RESUMO
Fatigue is a serious health problem, and long-term fatigue can lead to mental illnesses and accelerated aging. Oxidative stress, which causes excessive production of reactive oxygen species, is generally thought to increase during exercise and is an indicator of fatigue. Peptides obtained by enzymatic decomposition of mackerel (EMP) contain selenoneine, a strong antioxidant. Although antioxidants increase endurance, the effects of EMP on physical fatigue are unknown. The present study aimed to clarify this aspect. We investigated the effects of EMP on changes in locomotor activity, expression levels of silent mating type information regulation 2 homolog peroxisome 1 (SIRT1), proliferator-activated receptor-γ coactivator-1α (PGC1α), and antioxidative-related proteins including superoxide dismutase 1 (SOD1), SOD2, glutathione peroxidase 1, and catalase in the soleus muscle following EMP treatment before and/or after forced walking. Treatment with EMP before and after forced walking, and not only at one or another time point, improved the subsequent decrease in the locomotor activity and enhanced the levels of SIRT1, PGC1α, SOD1, and catalase expression in the soleus muscle of mice. Moreover, EX-527, a SIRT1 inhibitor, abolished these effects of EMP. Thus, we suggest that EMP combats fatigue by modulating the SIRT1/PGC1α/SOD1-catalase pathway.
Assuntos
Antioxidantes , Perciformes , Camundongos , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Catalase/farmacologia , Sirtuína 1/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Superóxido Dismutase-1/metabolismo , Superóxido Dismutase-1/farmacologia , Estresse Oxidativo , Fadiga/tratamento farmacológico , Fadiga/etiologia , Fadiga/metabolismo , Peptídeos/farmacologia , Músculo Esquelético/metabolismo , Perciformes/metabolismoRESUMO
Attention deficit/hyperactivity disorder (AD/HD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. In patients with AD/HD, a decrease in the total and rapid eye movement (REM) sleep times has been observed. We have previously reported that mice with REM sleep deprivation-induced stress (REMSD) may show the hyperactivity- and inattention-like symptoms of AD/HD. However, in this model, impulsivity has not yet been investigated. Impulsivity and anxiety-related behaviors are evaluated by the elevated plus maze test (EPM). In this study, we investigated whether REMSD causes changes in the EPM and expression of alpha2A-adrenoceptors in the hippocampus and frontal cortex in a mouse model. Mice were deprived of REM sleep intermittently using the small-platform method (20 h/d) for 3 d. The time spent in the open arm and the expression levels of alpha2A-adrenoceptor in the hippocampus were significantly increased and decreased, respectively, by the REMSD. The time spent in the open arm was significantly limited by oxymetazoline (an alpha2A-adrenoceptor agonist), methylphenidate, and atomoxetine, which are clinically used to treat AD/HD. Moreover, the positive effects of oxymetazoline were attenuated by yohimbine and BRL44408, which are selective alpha2- and alpha2A-adrenoceptor antagonists, respectively. These results suggest that the increase in the time spent in the open arm induced by REMSD may serve as a model of impulsivity in AD/HD. Furthermore, the REMSD eliciting impulsivity-like behavior and the low-levels of anxiety may be linked to alpha2A-adrenoceptor signaling, as indicated by a decrease in alpha2A-adrenoceptor signaling, particularly in the mouse hippocampus.
Assuntos
Ansiedade/etiologia , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Modelos Animais de Doenças , Hipocampo/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Privação do Sono/complicações , Sono REM/fisiologia , Animais , Teste de Labirinto em Cruz Elevado , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Camundongos , Receptores Adrenérgicos alfa 2/análiseRESUMO
BACKGROUND: Patients with inflammatory bowel disease (IBD), including those with ulcerative colitis and Crohn's disease, have higher rates of psychiatric disorders, such as depression and anxiety; however, the mechanism of psychiatric disorder development remains unclear. Mice with IBD induced by dextran sulfate sodium (DSS) in drinking water exhibit depressive-like behavior. The presence of Lactobacillus in the gut microbiota is associated with major depressive disorder. Therefore, we examined whether Enterococcus faecalis 2001 (EF-2001), a biogenic lactic acid bacterium, prevents DSS-induced depressive-like behavior and changes in peripheral symptoms. METHODS: We evaluated colon inflammation and used the tail suspension test to examine whether EF-2001 prevents IBD-like symptoms and depressive-like behavior in DSS-treated mice. The protein expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), X-linked inhibitor of apoptosis protein (XIAP), and cleaved caspase-3 in the rectum and hippocampus was assessed by western blotting. Hippocampal neurogenesis, altered nuclear factor-kappa B (NFκB) p65 morphometry, and the localization of activated NFκB p65 and XIAP were examined by immunohistochemistry. RESULTS: Treatment with 1.5% DSS for 7 days induced IBD-like pathology and depressive-like behavior, increased TNF-α and IL-6 expression in the rectum and hippocampus, activated caspase-3 in the hippocampus, and decreased hippocampal neurogenesis. Interestingly, these changes were reversed by 20-day administration of EF-2001. Further, EF-2001 administration enhanced NFκB p65 expression in the microglial cells and XIAP expression in the hippocampus of DSS-treated mice. CONCLUSION: EF-2001 prevented IBD-like pathology and depressive-like behavior via decreased rectal and hippocampal inflammatory cytokines and facilitated the NFκB p65/XIAP pathway in the hippocampus. Our findings suggest a close relationship between IBD and depression.
