Anorexia/etiologia , Células Ependimogliais/metabolismo , Inflamação/complicações , Inflamação/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Técnicas de Silenciamento de Genes , Imuno-Histoquímica , Hibridização In Situ , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , RatosRESUMO
INTRODUCTION: Sleep disturbances are a frequent complaint in women and are often attributed to hormonal fluctuations during the menstrual cycle. Rodents have been used as models to examine the effects of sleep deprivation on hormonal and behavioral changes. Among the many comorbidities common to sleep disorders, sexual behavior remains the least well studied. AIM: To determine whether paradoxical sleep deprivation (PSD) can affect sexual receptivity (male acceptance) and proceptivity (male solicitation) behaviors in female rats. METHODS: Female Wistar rats were subjected to PSD or were maintained as controls. After this period, the estrous cycle (proestrus, estrus, and diestrus) was determined, and all females were placed with a sexually experienced male. In order to investigate the role of hormones in sexual behavior, we included additional groups that were artificially induced to be sexually receptive via administration of a combination of estradiol and progesterone. MAIN OUTCOME MEASUREMENTS: Receptivity and proceptivity behaviors, as well as progesterone and corticosterone concentrations were monitored. RESULTS: Selective sleep loss caused a significant increase in proceptivity and receptivity behaviors in females exclusively during the proestrus phase. The rejection response was increased in PSD rats during the estrus and diestrus phases, as compared with PSD-receptive and proestrus females. PSD reduced progesterone levels during the proestrus phase relative to the respective control group during the same phase of the estrous cycle. The PSD-proestrus females that displayed the most robust sexual response exhibited greater concentrations of corticosterone than PSD-diestrus females, with an absence of sexual solicitation behaviors. CONCLUSIONS: PSD produced a distinct response in the hormonal profile that was consistent with the phase of the estrous cycle. These results show that sleep loss can affect sexual motivation and might lead to important clinical implications, including alterations in female physiology and reproductive abnormalities.
Assuntos
Estro , Comportamento Sexual Animal , Privação do Sono/complicações , Animais , Feminino , Hidrocortisona , Progesterona , Ratos , Ratos Wistar , Estatísticas não ParamétricasRESUMO
The psychostimulant drug modafinil has been used for many years for the treatment of sleep disorders. Recent studies have indicated that modafinil has immunomodulatory properties in the central nervous system (CNS) and peripheral immune cells. Thus, our aim was to determine the effects of in vivo therapeutic treatment with modafinil on the severity of clinical symptoms and immune response during the acute phase of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis. Modafinil treatment, given after the onset of symptoms, resulted in an improvement of EAE symptoms and motor impairment, which was correlated with reduced cellular infiltrate and a decreased percentage of T helper (Th) 1 cells in the CNS. The spinal cord analysis revealed that modafinil treatment decreased interferon (IFN)-γ and interleukin (IL)-6 protein levels and down regulated genes related to Th1 immunity, such as IFN-γ and TBX21, without affecting Th17-related genes. Our research indicates that therapeutic modafinil treatment has anti-inflammatory properties in an EAE model by inhibiting brain Th1 response, and may be useful as adjuvant treatment for multiple sclerosis.
Assuntos
Estimulantes do Sistema Nervoso Central/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Modafinila/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Citocinas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Camundongos Endogâmicos C57BL , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologiaRESUMO
Heat stress has been related to the impairment of behavioral and immunological parameters in broiler chickens. However, the literature is not clear on the involvement of neuroimmune interactions in a heat stress situation associated with bacterial and parasitic infections. The present study evaluated the production of monoamines and their metabolites in brain regions (rostral pallium, hypothalamus, brain stem, and midbrain) in broiler chickens submitted to chronic heat stress and/or infection and co-infection with Eimeria spp. and Clostridium perfringens type A. The heat stress and avian necrotic enteritis (NE) modulated the neurochemical profile of monoamines in different areas of the central nervous system, in particular, those related to the activity of the hypothalamus-hypophysis-adrenal (HPA) axis that is responsible for sickness behavior. C. perfringens and/or Eimeria infection, heat stress increased 5-hydroxytryptamine (5-HT), 4,4 dihydroxyphenylacetic acid (DOPAC), and DOPAC/dopamine (DA) in the rostral pallium; 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), homovanillic acid (HVA), HVA/DA, DOPAC/DA, and 5-hydroxyindoleacetic acid (5-HIAA)/5-HT in the hypothalamus; MHPG, 5-HIAA/5-HT, DOPAC/DA, and HVA/DA in the midbrain; and MHPG, DOPAC, HVA, HVA/DA, DOPAC/DA, and 5-HIAA/5-HT in the brainstem. Heat stress decreased noradrenaline + norepinephrine (NOR + AD) in all brain regions analyzed; 5-HT in the hypothalamus, midbrain, and brainstem; and DA in the midbrain. The results also showed the existence and activity of the brain-gut axis in broiler chickens. The brain neurochemical profile and corticosterone production are consistent with those observed in chronic stressed mammals, in animals with sickness behavior, and an overloading of the HPA axis.
