RESUMO
BACKGROUND: Current therapies targeting several neurotransmitter systems are only able to partially mitigate the symptoms of stress- and trauma-related disorder. Stress and trauma-related disorders lead to a prominent inflammatory response in humans, and in pre-clinical models. However, mechanisms underlying the induction of neuroinflammatory response in PTSD and anxiety disorders are not clearly understood. The present study investigated the mechanism underlying the activation of proinflammatory NLRP3 inflammasome and IL1ß in mouse models of stress. METHODS: We used two mouse models of stress, i.e., mice subjected to physical restraint stress with brief underwater submersion, and predator odor stress. Mice were injected with MCC950, a small molecule specific inhibitor of NLRP3 activation. To pharmacologically inhibit BTK, a specific inhibitor ibrutinib was used. To validate the observation from ibrutinib studies, a separate group of mice was injected with another BTK-specific inhibitor LFM-A13. Seven days after the induction of stress, mice were examined for anxious behavior using open field test (OFT), light-dark test (LDT), and elevated plus maze test (EPM). Following the behavior tests, hippocampus and amygdale were extracted and analyzed for various components of NLRP3-caspase 1-IL1ß pathway. Plasma and peripheral blood mononuclear cells were also used to assess the induction of NLRP3-Caspase 1-IL-1ß pathway in stressed mice. RESULTS: Using two different pre-clinical models of stress, we demonstrate heightened anxious behavior in female mice as compared to their male counterparts. Stressed animals exhibited upregulation of proinflammatory IL1ß, IL-6, Caspase 1 activity and NLRP3 inflammasome activation in brain, which were significantly higher in female mice. Pharmacological inhibition of NLRP3 inflammasome activation led to anxiolysis as well as attenuated neuroinflammatory response. Further, we observed induction of activated Bruton's tyrosine kinase (BTK), an upstream positive-regulator of NLRP3 inflammasome activation, in hippocampus and amygdala of stressed mice. Next, we conducted proof-of-concept pharmacological BTK inhibitor studies with ibrutinib and LFM-A13. In both sets of experiments, we found BTK inhibition led to anxiolysis and attenuated neuroinflammation, as indicated by significant reduction of NLRP3 inflammasome and proinflammatory IL-1ß in hippocampus and amygdala. Analysis of plasma and peripheral blood mononuclear cells indicated peripheral induction of NLRP3-caspase 1-IL1ß pathway in stressed mice. CONCLUSION: Our study identified BTK as a key upstream regulator of neuroinflammation, which drives anxiogenic behavior in mouse model of stress. Further, we demonstrated the sexually divergent activation of BTK, providing a clue to heightened neuroinflammation and anxiogenic response to stress in females as compared to their male counterparts. Our data from the pharmacological inhibition studies suggest BTK as a novel target for the development of potential clinical treatment of PTSD and anxiety disorders. Induction of pBTK and NLRP3 in peripheral blood mononuclear cells of stressed mice suggest the potential effect of stress on systemic inflammation.
Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Ansiedade/enzimologia , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Estresse Psicológico/enzimologia , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Amidas/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Feminino , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nitrilas/farmacologia , Odorantes , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Restrição Física/efeitos adversos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/psicologiaRESUMO
Alcohol use-associated disorders are highly comorbid with anxiety disorders; however, their mechanism remains unknown. The amygdala plays a central role in anxiety. We recently found that 7,8-dihydroxyflavone (7,8-DHF) significantly reduces withdrawal symptoms in a rat model of chronic intermittent alcohol (ethanol) exposure. This study aimed to determine the role of 7,8-DHF in regulating anxiety induced by chronic alcohol exposure and its associated underlying mechanism. Male C57BL/6J mice were exposed to chronic intermittent alcohol for 3 weeks followed by alcohol withdrawal for 12 h with or without 7,8-DHF administered intraperitoneally. All mice were tested using an open field test and elevated plus maze to assess anxiety-like behaviors. Synaptic activity and intrinsic excitability in basal and lateral amygdala (BLA) neurons were assessed using electrophysiological recordings. 7,8-DHF alleviated alcohol-induced anxiety-like behavior and attenuated alcohol-induced enhancement of activities in BLA pyramidal neurons. Furthermore, 7,8-DHF prevented alcohol withdrawal-evoked augmentation of glutamatergic transmission in the amygdala and had no effect on GABAergic transmission in the amygdala, as demonstrated by unaltered frequency and amplitude of spontaneous inhibitory postsynaptic currents. Microinjection of K252a, a tropomyosin-related kinase B (TrkB) antagonist, into the BLA blocked the effects of 7,8-DHF on anxiety-like behavior and neuronal activity in the BLA. Our findings suggest that 7,8-DHF alleviates alcohol-induced anxiety-like behavior induced by chronic alcohol exposure through regulation of glutamate transmission involving TrKB in the BLA.