Assuntos
Colite/microbiologia , Colite/fisiopatologia , Depressão/fisiopatologia , Enterococcus faecalis , Neuroimunomodulação/fisiologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Colite/induzido quimicamente , Depressão/etiologia , Sulfato de Dextrana/toxicidade , Masculino , CamundongosRESUMO
Olfactory bulbectomized (OBX) mice are characterized by impaired performance in the passive avoidance test and decreased number of cholinergic neurons in the hippocampus. Several studies have reported that κ-opioid receptor agonists improve cognitive function in mice. However, their influence on OBX-induced cognitive dysfunction remains unclear. To address this question, we evaluated the effects of the endogenous κ-opioid receptor agonist dynorphin A (Dyn A) and the selective agonist trans-(-)-U-50488 on the behavior of OBX mice in the passive avoidance test. The cognitive dysfunction of OBX mice was significantly recovered by the intracerebroventricular administration of Dyn A or trans-(-)-U-50488. The effects of these two agonists were counteracted by the selective κ-opioid receptor antagonist nor-binaltorphimine or the inhibitor of acetylcholine release ß-bungarotoxin. These findings suggest that κ-opioid receptor agonists produce anti-dementia effects through activation of cholinergic neurons in OBX mice.
Assuntos
Disfunção Cognitiva/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Receptores Opioides kappa/agonistas , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/uso terapêutico , Animais , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/fisiologia , Disfunção Cognitiva/fisiopatologia , Dinorfinas/farmacologia , Dinorfinas/uso terapêutico , Hipocampo/fisiologia , Masculino , Transtornos da Memória/fisiopatologia , Camundongos , Bulbo Olfatório/cirurgia , Receptores Opioides kappa/fisiologiaRESUMO
Recent studies suggest that histamine-a regulator of the microcirculation-may play important roles in exercise. We have shown that the histamine-forming enzyme histidine decarboxylase (HDC) is induced in skeletal muscles by prolonged muscular work (PMW). However, histological analysis of such HDC induction is lacking due to appropriate anti-HDC antibodies being unavailable. We also showed that the inflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-α can induce HDC, and that PMW increases both IL-1α and IL-1ß in skeletal muscles. Here, we examined the effects (a) of PMW on the histological evidence of HDC induction and (b) of IL-1ß and TNF-α on HDC activity in skeletal muscles. By immunostaining using a recently introduced commercial polyclonal anti-HDC antibody, we found that cells in the endomysium and around blood vessels, and also some muscle fibers themselves, became HDC-positive after PMW. After PMW, TNF-α, but not IL-1α or IL-1ß, was detected in the blood serum. The minimum intravenous dose of IL-1ß that would induce HDC activity was about 1/10 that of TNF-α, while in combination they synergistically augmented HDC activity. These results suggest that PMW induces HDC in skeletal muscles, including cells in the endomysium and around blood vessels, and also some muscle fibers themselves, and that IL-1ß and TNF-α may cooperatively mediate this induction.
Assuntos
Citocinas/sangue , Histamina/metabolismo , Histidina Descarboxilase/metabolismo , Músculo Esquelético/fisiologia , Caminhada/fisiologia , Animais , Citocinas/farmacologia , Masculino , Camundongos Endogâmicos BALB CRESUMO
Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phospho-p38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicle-treated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors.