RESUMO
Dopamine (DA) has, as of late, become singled out from the profusion of other neurotransmitters as what could be called a key substance, in the regulation of the sleep-wake states. We have hypothesized that dopaminergic D(2) receptor blockage induced by haloperidol could generate a reduction or even an ablation of rapid eye movement (REM) sleep. Otherwise, the use of the selective D(2) agonist, piribedil, could potentiate REM sleep. Electrophysiological findings demonstrate that D(2) blockage produced a dramatic reduction of REM sleep during the rebound (REB) period after 96 h of REM sleep deprivation (RSD). This reduction of REM sleep was accompanied by an increment in SWS, which is possibly accounted for the observed increase in the sleep efficiency. Conversely, our findings also demonstrate that the administration of piribedil did not generate additional increase of REM sleep. Additionally, D(2) receptors were found down-regulated, in the haloperidol group, after RSD, and subsequently up-regulated after REB group, contrasting to the D(1) down-regulation at the same period. In this sense, the current data indicate a participation of the D(2) receptor for REM sleep regulation and consequently in the REM sleep/SWS balance. Herein, we propose that the mechanism underlying the striatal D(2) up-regulation is due to an effect as consequence of RSD which originally produces selective D(2) supersensitivity, and after its period probably generates a surge in D(2) expression. In conclusion we report a particular action of the dopaminergic neurotransmission in REM sleep relying on D(2) activation.
Assuntos
Receptores de Dopamina D2/fisiologia , Privação do Sono/fisiopatologia , Sono REM/fisiologia , Sono/fisiologia , Análise de Variância , Animais , Comportamento Animal , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Haloperidol/farmacologia , Masculino , Piribedil/farmacologia , Ratos , Receptores de Dopamina D1/metabolismo , Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , Vigília/efeitos dos fármacos , Vigília/fisiologiaRESUMO
The wake-promoting drug Modafinil has been used for many years for treatment of Narcolepsy and Excessive Daytime Sleepiness, due to a dopamine-related psychostimulant action. Recent studies have indicated that Modafinil prevents neuroinflammation in animal models. Thus, the aim of the present study was to evaluate the effect of Modafinil pretreatment in the Lipopolysaccharide (LPS)-induced sickness and depressive-like behaviors. Adult male C57BL/6J mice were pretreated with Vehicle or Modafinil (90mg/Kg) and, 30min later, received a single saline or LPS (2mg/Kg) administration, and were submitted to the open field and elevated plus maze test 2h later. After 24h, mice were subjected to tail suspension test, followed by either flow cytometry with whole brain for CD11b+CD45+ cells or qPCR in brain areas for cytokine gene expression. Modafinil treatment prevented the LPS-induced motor impairment, anxiety-like and depressive-like behaviors, as well as the increase in brain CD11b+CD45high cells induced by LPS. Our results indicate that Modafinil pretreatment also decreased the IL-1ß gene upregulation caused by LPS in brain areas, which is possibly correlated with the preventive behavioral effects. The pharmacological blockage of the dopaminergic D1R by the drug SCH-23390 counteracted the effect of Modafinil on locomotion and anxiety-like behavior, but not on depressive-like behavior and brain immune cells. The dopaminergic D1 receptor signaling is essential to the Modafinil effects on LPS-induced alterations in locomotion and anxiety, but not on depression and brain macrophages. This evidence suggests that Modafinil treatment might be useful to prevent inflammation-related behavioral alterations, possibly due to a neuroimmune mechanism.
Assuntos
Compostos Benzidrílicos/farmacologia , Dopaminérgicos/farmacologia , Comportamento de Doença/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Transtornos dos Movimentos/tratamento farmacológico , Receptores de Dopamina D1/metabolismo , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Ansiedade/patologia , Benzazepinas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/patologia , Modelos Animais de Doenças , Escherichia coli , Comportamento de Doença/fisiologia , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Modafinila , Atividade Motora/fisiologia , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/metabolismo , Transtornos dos Movimentos/patologia , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Receptores de Dopamina D1/antagonistas & inibidores , Promotores da Vigília/farmacologiaRESUMO
The dopaminergic antagonist drug Domperidone has immunomodulatory effects. We investigated the effects of repeated Domperidone treatment in a model of Lypopolyssacharide (LPS)-induced acute lung inflammation. Adult C57BL/6J mice were treated with either Vehicle or Domperidone for 5days, and challenged intranasally with LPS in the following day. The behavior of mice was analyzed in the open field and elevated plus-maze test before and 24h after LPS challenge. The bronchoalveolar lavage fluid, blood and lung tissue were collected 24h and 48h after LPS challenge. Domperidone treatment increased LPS-induced tumor necrosis factor (TNF) and interleukin (IL)-6 production in the bronchoalveolar lavage fluid, without altering tissue damage and the number of immune cells in the lungs and circulation. Locomotor and anxiety-like behavior were unchanged after Domperidone and/or LPS treatment. Cytokine data indicate that Domperidone promotes a change in activity of other cell types, likely alveolar epithelial cells, without affecting immune cell migration in the present model. Due to the role of these cytokines in progression of inflammation, Domperidone treatment may exacerbate a subsequent inflammatory injury.