Assuntos
Tonsila do Cerebelo/enzimologia , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Comportamento Animal , Flavonas/uso terapêutico , Receptor trkB/metabolismo , Animais , Ansiedade/enzimologia , Comportamento Animal/efeitos dos fármacos , Carbazóis/farmacologia , Modelos Animais de Doenças , Etanol , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Flavonas/farmacologia , Ácido Glutâmico/metabolismo , Alcaloides Indólicos/farmacologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Síndrome de Abstinência a Substâncias/patologia , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismoRESUMO
Excessive binge alcohol intake is a common drinking pattern in humans, especially during holidays. Cessation of the binge drinking often leads to aberrant withdrawal behaviors, as well as serious heart rhythm abnormalities (clinically diagnosed as Holiday Heart Syndrome (HHS)). In our HHS mouse model with well-characterized binge alcohol withdrawal (BAW)-induced heart phenotypes, BAW leads to anxiety-like behaviors and cognitive impairment. We have previously reported that stress-activated c-Jun NH(2)-terminal kinase (JNK) plays a causal role in BAW-induced heart phenotypes. In the HHS brain, we found that activation of JNK2 (but not JNK1 and JNK3) in the prefrontal cortex (PFC), but not hippocampus and amygdala, led to anxiety-like behaviors and impaired cognition. DNA methylation mediated by a crucial DNA methylation enzyme, DNA methyltransferase1 (DNMT1), is known to be critical in alcohol-associated behavioral deficits. In HHS mice, JNK2 in the PFC (but not hippocampus and amygdala) causally enhanced total genomic DNA methylation via increased DNMT1 expression, which was regulated by enhanced binding of JNK downstream transcriptional factor c-JUN to the DNMT1 promoter. JNK2-specific inhibition either by an inhibitor JNK2I or JNK2 knockout completely offset c-JUN-regulated DNMT1 upregulation and restored the level of DNA methylation in HHS PFC to the baseline levels seen in sham controls. Strikingly, either JNK2-specific inhibition or genetic JNK2 depletion or DNMT1 inhibition (by an inhibitor 5-Azacytidine) completely abolished BAW-evoked behavioral deficits. In conclusion, our studies revealed a novel mechanism by which JNK2 drives BAW-evoked behavioral deficits through a DNMT1-regulated DNA hypermethylation. JNK2 could be a novel therapeutic target for alcohol withdrawal treatment and/or prevention.
Assuntos
Comportamento Animal , Consumo Excessivo de Bebidas Alcoólicas , Metilação de DNA , Proteína Quinase 9 Ativada por Mitógeno , Síndrome de Abstinência a Substâncias , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/enzimologia , Ansiedade/genética , Consumo Excessivo de Bebidas Alcoólicas/enzimologia , Consumo Excessivo de Bebidas Alcoólicas/genética , Cognição , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/genética , Córtex Pré-Frontal/metabolismo , Síndrome de Abstinência a Substâncias/enzimologia , Síndrome de Abstinência a Substâncias/genéticaRESUMO
Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5'-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme's role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.
Assuntos
Fosfatase Alcalina/genética , Ansiedade/genética , Osso e Ossos/enzimologia , Depressão/genética , Hipofosfatasia/genética , Convulsões/genética , Dente/enzimologia , Fosfatase Alcalina/deficiência , Animais , Ansiedade/enzimologia , Ansiedade/patologia , Osso e Ossos/patologia , Calcificação Fisiológica/genética , Depressão/enzimologia , Depressão/patologia , Difosfatos/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Humanos , Hipofosfatasia/enzimologia , Hipofosfatasia/patologia , Mutação , Convulsões/enzimologia , Convulsões/patologia , Índice de Gravidade de Doença , Dente/crescimento & desenvolvimento , Vitamina B 6/metabolismoRESUMO
Acyl-CoA dehydrogenase 10 (Acad10)-deficient mice develop impaired glucose tolerance, peripheral insulin resistance, and abnormal weight gain. In addition, they exhibit biochemical features of deficiencies of fatty acid oxidation, such as accumulation of metabolites consistent with abnormal mitochondrial energy metabolism and fasting induced rhabdomyolysis. ACAD10 has significant expression in mouse brain, unlike other acyl-CoA dehydrogenases (ACADs) involved in fatty acid oxidation. The presence of ACAD10 in human tissues was determined using immunohistochemical staining. To characterize the effect of ACAD10 deficiency on the brain, micro-MRI and neurobehavioral evaluations were performed. Acad10-deficient mouse behavior was examined using open field testing and DigiGait analysis for changes in general activity as well as indices of gait, respectively. ACAD10 protein was shown to colocalize to mitochondria and peroxisomes in lung, muscle, kidney, and pancreas human tissue. Acad10-deficient mice demonstrated subtle behavioral abnormalities, which included reduced activity and increased time in the arena perimeter in the open field test. Mutant animals exhibited brake and propulsion metrics similar to those of control animals, which indicates normal balance, stability of gait, and the absence of significant motor impairment. The lack of evidence for motor impairment combined with avoidance of the center of an open field arena and reduced vertical and horizontal exploration are consistent with a phenotype characterized by elevated anxiety. These results implicate ACAD10 function in normal mouse behavior, which suggests a novel role for ACAD10 in brain metabolism.