Assuntos
Angiotensina II/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Neuralgia/complicações , Neuralgia/metabolismo , Medula Espinal/metabolismo , Animais , Biomarcadores/metabolismo , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/sangue , Imunofluorescência , Hiperalgesia/complicações , Injeções , Vértebras Lombares/enzimologia , Vértebras Lombares/patologia , Masculino , Camundongos , Neuralgia/sangue , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/genética , Medula Espinal/enzimologia , Medula Espinal/patologia , Corno Dorsal da Medula Espinal/metabolismo , Corno Dorsal da Medula Espinal/patologia , Estreptozocina , Fatores de Tempo , Tato , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Pain is sensed, transmitted, and modified by a variety of mediators and receptors. Histamine is a well-known mediator of pain. In addition to their anti-histaminic effects, the classical, or 1st generation, anti-histamines (1st AHs) possess, to various degrees, anti-muscarinic, anti-serotonergic, anti-adrenergic, and other pharmacologic effects. Although there have been attempts to use 1st AHs as analgesics and/or analgesic adjuvants, the advent of non-steroidal anti-inflammatory drugs (NSAIDs) discouraged such trials. We previously reported that in patients with temporomandibular disorders, osteoporosis, and/or osteoarthritis, the analgesic effects of certain 1st AHs (chlorpheniramine and diphenhydramine) are superior to those of the NSAIDs flurbiprofen and indomethacin. Here, we compared analgesic effects among 1st AHs and NSAIDs against responses shown by mice to intraperitoneally injected 0.7% acetic acid. Since 1st AHs are water soluble, we selected water-soluble NSAIDs. For direct comparison, drugs were intravenously injected 30 min before the above tests. Histamine-H1-receptor-deficient (H1R-KO) mice were used for evaluating H1-receptor-independent effects. The tested 1st AHs (especially cyproheptadine) displayed or tended to display analgesic effects comparable to those of NSAIDs in normal and H1R-KO mice. Our data suggest that the anti-serotonergic and/or anti-adrenergic effects of 1st AHs make important contributions to their analgesic effects. Moreover, combination of a 1st AH with an NSAID (cyclooxygenase-1 inhibitor) produced remarkably potent analgesic effects. We propose that a 1st AH, by itself or in combination with a cyclooxygenase-1 inhibitor, should undergo testing to evaluate its usefulness in analgesia.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Dor/tratamento farmacológico , Ácido Acético , Antagonistas Adrenérgicos/uso terapêutico , Animais , Antagonistas Colinérgicos/uso terapêutico , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dor/induzido quimicamente , Antagonistas da Serotonina/uso terapêuticoRESUMO
Ulcerative colitis (UC) is a refractory inflammatory bowel disease, which is known to cause psychiatric disorders such as anxiety and depression at a high rate in addition to peripheral inflammatory symptoms. However, the pathogenesis of these psychiatric disorders remains mostly unknown. While prior research revealed that the Enterococcus faecalis 2001 (EF-2001) suppressed UC-like symptoms and accompanying depressive-like behaviors, observed in a UC model using dextran sulfate sodium (DSS), whether it has an anxiolytic effect remains unclear. Therefore, we examined whether EF-2001 attenuates DSS-induced anxiety-like behaviors. Treatment with 2% DSS for seven days induced UC-like symptoms and anxiety-like behavior through the hole-board test, increased serum lipopolysaccharide (LPS) and corticosterone concentration, and p-glucocorticoid receptor (GR) in the prefrontal cortex (PFC), and decreased N-methyl-D-aspartate receptor subunit (NR) 2A and NR2B expression levels in the PFC. Interestingly, these changes were reversed by EF-2001 administration. Further, EF-2001 administration enhanced CAMKII/CREB/BDNF-Drebrin pathways in the PFC of DSS-treated mice, and labeling of p-GR, p-CAMKII, and p-CREB showed colocalization with neurons. EF-2001 attenuated anxiety-like behavior by reducing serum LPS and corticosterone levels linked to the improvement of UC symptoms and by facilitating the CAMKII/CREB/BDNF-Drebrin pathways in the PFC. Our findings suggest a close relationship between UC and anxiety.