Assuntos
Lesão Pulmonar Aguda/imunologia , Domperidona/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Mucosa Respiratória/fisiologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Progressão da Doença , Domperidona/efeitos adversos , Antagonistas de Dopamina/efeitos adversos , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Respiratória/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The wake-promoting drug Modafinil has been used for treatment of sleep disorders, such as Narcolepsy, excessive daytime sleepiness and sleep apnea, due to its stimulant action. Despite the known effect of Modafinil on brain neurochemistry, particularly on brain dopamine system, recent evidence support an immunomodulatory role for Modafinil treatment in neuroinflammatory models. Here, we aimed to study the effects of in vitro and in vivo Modafinil treatment on activation, proliferation, cell viability, and cytokine production by immune cells in splenocytes culture from mice. The results show that in vitro treatment with Modafinil increased Interferon (IFN)-γ, Interleukin (IL)-2 and IL-17 production and CD25 expression by T cells. In turn, in vivo Modafinil treatment enhanced splenocyte production of IFN-γ, IL-6 and tumor necrosis factor (TNF), and increased the number of IFN-γ producing cells. Next, we addressed the translational value of the observed effects by testing PBMCs from Narcolepsy type 1 patients that underwent Modafinil treatment. We reported increased number of IFN-γ producing cells in PBMCs from Narcolepsy type 1 patients following continuous Modafinil treatment, corroborating our animal data. Taken together, our results show, for the first time, a pro-inflammatory action of Modafinil, particularly on IFN-mediated immunity, in mice and in patients with Narcolepsy type 1. The study suggests a novel effect of this drug treatment, which should be taken into consideration when given concomitantly with an ongoing inflammatory or autoimmune process.
Assuntos
Compostos Benzidrílicos/farmacologia , Fatores Imunológicos/farmacologia , Interferons/metabolismo , Promotores da Vigília/farmacologia , Animais , Compostos Benzidrílicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Modafinila , Narcolepsia/sangue , Narcolepsia/tratamento farmacológico , Narcolepsia/imunologia , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Promotores da Vigília/uso terapêuticoRESUMO
Early life experiences, particularly during the gestational period, are homeostatic determinants for an individual's brain development. However, recent data suggest that the immune response of the offspring is also affected by events during the gestational period. Here, we evaluated the impact of prenatal immune activation on the innate and adaptive immune responses of adult offspring. Pregnant Swiss mice received saline or lipopolysaccharide (LPS) on gestational day 17. In adulthood, male offspring were analyzed using 2 experimental techniques: in vitro analysis of cytokine production and immune cell activity and development of the delayed-type hypersensitivity (DTH) responses of ovalbumin-sensitized mice. We analyzed Th1/Th2/Th17 cytokine production in vitro, neutrophil and dendritic cell function, and the DTH response. Offspring from LPS-treated dams displayed increased cell-mediated immunity as indicated by increased IL-12 production by cultured antigen-presenting cells and an enhanced DTH response as well as impaired production of the regulatory cytokine IL-10. This study provides new insights regarding the influence of immune activation during late gestation on the immunological homeostasis of offspring, particularly on Th1 immunity.
Assuntos
Hipersensibilidade Tardia/imunologia , Imunidade Celular , Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal , Alérgenos/imunologia , Animais , Células Cultivadas , Citocinas/imunologia , Células Dendríticas , Feminino , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Neutrófilos/imunologia , Ovalbumina/imunologia , Baço/citologiaRESUMO
While the effects of sleep deprivation (SD) on the acquisition and consolidation phases of memory have been extensively characterized, its effects on memory retrieval remain overlooked. SD alone is a stressor, and stress-activated glucocorticoids promote bimodal effects on memory. Because we have recently demonstrated that 72h SD impairs memory retrieval in the plus-maze discriminative avoidance task (PM-DAT) in mice, this study investigated whether shorter SD periods would facilitate retrieval. In Experiment I, the temporal forgetting curve of the PM-DAT was determined and an interval between training/testing in which retrieval was no longer present was used in all subsequent experiments. In Experiments II and III, retrieval performance and corticosterone concentration, respectively, were quantified in mice that were sleep deprived for 12 or 24h before testing. In Experiments IV and V, the effects of the corticosterone synthesis inhibitor metyrapone were evaluated on 12h SD-induced retrieval reinstatement and corticosterone concentration enhancement, respectively. Experiment VI determined whether pre-test acute administration of exogenous corticosterone would mimic the facilitatory effects of 12h SD on retrieval. Thirty days after training, mice presented poor performance of the task; however, SD for 12h (but not for 24) before testing reinstated memory retrieval. This facilitatory effect was accompanied by increased corticosterone concentration, abolished by metyrapone, and mimicked by pre-test acute corticosterone administration. Collectively, short-term SD can facilitate memory retrieval by enhancing corticosterone secretion. This facilitatory effect is abolished by longer periods of SD.