Assuntos
Acil-CoA Desidrogenase/genética , Ansiedade/genética , Encéfalo/enzimologia , Metabolismo Energético/genética , Mitocôndrias/enzimologia , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/metabolismo , Animais , Ansiedade/enzimologia , Ansiedade/fisiopatologia , Comportamento Animal , Encéfalo/diagnóstico por imagem , Carnitina/análogos & derivados , Carnitina/metabolismo , Marcha/fisiologia , Humanos , Rim/enzimologia , Fígado/enzimologia , Pulmão/enzimologia , Imageamento por Ressonância Magnética , Aprendizagem em Labirinto , Camundongos , Camundongos Knockout , Músculo Esquelético/enzimologia , Pâncreas/enzimologia , Peroxissomos/enzimologiaRESUMO
Intracellular signalling pathways have been extensively studied as therapeutic targets for the treatment of mental diseases. Our attention has been caught by two kinases potentially involved in anxiety, ERK1/2 and CaMKII. The study aimed to examine changes in the activation of ERK1/2 and CaMKII concerning anxiolytic-like behaviours in mice. To evaluate anxiety-related response in mice, we used the open field test and the elevated plus maze test. Behavioural studies were complemented with the immunoblotting analysis to identify proteins of interest in the cortex, hippocampus, and striatum. We analysed the phosphorylation status of ERK1/2 and CaMKII in mice treated with a well-known anxiolytic drug - diazepam. Next, the blockade of ERK1/2 pathway by SL-327, a selective MEK1/2 inhibitor, was checked for anxiolytic action. Finally, the co-administration of subeffective doses of diazepam and SL-327 was investigated for a potential synergistic anxiolytic effect. Anxiolytic effects of acute diazepam are accompanied by decreased p-ERK1/2 and upregulation of p-CaMKII. Subchronic treatment with SL-327 leads to the manifestation of anxiolytic-like behaviours and changes in the phosphorylation status of both kinases in a diazepam-like manner. Co-administration of subeffective doses of SL-327 and diazepam induces anxiolysis, which is CaMKII-independent and correlates to selectively decreased phosphoactive ERK1/2 in the hippocampus. The MEK-ERK pathway is significantly involved in anxiolytic action of diazepam and its prolonged inhibition produces anxiolytic-like phenotype in mice. ERK inhibition could be used to manage anxiety symptoms in a benzodiazepine-sparing regimen for treatment of anxiety.
Assuntos
Aminoacetonitrila/análogos & derivados , Ansiolíticos/administração & dosagem , Ansiedade/prevenção & controle , Diazepam/administração & dosagem , Hipocampo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Aminoacetonitrila/administração & dosagem , Animais , Ansiedade/enzimologia , Ansiedade/psicologia , Sinergismo Farmacológico , Hipocampo/enzimologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologiaRESUMO
Cyclooxygenases are a group of heme-containing isozymes (namely Cox-1 and Cox-2) that catalyze the conversion of arachidonic acid to largely bioactive prostaglandins (PGs). Cox-1 is the ubiquitous housekeeping enzyme, and the mitogen-inducible Cox-2 is activated to cause inflammation. Interestingly, Cox-2 is constitutively expressed in the brain at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Neuronal Cox-2 is activated in response to synaptic excitation to yield PGE2, the predominant Cox-2 metabolite in the brain, which in turn stimulates the release of glutamate and neuronal firing in a retrograde fashion. Cox-2 is also engaged in the metabolism of new endocannabinoids from 2-arachidonoyl-glycerol to modulate their actions at presynaptic terminals. In addition to these interactions, the induction of neuronal Cox-2 is coupled to the trans-synaptic activation of the dopaminergic mesolimbic system and some serotoninergic receptors, which might contribute to the development of emotional behavior. Although much of the focus regarding the induction of Cox-2 in the brain has been centered on neuroinflammation-related neurodegenerative and psychiatric disorders, some evidence also suggests that Cox-2 release during neuronal signaling may be pivotal for the fine tuning of cortical networks to regulate behavior. This review compiles the evidence supporting the homeostatic role of neuronal Cox-2 in synaptic transmission and plasticity, since neuroinflammation is originally triggered by the induction of glial Cox-2 expression. The goal is to provide perspective on the roles of Cox-2 beyond neuroinflammation, such as those played in memory and anxiety, and whose evidence is still scant.