Assuntos
Ansiolíticos , Sulfato de Dextrana , Modelos Animais de Doenças , Enterococcus faecalis , Animais , Camundongos , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Sulfato de Dextrana/toxicidade , Masculino , Ansiedade/tratamento farmacológico , Lipopolissacarídeos , Corticosterona/sangue , Córtex Pré-Frontal/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colite Ulcerativa/microbiologia , Camundongos Endogâmicos C57BLRESUMO
Impaired olfactory function may be associated with the development of psychiatric disorders such as depression and anxiety; however, knowledge on the mechanisms underlying psychiatric disorders is incomplete. A reversible model of olfactory dysfunction, zinc sulfate (ZnSO4) nasal-treated mice, exhibit depression-like behavior accompanying olfactory dysfunction. Therefore, we investigated olfactory function and depression-like behaviors in ZnSO4-treated mice using the buried food finding test and tail suspension test, respectively; investigated the changes in the hippocampal microglial activity and neurogenesis in the dentate gyrus by immunohistochemistry; and evaluated the inflammation and microglial polarity related-proteins in the hippocampus using western blot study. On day 14 after treatment, ZnSO4-treated mice showed depression-like behavior in the tail suspension test and recovery of the olfactory function in the buried food finding test. In the hippocampus of ZnSO4-treated mice, expression levels of ionized calcium-binding adapter molecule 1 (Iba1), cluster of differentiation 40, inducible nitric oxide synthase, interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, cleaved caspase-3, as well as the number of Iba1-positive cells and cell body size increased, and arginase-1 expression and neurogenesis decreased. Except for the increased IL-6, these changes were prevented by a microglia activation inhibitor, minocycline. The findings suggest that neuroinflammation due to polarization of M1-type hippocampal microglia is involved in depression accompanied with olfactory dysfunction.
Assuntos
Depressão , Transtornos do Olfato , Humanos , Camundongos , Animais , Depressão/metabolismo , Microglia/metabolismo , Interleucina-6/metabolismo , Hipocampo/metabolismoRESUMO
BACKGROUND: It has been demonstrated that angiotensin II (Ang II) participates in either the inhibition or the facilitation of nociceptive transmission depending on the brain area. Neuronal Ang II is locally synthesized not only in the brain, but also in the spinal cord. Though the spinal cord is an important area for the modulation of nociception, the role of spinal Ang II in nociceptive transmission remains unclear. Therefore, in order to elucidate the role of Ang II in nociceptive transmission in the spinal cord, we examined the effect of intrathecal (i.t.) administration of Ang II into mice. RESULTS: I.t. administration of Ang II produced a behavioral response in mice mainly consisting of biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank. The behavior induced by Ang II (3 pmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.1-0.3 mg/kg), suggesting that the behavioral response is related to nociception. The nociceptive behavior was also inhibited dose-dependently by i.t. co-administration of losartan (0.3-3 nmol), an Ang II type 1 (AT1) receptor antagonist, and SB203580 (0.1-1 nmol), a p38 MAPK inhibitor. However, the Ang II type 2 (AT2) receptor antagonist PD123319, the upstream inhibitor of ERK1/2 phosphorylation U0126, and the JNK inhibitor SP600125 had no effect on Ang II-induced nociceptive behavior. Western blot analysis showed that the i.t. injection of Ang II induced phosphorylation of p38 MAPK in the lumbar dorsal spinal cord, which was inhibited by losartan, without affecting ERK1/2 and JNK. Furthermore, we found that AT1 receptor expression was relatively high in the lumbar superficial dorsal horn. CONCLUSIONS: Our data show that i.t. administration of Ang II induces nociceptive behavior accompanied by the activation of p38 MAPK signaling mediated through AT1 receptors. This observation indicates that Ang II may act as a neurotransmitter and/or neuromodulator in the spinal transmission of nociceptive information.
Assuntos
Angiotensina II/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Imidazóis/metabolismo , Imidazóis/farmacologia , Losartan , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Piridinas/metabolismo , Piridinas/farmacologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
It is reported that liver hydrolysate (LH) enhances liver function. However, the effects of LH on physical fatigue are unknown. The aim of this study was to investigate the effect of LH on alterations in locomotor activity and energy metabolism such as 5'-AMP-activated protein kinase (AMPK), glycogen content, and blood lactic acid, after forced walking. Adult male ddY mice were used. Locomotor activity, AMPK phosphorylation, and glycogen content in the liver and soleus muscle, as well as blood lactic acid were determined following LH treatment before and/or after forced walking. The locomotor activity significantly decreased after forced walking for 3 h. Two administrations of LH (30 or 100 mg/kg) significantly increased the locomotor activity, while a single administration either before or after forced walking did not show any specific effect. Administering LH twice activated AMPK in the liver and soleus muscle. Glycogen levels significantly decreased in both the liver and soleus muscle after forced walking, whereas the blood lactate level significantly increased. In contrast, administering LH twice increased muscle glycogen and decreased blood lactic acid. These findings indicate that LH produced an anti-fatigue effect and that this effect appears to involve the efficient glycogen utilization through activation of AMPK.