Assuntos
Ansiedade/enzimologia , Ansiedade/fisiopatologia , Encéfalo/enzimologia , Ciclo-Oxigenase 2/metabolismo , Homeostase , Inflamação/patologia , Memória/fisiologia , Neurônios/patologia , Animais , HumanosRESUMO
Growing evidence demonstrates that Oxaliplatin (OXA) is commonly associated with neurotoxicity that leads to emotional and cognitive impairments. The aim of the present study was to evaluate the OXA and Na+, K+-ATPase interaction and to correlate anxious behavior and cognitive impairment induced by this chemotherapeutic in Swiss mice. Also, considering the pharmacological modulation of Na+, K+-ATPase as a potential target for OXA-induced neurotoxicity, the therapeutic potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) was evaluated. Mice received OXA (10 mg kg-1) or vehicle by intraperitoneal route (days 0 and 2). Oral administration of 4-PSQ (1 mg kg-1) or vehicle was performed from days 2-14. Behavioral tasks started from day 12 onwards. On day 15, the animals were sacrificed, and the tissues collected. The effects of OXA and 4-PSQ on activity and expression level of Na+, K+-ATPase in the hippocampus and cerebral cortex, and the plasmatic corticosterone levels were determined. The findings demonstrated a significant positive correlation between anxious behavior and cognitive impairment induced by OXA. OXA caused an increase on the plasmatic corticosterone levels and reduced activity and expression level of Na+, K+-ATPase. 4-PSQ reduced both anxious behavior and cognitive impairment induced by OXA. 4-PSQ effect seems to be due to the modulation of Na+, K+-ATPase and reduction of corticosterone levels. Our results helped to expand knowledge about the mechanisms involved in the physiopathology of the OXA-induced neurotoxicity and strongly indicated that 4-PSQ may be a good prototype for the treatment of anxious behavior and cognitive impairment induced by OXA exposure.
Assuntos
Ansiedade/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Oxaliplatina/toxicidade , Quinolinas/uso terapêutico , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Animais , Antineoplásicos/toxicidade , Ansiedade/induzido quimicamente , Ansiedade/enzimologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/enzimologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Changes in sphingolipid metabolism have been suggested to contribute to the pathophysiology of major depression. In this study, we investigated the activity of acid and neutral sphingomyelinases (ASM, NSM) and ceramidases (AC, NC), respectively, in twelve brain regions of female rats selectively bred for high (HAB) versus low (LAB) anxiety-like behavior. Concomitant with their highly anxious and depressive-like phenotype, HAB rats showed increased activity of ASM and NSM as well as of AC and NC in multiple brain regions associated with anxiety- and depressive-like behavior, including the lateral septum, hypothalamus, ventral hippocampus, ventral and dorsal mesencephalon. Strong correlations between anxiety-like behavior and ASM activity were found in female HAB rats in the amygdala, ventral hippocampus and dorsal mesencephalon, whereas NSM activity correlated with anxiety levels in the dorsal mesencephalon. These results provide novel information about the sphingolipid metabolism, especially about the sphingomyelinases and ceramidases, in major depression and comorbid anxiety.
Assuntos
Ansiedade/enzimologia , Encéfalo/enzimologia , Depressão/enzimologia , Esfingolipídeos/metabolismo , Animais , Comportamento Animal , Feminino , Fenótipo , RatosRESUMO
Cytochrome P450 C19 (CYP2C19) metabolizes exogenous and endogenous compounds. Although CYP2C19 is highly expressed in the liver, it is also expressed in the brain during early life. Previous human and animal studies have linked CYP2C19 genotype-predicted enzyme activity to hippocampal volumes, depressive symptoms, and anxiety-like behaviors. We examined these promising associations in a general community sample comprising 386 Caucasian adults with no history of psychiatric or neurological illnesses. Contrary to previous findings, CYP2C19 genotype-predicted enzyme activity was not associated with hippocampal volumes, nor depressive and anxiety symptoms. Interstudy differences in CYP2C19 frequencies and/or study methodology may explain this discrepancy.