Assuntos
Fadiga/tratamento farmacológico , Extratos Hepáticos/farmacologia , Hidrolisados de Proteína/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Metabolismo Energético/efeitos dos fármacos , Fadiga/metabolismo , Fadiga/fisiopatologia , Ácido Láctico/sangue , Fígado/metabolismo , Extratos Hepáticos/administração & dosagem , Extratos Hepáticos/uso terapêutico , Masculino , Metilmetacrilatos/metabolismo , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Músculo Esquelético/metabolismo , Fosforilação/efeitos dos fármacos , Hidrolisados de Proteína/administração & dosagem , Hidrolisados de Proteína/uso terapêuticoRESUMO
Bruxism and/or clenching, resulting in fatigue or dysfunction of masseter muscles (MM), may cause temporomandibular disorders. Functional support of the microcirculation is critical for prolonged muscle activity. Histamine is a regulator of the microcirculation and is supplied by release from its stores and/or by de novo production via the induction of histidine decarboxylase (HDC). Interleukin (IL)-1, a cytokine involved in temporomandibular disorders, is an inducer of HDC. In the present study, we examined the roles of histamine, HDC and IL-1 in MM activity. Experiments were conducted using our R+G+ model. A mouse restrained (R+) inside a narrow cylinder (front end blocked with a thin plastic strip) gnaws away (G+) the strip to escape, with the weight reduction in the strip serving as an index of MM activity. Fexofenadine (a peripherally acting histamine H1 receptor antagonist) reduced MM activity in normal mice. Both H1 receptor-deficient and HDC-deficient mice exhibited low MM activity. Prolonged R+G+ induced HDC activity in MM. Mast cell-deficient mice exhibited strikingly low HDC induction in MM (and also in the quadriceps femoris muscle) in response to muscle activity or IL-1ß. Mast cells were present around blood vessels and nerves in the epimysium and perimysium of MM. These results, together with others reported previously, suggest that: (i) peripheral histamine supports strenuous MM activity; (ii) strenuous MM activity stimulates mast cells to release histamine and to induce HDC (which replenishes the histamine pool in mast cells, possibly mediated by IL-1); and (iii) peripheral histamine H1 receptor antagonists may be effective in treating temporomandibular disorders or preventing prolonged clenching and/or bruxism.
Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Histamina/fisiologia , Músculo Masseter/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Animais , Bruxismo/metabolismo , Bruxismo/prevenção & controle , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Histidina Descarboxilase/genética , Histidina Descarboxilase/metabolismo , Masculino , Músculo Masseter/irrigação sanguínea , Músculo Masseter/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Restrição FísicaRESUMO
The populations of the Kii Peninsula in Japan and of Guam present high incidences of amyotrophic lateral sclerosis and Parkinsonism-dementia complex. It is thought that low levels of calcium (Ca) and magnesium (Mg) in the drinking water are involved in the pathogenesis of these diseases. The present study aimed to test the hypothesis that catalepsy, behavioral immobility and a Parkinsonian symptom results from functionally impaired dopaminergic neurons in mice fed low amounts of Ca and Mg (LCa/Mg). A group of mice fed a LCa/Mg diet for 6 weeks was compared to a control group on a standard diet. Cataleptic symptoms such as akinesia and rigidity were measured by the bar test. The anti-parkinsonian drugs dopamine (DA) precursor L-3,4-dihydroxy phenylamine (L-DOPA), the selective DA receptor D(2) agonist bromocriptine, and the DA releaser amantadine were tested for their effects on induced catalepsy. The mice developed catalepsy after 3 weeks on the LCa/Mg diet. LCa/Mg diet-induced catalepsy was improved by the administration of L-DOPA (50-200 mg/kg i.p.) in combination with benserazide (25 mg/kg i.p.), or of bromocriptine (0.25-4 mg/kg i.p.) or of amantadine (5-20 mg/kg i.p.). Immunohistochemical staining revealed that the intensity of tyrosine hydroxylase fluorescence was significantly decreased in the substantia nigra at the 6th week of LCa/Mg feeding in comparison with pair-fed controls. These results suggest that catalepsy in LCa/Mg mice results from hypofunction of the dopaminergic neurons. Moreover, our results support the hypothesis that LCa/Mg intake is one etiological factor in neurodegenerative disorders, including Parkinson's disease.