Assuntos
Ansiedade/diagnóstico por imagem , Citocromo P-450 CYP2C19/metabolismo , Depressão/diagnóstico por imagem , Genótipo , Hipocampo/diagnóstico por imagem , Adulto , Animais , Ansiedade/enzimologia , Ansiedade/genética , Estudos Transversais , Citocromo P-450 CYP2C19/genética , Depressão/enzimologia , Depressão/genética , Ativação Enzimática/fisiologia , Feminino , Hipocampo/enzimologia , Humanos , Masculino , Tamanho do Órgão/fisiologiaRESUMO
Anxiety and depression impact dramatically on public health, underlying the importance of alternative cost-effective treatments. Previous studies have shown that biophysical treatment can significantly reduce anxiety symptoms and recently, salivary alpha-amylase (SAA) has been identified as an objective correlate of the sympathetic-parasympathetic imbalance related to increased stress burden, defined as allostatic load. The aim of this study was to evaluate the effect of biophysical therapy on SAA levels, in addition to the Depression Anxiety Stress Scale (DASS)-21 questionnaire. Twenty-four workers (sales representatives) presenting with mild anxiety/stress symptoms (Generalized Anxiety Disorder 7-item scale of > 5) were randomized to biophysical treatment (N = 12) or placebo control (N = 12). The biophysical group underwent electromagnetic information transfer through an aqueous system procedure, with daily self-administration for one month. SAA collection and the DASS-21 questionnaire were undertaken at baseline and after one month in all patients. Clinical characteristics and baseline DASS-21 subscale scores were similar between placebo and biophysical group at baseline. After one month, patients receiving biophysical therapy had significantly reduced SAA levels compared to the placebo group (27.8 ± 39.4 vs. 116.8 ± 114.9 U/mL, p = 0.019). All three DASS-21 subscales, depression (9.3 ± 5.1 vs. 5.7 ± 5.5, p = 0.1), anxiety (6.7 ± 25 vs. 3.7 ± 2.2, p = 0.0049) and stress (10.8 ± 4.2 vs. 7.3 ± 3.7, p = 0.041) were also decreased after biophysical treatment compared to placebo after one month. Our findings suggest that biophysical therapy can benefit workers with mild (subclinical) anxiety/stress. These results were also validated by the concomitant reduction of SAA levels and an improvement in DASS-21 subscales. The underlying molecular mechanisms of this therapy remain to be characterized.
Assuntos
Ansiedade/enzimologia , Ansiedade/terapia , Campos Eletromagnéticos , alfa-Amilases Salivares/metabolismo , Estresse Psicológico/terapia , Adulto , Humanos , Projetos Piloto , Placebos , Inquéritos e QuestionáriosRESUMO
The aim of the present study was to investigate the effect of rutin administration (100â¯mg/kg/day) to pentylenetetrazol (PTZ)-treated Balb-c mice (60â¯mg/kg/day), with respect to anxiety-like behavior using both open-field and elevated plus-maze (EPM) tests, and acetylcholinesterase (AChE) activity in salt-soluble (SS) fraction and detergent-soluble (DS) fraction of the cerebral cortex, hippocampus, striatum, midbrain, and diencephalon. Our results demonstrated that the administration of PTZ in 3 doses and the induction of seizures increased significantly anxiety behavior of mice and reduced significantly DS-AChE activity in all brain regions examined, while the reduction in the SS fraction was brain region-specific. Rutin administration to normal mice did not affect their behavior, while it induced a brain region-specific reduction in SS-AChE and a significant decrease in DS-AChE in all brain regions. We demonstrated for the first time that pretreatment of PTZ-mice with rutin (PTZâ¯+â¯Rutin group) prevented the manifestation of anxiety and induced interestingly a further significant reduction on the SS- and DS-AChE activities only in the cerebral cortex and striatum, in comparison with PTZ group. Our results show that rutin exhibits an important anxiolytic effect and an anticholinesterase activity in specific brain areas in the seizure model of PTZ.
Assuntos
Acetilcolinesterase/metabolismo , Ansiedade/tratamento farmacológico , Ansiedade/enzimologia , Encéfalo/enzimologia , Pentilenotetrazol/toxicidade , Rutina/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/enzimologia , Animais , Encéfalo/efeitos dos fármacos , Isoenzimas/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Rutina/farmacologia , Convulsões/induzido quimicamente , Resultado do TratamentoRESUMO
BACKGROUND: The cholinergic system has an important role in mood regulation. Cholinesterase inhibitor pesticides (e.g. organophosphates) appear to increase depression and anxiety symptoms in the few existing animal and human studies. Human studies have not described such associations using biomarkers of exposure and studies among children are needed. METHODS: We studied 529 adolescents (ages 11-17y) in agricultural communities in the Ecuadorian Andes (ESPINA study). Acetylcholinesterase (AChE) activity was measured in a finger-stick sample. Anxiety and depression symptoms were assessed using the CDI-2 and MASC-2 (greater scores reflect greater internalizing symptoms). Models adjusted for age, gender, hemoglobin, income among others. RESULTS: The median age was 14.38y and 51% were female. The mean (SD) of the following parameters were: AChE 3.7 U/mL (0.55), depression T-score 53.0 (9.4) and anxiety T-score: 57.6 (9.8). Lower AChE activity (reflecting greater cholinesterase inhibitor exposure) was associated with higher depression symptoms (difference per SD decrease of AChE [ß [95% CI:]]: 1.09 [0.02, 2.16]), was stronger among girls (ßâ¯=â¯1.61) than boys (ßâ¯=â¯0.69), and among younger (<14.38y, ßâ¯=â¯1.61) vs. older children (ßâ¯=â¯0.57). The associations were strongest among girls <14.38y (ßâ¯=â¯3.30 [0.54, 6.05], OR for elevated symptoms per SD decrease in AChEâ¯=â¯2.58 [1.26, 5.27]). No associations were observed with anxiety scores. Analyses of AChE change between 2008 and 2016 concurred with these findings. DISCUSSION: We observed associations between a biomarker of pesticide exposure and children's depression symptoms. Lower AChE activity may create risk for depression in teenagers, particularly among girls during early adolescence.