Assuntos
Cálcio/deficiência , Catalepsia/metabolismo , Alimentos Formulados/efeitos adversos , Deficiência de Magnésio/metabolismo , Magnésio/metabolismo , Doença de Parkinson Secundária/metabolismo , Amantadina/farmacologia , Animais , Antiparkinsonianos/farmacologia , Benserazida/farmacologia , Bromocriptina/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Agonistas de Dopamina/farmacologia , Levodopa/farmacologia , Deficiência de Magnésio/induzido quimicamente , Deficiência de Magnésio/tratamento farmacológico , Masculino , Camundongos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológico , Receptores Dopaminérgicos/metabolismo , Fatores de Risco , Substância Negra/efeitos dos fármacos , Substância Negra/enzimologia , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Alzheimer's disease is associated with marked olfactory dysfunction observed in the early stages. Clinical studies reported that acetylcholinesterase inhibitor donepezil (DNP) attenuated this deficit; however, the underlying mechanism remains unclear. Herein, we aimed to examine the effects and underlying mechanisms of DNP on olfactory deficits in zinc sulfate (ZnSO4) nasal-treated mice, which were used as a model of reversible olfactory impairment. We evaluated olfactory function using the buried food finding test and neurogenesis in the subventricular zone (SVZ) using immunohistochemistry. Finally, we measured the expression of doublecortin (DCX), neuronal nuclear antigen (NeuN), olfactory marker protein, tyrosine hydroxylase (TH), tryptophan hydroxylase 2, glutamic acid decarboxylase 67, p-α-synuclein (Ser129), α-synuclein, p-AMPK, p-p70S6 kinase (p70S6K) (Thr389), LC3 â ¡/â , and p-p62 in the olfactory bulb (OB) by western blotting. On day 7 after treatment, ZnSO4-treated mice exhibited prolonged time to find the buried food, cell proliferation enhancement in the SVZ, increased NeuN, p-α-synuclein (Ser129), and α-synuclein levels, and decreased DCX and TH levels in the OB; except for TH, these changes normalized on day 14 after treatment. Repeated administration of DNP prevented the ZnSO4-induced changes on day 7 after treatment. Moreover, DNP increased p-AMPK and LC3 â ¡/â , and decreased p-p70S6K and p-p62 (Ser351) levels in the OB, suggesting that DNP enhances autophagy in the OB. These findings indicate that DNP may help prevent olfactory dysfunction by autophagy that reduces α-synuclein aggregation via the AMPK/mTOC1 pathway.
Assuntos
Transtornos do Olfato , Bulbo Olfatório , Animais , Camundongos , Bulbo Olfatório/metabolismo , alfa-Sinucleína/metabolismo , Donepezila/farmacologia , Sulfato de Zinco/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Acetilcolinesterase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , AutofagiaRESUMO
Previously, we reported that α1,6-fucosyltransferase (Fut8)-deficient (Fut8(-/-)) mice exhibit emphysema-like changes in the lung and severe growth retardation due to dysregulation of TGF-ß1 and EGF receptors and to abnormal integrin activation, respectively. To study the role of α1,6-fucosylation in brain tissue where Fut8 is highly expressed, we examined Fut8(-/-) mice using a combination of neurological and behavioral tests. Fut8(-/-) mice exhibited multiple behavioral abnormalities consistent with a schizophrenia-like phenotype. Fut8(-/-) mice displayed increased locomotion compared with wild-type (Fut8(+/+)) and heterozygous (Fut8(+/-)) mice. In particular, Fut8(-/-) mice showed strenuous hopping behavior in a novel environment. Working memory performance was impaired in Fut8(-/-) mice as evidenced by the Y-maze tests. Furthermore, Fut8(-/-) mice showed prepulse inhibition (PPI) deficiency. Intriguingly, although there was no significant difference between Fut8(+/+) and Fut8(+/-) mice in the PPI test under normal conditions, Fut8(+/-) mice showed impaired PPI after exposure to a restraint stress. This result suggests that reduced expression of Fut8 is a plausible cause of schizophrenia and related disorders. The levels of serotonin metabolites were significantly decreased in both the striatum and nucleus accumbens of the Fut8(-/-) mice. Likewise, treatment with haloperidol, which is an antipsychotic drug that antagonizes dopaminergic and serotonergic receptors, significantly reduced hopping behaviors. The present study is the first to clearly demonstrate that α1,6-fucosylation plays an important role in the brain, and that it might be related to schizophrenia-like behaviors. Thus, the results of the present study provide new insights into the underlying mechanisms responsible for schizophrenia and related disorders.
Assuntos
Comportamento Animal , Encéfalo/enzimologia , Dopamina/metabolismo , Fucosiltransferases , Esquizofrenia/enzimologia , Serotonina/metabolismo , Animais , Antipsicóticos/farmacologia , Dopamina/genética , Haloperidol/farmacologia , Humanos , Locomoção/efeitos dos fármacos , Locomoção/genética , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Knockout , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Serotonina/genéticaRESUMO
Exercise necessitates a large supply of O(2) and nutrients and rapid removal of CO(2) and waste products. Histamine is a regulator of the microcirculation (which performs these exchanges), suggesting a possible involvement of histamine in exercise. Histamine is released from either mast cells or non-mast cells. In the latter, histamine is newly formed via the induction of histidine decarboxylase (HDC) in response to an appropriate stimulus, and it is released without being stored. Here, in mice, we examined the role of histamine or HDC induction in exercise. Prolonged walking (PW) (in a cylindrical cage turned electrically) increased HDC mRNA and HDC activity in quadriceps femoris muscles. Mice given a histamine H1-receptor antagonist [fexofenadine (peripherally acting) or pyrilamine (peripherally and centrally acting)] or an irreversible HDC inhibitor (α-fluoromethylhistidine) displayed less PW endurance than control mice. Ranitidine (H2-receptor antagonist) tended to reduce endurance. Other histamine-receptor (H3 and H4) antagonists had no significant effects on endurance. Mice deficient in HDC or histamine H1-receptors displayed markedly less endurance than control mice, and HDC activity in the quadriceps femoris of H1-deficient mice was rapidly elevated by PW. Fexofenadine significantly reduced the muscle levels of nitric oxide (NO) metabolites and glycogen after PW. The results support the ideas that (i) histamine is involved in protecting against exercise-induced fatigue or exhaustion, (ii) histamine exerts its protective effect via H1 receptors and the ensuing production of NO in skeletal muscle, and (iii) histamine is provided, at least in part, by HDC induction in skeletal muscles during prolonged exercise.
Assuntos
Fadiga/metabolismo , Histamina/metabolismo , Histidina Descarboxilase/metabolismo , Condicionamento Físico Animal/fisiologia , Resistência Física/fisiologia , Receptores Histamínicos H1/metabolismo , Caminhada/fisiologia , Animais , Ativação Enzimática , Fadiga/etiologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Histidina Descarboxilase/antagonistas & inibidores , Histidina Descarboxilase/genética , Metilistidinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Músculo Quadríceps/metabolismo , RNA Mensageiro/metabolismo , Ranitidina/farmacologiaRESUMO
We investigated whether postweaning protein malnutrition (PM) affects serotonergic systems. Mice were fed a PM diet or normal protein (control) diet from weaning (21 d of age). Twenty days later, we tested for behavioral effects of the selective serotonin (5-HT)(1A) receptor agonist 8-hydroxy-N,N-dipropyl-2-aminoteralin (8-OH-DPAT) and the 5-HT releaser d-fenfluramine. The number of head weaving responses induced by 8-OH-DPAT or d-fenfluramine in the PM mice was significantly increased compared with the control diet group. The effects of 8-OH-DPAT and d-fenfluramine were blocked by pretreatment with the selective 5-HT(1A) receptor antagonist WAY-100635 (0.01 mg/kg). However, postpubertal (56 d of age) mice fed with the PM diet did not show an enhancement of the 8-OH-DPAT-induced head weaving response. These results indicate the occurence of a supersensitivity of postsynaptic 5-HT(1A) receptor in the postweaning PM group. Moreover, they highlight the postweaning stage as a vulnerable period to malnutrition-induced alterations in central serotonergic systems.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Comportamento Animal/efeitos dos fármacos , Desnutrição/fisiopatologia , Agonistas do Receptor de Serotonina/farmacologia , Animais , Animais Recém-Nascidos , Proteínas Alimentares , Fenfluramina/farmacologia , Masculino , Camundongos , Receptor 5-HT1A de Serotonina/fisiologiaRESUMO