Assuntos
Acetilcolinesterase/sangue , Ansiedade/enzimologia , Inibidores da Colinesterase , Depressão/enzimologia , Exposição Ambiental , Praguicidas , Adolescente , Biomarcadores/sangue , Criança , Equador , Feminino , Horticultura , Humanos , MasculinoRESUMO
UBA6 is an alternative enzyme for ubiquitin activation in vertebrates that plays a pivotal role in early mouse development. Previously, we reported that the Uba6 brain-specific knockout (NKO) mouse is a novel autism spectrum disorder (ASD) mouse model that displays decreased social behavior and communication. To determine the therapeutic impact of environmental stimulation in ASDs, we investigated the behavioral and molecular changes of the NKO and control mice after exposure to environmental enrichment and paired housing in different developmental phases. Our results demonstrated that early paired housing could diminish the ASD phenotypes of NKO mice such as impaired nest building and social interaction and anxiety. Additionally, increased histone acetylation in the amygdala was observed in NKO mice after paired housing without a change in Ube3a levels. Our data suggest that paired housing at an early time point can play a crucial role in ameliorating ASD behavior and can be applied in other ASD animal models or clinical settings.
Assuntos
Tonsila do Cerebelo/enzimologia , Ansiedade/genética , Transtorno do Espectro Autista/genética , Abrigo para Animais , Enzimas Ativadoras de Ubiquitina/genética , Acetilação , Animais , Ansiedade/enzimologia , Ansiedade/fisiopatologia , Ansiedade/prevenção & controle , Transtorno do Espectro Autista/enzimologia , Transtorno do Espectro Autista/fisiopatologia , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Expressão Gênica , Histonas/genética , Histonas/metabolismo , Relações Interpessoais , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Knockout , Comportamento de Nidação/fisiologia , Ubiquitina/genética , Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/deficiência , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Phosphodiesterase-2 (PDE2) is a cyclic nucleotide phosphodiesterase and is highly expressed in the amygdala, which suggests its important role in anxiety-like behavior. AIMS: The present study examined whether reduced PDE2A expression in the central nucleus of the amygdala (CeA) produces anxiolytic-like effects in mice. METHODS: PDE2A knockdown in amygdaloid (AR5) cells or the CeA was established using a lentiviral vector-based siRNA system. The anxiety-like behaviors were detected by the elevated plus maze (EPM) and hole-board tests in mice. The related proteins involved in cAMP/cGMP-dependent signaling, such as specific marker VASPser239, CREBser133 and BDNF were detected by immunoblot analysis. RESULTS: PDE2A inhibition in AR-5 cells resulted in increases in cAMP/cGMP-related pVASPser239 and pCREBser133. Behavioral tests showed that PDE2A knockdown in the CeA induced anxiolytic-like effects as evidenced by the increases in percentages of open-arm entries and time spent in the open arms in the EPM test, and the increases in head dips and time spent in head dipping in the hole-board test. However, these anxiolytic-like effects were antagonized by pre-treatment of soluble guanylyl cyclase inhibitor ODQ or adenylate cyclase inhibitor SQ. Furthermore, PDE2A knockdown significantly increased pVASPSer239, pCREBSer133 and decreased BDNF expression in the amygdala. Pre-intra-CeA of ODQ or SQ reversed or partially prevented the eï¬ects of PDE2A knockdown on these proteins. CONCLUSIONS: The results suggest that PDE2A plays a crucial role in the regulation of anxiety by the cGMP/cAMP-dependent pVASP-pCREB-BDNF signaling pathway.
Assuntos
Ansiedade/metabolismo , Comportamento Animal/fisiologia , Núcleo Central da Amígdala/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Transdução de Sinais/fisiologia , Animais , Ansiedade/enzimologia , Linhagem Celular , Núcleo Central da Amígdala/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/deficiência , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Accumulating evidence from preclinical and clinical studies indicates prenatal exposure to stress or excess glucocorticoids can affect offspring brain. HDAC2 is an important target of glucocorticoid. Here we detected HDAC2 expression in male offspring hippocampus from gestational restraint stressed rat during development and the relationship between HDAC2 expression and behaviors and neurogenesis in male offspring. Pregnant rats received restrained stress during the last week of pregnancy. Expressions of HDAC2 in offspring hippocampus were detected on postnatal 0 day (P0) and 60 days (P60). Neurogenesis was evaluated by Doublecortin (DCX) staining on P60. Anxiety-like behavior and cognition were detected in open field, elevated plus maze, novel object recognition test, and Barnes maze. We found that HDAC2 expression in the hippocampus of male prenatally stressed offspring (MPSO) was similar to the male control offspring on P0, but significantly lower on P60. Corresponding to the decreased expression of HDAC2 in MPSO hippocampus at P60, neurogenesis in the dentate gyrus of MPSO was significantly lower than the control male offspring. And MPSO also showed greater anxiety and poorer learning and memories abilities than control male offspring. These showed that HDAC2 could partly explain the effects of gestational stress on male offspring behaviors.
Assuntos
Hipocampo/embriologia , Hipocampo/enzimologia , Histona Desacetilase 2/metabolismo , Complicações na Gravidez/enzimologia , Efeitos Tardios da Exposição Pré-Natal/enzimologia , Animais , Ansiedade/enzimologia , Giro Denteado/embriologia , Giro Denteado/enzimologia , Proteína Duplacortina , Feminino , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Atividade Motora/fisiologia , Neurogênese , Gravidez , Complicações na Gravidez/psicologia , Ratos , Ratos Sprague-Dawley , Restrição Física , Estresse Psicológico/metabolismoRESUMO
BACKGROUND: Patients undergoing surgery often feel anxious. Accumulating evidence indicated that presurgical anxiety was related to the more severe postsurgical pain. An animal model was established that exposed Sprague-Dawley rats to a single-prolonged stress (SPS) procedure to induce presurgical anxiety-like behaviors. The experiment revealed that presurgical anxiety not only aggravated but also prolonged postsurgical pain. However, the underlying mechanisms were unknown. METHODS: The rats in group C + Cort, group I + Cort, group A + Cort, and group AI + Cort were injected with corticosterone. The rats in group C + RU486, group I + RU486, group A + RU486, and group AI + RU486 were injected with mifepristone (RU486). The rats in group C + GSK650394 and group AI + GSK650394 were injected with GSK650394. The rats in group C + FC1 and group AI + FC1 were injected with fluorocitrate (FC) 30 minutes before SPS, 30 minutes before incision, and on postoperative days 1, 2, 3, 4, and 5. The rats in group C + FC2 and group AI + FC2 were injected with FC on postoperative days 7, 8, 9, 10, 11, 12, and 13. The paw withdrawal mechanical threshold was assessed 24 hours before SPS and from postoperative days 1 to 28. The level of corticosterone was determined by enzyme-linked immunosorbent assay. The expression of serum/glucocorticoid regulated kinase 1 (SGK1), interleukin-1ß, and tumor necrosis factor-α was visualized by Western blot. The concentrations of adenosine triphosphate (ATP) were measured by ATP assay kit. RESULTS: This study showed SPS elevated plasma glucocorticoids and ATP release from astrocytes, which meant the mechanical pain hypersensitivity in presurgical anxiety-induced postsurgical hyperalgesia was dependent on GCs-SGK1-ATP signaling pathway. SGK1 protein level in astrocytes was increased in response to the glucocorticoid stimuli and enhanced the extracellular release of ATP. Furthermore, spinal astrocytes played a key role in the maintenance. Targeting spinal astrocytes in maintenance phase prevented the pathological progression. CONCLUSIONS: These data suggested an important signaling pathway that affected the pain sensitivity after operation caused by presurgical anxiety.
Assuntos
Trifosfato de Adenosina/metabolismo , Ansiedade/complicações , Astrócitos/efeitos dos fármacos , Corticosterona/farmacologia , Hiperalgesia/etiologia , Proteínas Imediatamente Precoces/metabolismo , Limiar da Dor/efeitos dos fármacos , Dor Pós-Operatória/etiologia , Proteínas Serina-Treonina Quinases/metabolismo , Medula Espinal/efeitos dos fármacos , Procedimentos Cirúrgicos Operatórios , Animais , Ansiedade/enzimologia , Ansiedade/fisiopatologia , Astrócitos/enzimologia , Corticosterona/metabolismo , Modelos Animais de Doenças , Hiperalgesia/enzimologia , Hiperalgesia/fisiopatologia , Interleucina-1beta/metabolismo , Masculino , Dor Pós-Operatória/enzimologia , Dor Pós-Operatória/fisiopatologia , Ratos Sprague-Dawley , Sistemas do Segundo Mensageiro , Medula Espinal/enzimologia , Medula Espinal/fisiopatologia , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Procedimentos Cirúrgicos Operatórios/psicologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Soluble epoxide hydrolase (sEH), an enzyme with COOH-terminal hydrolase and NH2-terminal lipid phosphatase activities, is expressed in regions of the brain such as the cortex, white matter, hippocampus, substantia nigra, and striatum. sEH is involved in the regulation of cerebrovascular and neuronal function upon pathological insults. However, the physiological significance of sEH and its underlying mechanism in modulating brain function are not fully understood. In this study, we investigated the role of sEH in anxiety and potential underlying mechanisms in mice. Western blot for protein phosphorylation and expression was performed. Immunohistochemical analyses and Nissl and Golgi staining were performed for histological examination. Mouse behaviors were evaluated by open field activity, elevated plus maze, classical fear conditioning, social preference test, and Morris water maze. Our results demonstrated that the expression of sEH was upregulated during postnatal development in wild-type (WT) mice. Genetic deletion of sEH (sEH-/-) in mice resulted in anxiety-like behavior and disrupted social preference. Increased olfactory bulb (OB) size and altered integrity of neurites were observed in sEH-/- mice. In addition, ablation of sEH in mice decreased protein expression of tyrosine hydroxylase and reduced dopamine production in the brain. Moreover, the level of phosphorylated calmodulin kinase II (CaMKII) and glycogen synthase kinase 3 α/ß (GSK3α/ß) was higher in sEH-/- mice than in WT mice. Collectively, these findings suggest that sEH is a key player in neurite outgrowth of neurons, OB development in the brain, and the development of anxiety-like behavior, by regulating the CaMKII-GSK3α/ß signaling pathway.