A therapeutic strategy through the gut-brain axis has been proven to be effective in treatment for depression. In our previous study, we demonstrated that Enterococcus faecalis 2001 (EF-2001) prevents colitis-induced depressive-like behavior through the gut-brain axis in mice. More recently, we found that demyelination in the prefrontal cortex (PFC) was associated with depressive-like behavior in an animal model of major depressive disorder, olfactory bulbectomized (OBX) mice. The present study investigated the effects of EF-2001 on depressive-like behaviors in OBX mice and the underlying molecular mechanisms from the perspective of myelination in the PFC. OBX mice exhibited depressive-like behaviors in the tail-suspension, splash, and sucrose preference tests, and decreased myelin and paranodal proteins along with mature oligodendrocytes in the PFC. These behavioral and biochemical changes were all prevented by treatment with EF-2001. Further, EF-2001 treatment increased brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) in the PFC. Interestingly, an immunohistochemical analysis revealed enhanced phospho (p) -cAMP-responsive element binding protein (CREB) expression in neurons, p-nuclear factor-kappa B (NFκB) p65 (Ser536) expression in astrocytes, and p-signal transducer and activator of transcription 3 (STAT3) (Ty705) expression in mature oligodendrocytes in the PFC of OBX mice. From these results, we suggest that EF-2001 administration prevents depressive-like behaviors by regulating prefrontal cortical myelination via the enhancement of CREB/BDNF and NFκB p65/LIF/STAT3 pathways. Our findings strongly support the idea that a therapeutic strategy involving the gut microbiota may be a promising alternative treatment for alleviating symptoms of depression.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Transtorno Depressivo Maior , Animais , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/uso terapêutico , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Modelos Animais de Doenças , Enterococcus faecalis/metabolismo , Hipocampo , Humanos , Fator Inibidor de Leucemia/metabolismo , Fator Inibidor de Leucemia/farmacologia , Fator Inibidor de Leucemia/uso terapêutico , Camundongos , NF-kappa B/metabolismo , NF-kappa B/farmacologia , NF-kappa B/uso terapêutico , Bulbo Olfatório/metabolismo , Bulbo Olfatório/cirurgia , Córtex Pré-Frontal/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/farmacologia , Fator de Transcrição STAT3/uso terapêuticoRESUMO
Genetic studies in humans have implicated the gene encoding neuregulin-1 (NRG-1) as a candidate susceptibility gene for schizophrenia. Furthermore, it has been suggested that NRG-1 is involved in regulating the expression and function of the N-methyl-D-aspartate receptor and the GABAA receptor in several brain areas, including the prefrontal cortex (PFC), the hippocampus, and the cerebellum. Neonatal ventral hippocampal lesioned (NVHL) rats have been considered as a putative model for schizophrenia with characteristic post-pubertal alteration in response to stress and neuroleptics. In this study, we examined NRG-1, erb-b2 receptor tyrosine kinase 4 (erbB4), and phospho-erbB4 (p-erbB4) levels in the PFC and the distribution of NRG-1 in the NVHL rats by using immunoblotting and immunohistochemical analyses. Neonatal lesions were induced by bilateral injection of ibotenic acid in the ventral hippocampus of postnatal day 7 Sprague-Dawley (SD)-rats. NVHL rats showed significantly decreased levels of NRG-1 and p-erbB4 in the PFC compared to sham controls at post-pubertal period, while the level of erbB4 did not differ between sham and NVHL rats. Moreover, microinjection of NRG-1 into the mPFC improved NVHL-induced prepulse inhibition deficits. Our study suggests PFC NRG-1 alteration as a potential mechanism in schizophrenia-like behaviors in the NVHL model.
RESUMO
It is well known that nutritional status during the fetal and/or lactation period is important for the development of the central nervous system (CNS). In contrast, the effect of malnutrition on postweaning development has not yet been thoroughly investigated. In the present study, we analyzed the behavioral and neuroanatomical effects of protein malnutrition (PM) postweaning in mice. Starting at 20-21 d of age, male ddY mice were maintained on a 5% casein diet (PM group) or 20% casein diet (control group) for 20 d. On the 20th d, body and brain weights of PM mice were lower than those of the control group. PM mice exhibited excessive alertness and spontaneous activity under novel conditions in the Irwin test. In addition, PM mice showed increased open arm exploration in the elevated plus maze compared to control mice. These results suggest that hyperactivity and reduced anxiety behavior or higher impulsiveness in PM mice could be due to an immature brain.