Assuntos
Ansiedade/enzimologia , Comportamento Animal , Epóxido Hidrolases/genética , Deleção de Genes , Tonsila do Cerebelo/enzimologia , Tonsila do Cerebelo/patologia , Animais , Ansiedade/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dopamina/metabolismo , Medo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/enzimologia , Memória , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuritos/metabolismo , Bulbo Olfatório/anormalidades , Bulbo Olfatório/patologia , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Reconhecimento Psicológico , Tirosina 3-Mono-Oxigenase/metabolismo , Substância Branca/patologiaRESUMO
BACKGROUND: Anhedonia (loss of pleasure) is characterized by low responsiveness to rewards and, by virtue of being one of the two core symptoms of depression, by altered responses to stress. We investigated the effect of an acute stress experience (i.e., a tandem skydive) that was expected to elicit both intense fear and intense euphoria in a sample of anhedonic young adults. OBJECTIVE: (1) To examine individual differences in alpha-amylase reactivity to and recovery from a tandem skydive in anhedonic young adults; (2) to investigate whether trait depressive and anxiety problems, trait positive affect (PA), i.e., level of pleasure and reward responsiveness, and state anxiety, PA and self-esteem prior to the skydive were associated with alpha-amylase reactivity and recovery patterns; (3) to investigate whether alpha-amylase reactivity and recovery patterns were associated with pre- to post-jump changes in state anxiety, PA, and self-esteem. METHOD: Participants were 61 individuals with persistent anhedonia (Mage = 21.38, 78.7% female), who filled out a baseline questionnaire at the start of the study, and momentary questionnaires (3 times per day) before and after the tandem skydive. Alpha-amylase was measured at four time points by means of salivettes (2 before and 2 after the skydive). RESULTS: Alpha-amylase reactivity and recovery patterns were highly similar across individuals, although mean levels varied greatly. No associations were found between any of the trait and state measures and reactivity and recovery. Only state self-esteem was affected by the reactivity and recovery patterns, in that individuals who showed high reactivity and low recovery experienced decreases in self-esteem after the skydive. CONCLUSIONS: Alpha-amylase patterns following a tandem skydive in anhedonic individuals are highly similar to patterns previously found in healthy individuals. Although replication is warranted, our findings tentatively suggest that a strong stress response that cannot be downregulated well predicts a decrease in self-esteem.
Assuntos
Anedonia/fisiologia , Estresse Psicológico/enzimologia , alfa-Amilases/metabolismo , Ansiedade/enzimologia , Feminino , Humanos , Masculino , Personalidade/fisiologia , Assunção de Riscos , Saliva/enzimologia , Autoimagem , Comportamento Social , Esportes/fisiologia , Fatores de Tempo , Adulto JovemRESUMO
Modulation of behavioural responses by neuronal signalling pathways remains incompletely understood. Signalling via mitogen-activated protein (MAP) kinase cascades regulates multiple neuronal functions. Here, we show that neuronal p38α, a MAP kinase of the p38 kinase family, has a critical and specific role in modulating anxiety-related behaviour in mice. Neuron-specific p38α-knockout mice show increased levels of anxiety in behaviour tests, yet no other behavioural, cognitive or motor deficits. Using CRISPR-mediated deletion of p38α in cells, we show that p38α inhibits c-Jun N-terminal kinase (JNK) activity, a function that is specific to p38α over other p38 kinases. Consistently, brains of neuron-specific p38α-knockout mice show increased JNK activity. Inhibiting JNK using a specific blood-brain barrier-permeable inhibitor reduces JNK activity in brains of p38α-knockout mice to physiological levels and reverts anxiety behaviour. Thus, our results suggest that neuronal p38α negatively regulates JNK activity that is required for specific modulation of anxiety-related behaviour.