RESUMEN
Brain-derived neurotrophic factor (BDNF) plays a crucial role in numerous brain functions, including memory consolidation. Previously, we generated a Bdnf-Luciferase transgenic (Bdnf-Luc) mouse strain to visualize changes in Bdnf expression using in vivo bioluminescence imaging. We successfully visualized activity-dependent Bdnf induction in living mouse brains using a d-luciferin analog, TokeOni, which distributes to the brain and produces near-infrared bioluminescence. In this study, we compared the patterns of bioluminescence signals within the whole body of the Bdnf-Luc mice produced by d-luciferin, TokeOni and seMpai, another d-luciferin analog that produces a near-infrared light. As recently reported, hepatic background signals were observed in wild-type mice when using TokeOni. Bioluminescence signals were strongly observed from the region containing the liver when using d-luciferin and TokeOni. Additionally, we detected signals from the brain when using TokeOni. Compared with d-luciferin and TokeOni, signals were widely detected in the whole body of Bdnf-Luc mice by seMpai. The signals produced by seMpai were strong in the regions containing skeletal muscles in particular. Taken together, the patterns of bioluminescence signals in Bdnf-Luc mice vary when using different luciferase substrates. Therefore, the expression of Bdnf in tissues and organs of interest could be visualized by selecting an appropriate substrate.
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Factor Neurotrófico Derivado del Encéfalo , Luciferinas , Animales , Ratones , Factor Neurotrófico Derivado del Encéfalo/genética , Luciferasas/genética , Luciferasas/metabolismoRESUMEN
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.
RESUMEN
Ameliorating reduced brain-derived neurotrophic factor (BDNF) expression or maintaining high BDNF levels in the brain has been suggested to improve brain function in neurological diseases and prevent aging-related brain dysfunction. In this study, we found that a food-derived product, Aminothioneine® (AT), which is prepared from the extract of golden oyster mushrooms (Pleurotus cornucopiae var. citrinopileatus), increased Bdnf mRNA expression levels in primary rat cortical neuron cultures. Ergothioneine (ET) comprises more than 1% in AT and is an active constituent of AT, and ET has been reported to increase neurotrophin-4/5, but not BDNF, expression levels in neural stem cells. ET also did not affect Bdnf mRNA expression in cultured cortical neurons, suggesting that AT contains other active constituents that induce Bdnf mRNA expression in neurons. AT-induced Bdnf mRNA expression was completely blocked by d-(-)-2-Amino-5-phosphonopentanoic acid but partially blocked by nicardipine, U0126, and FK506. This result suggested that N-methyl-d-aspartate receptor-derived Ca2+ signals, including those mediated by extracellular signal-regulated kinase/mitogen-activated protein kinase and calcineurin, are the main contributors to Bdnf mRNA induction. In addition, AT increased cAMP-response element-binding protein (CREB) phosphorylation and the nuclear localization of CREB-regulated transcriptional coactivator 1 in neurons. Thus, AT can increase Bdnf mRNA expression via Ca2+ signal-induced CREB-dependent transcription in neurons. Because AT is a food-derived product, increasing and/or maintaining BDNF levels in the brain by daily intake of the product could be possible, which may be beneficial for neurological and aging-related disorders.
RESUMEN
Neonatal ventral hippocampal-lesioned (NVHL) rats have been shown to display neurochemical and behavioral abnormalities at adulthood, analogous to some of those seen in schizophrenia. Serotonergic neurotransmission is implicated the pathophysiology and treatment of schizophrenia. In this study, we evaluated possible role of serotonergic transmission is the behaviors of NVHL-lesioned rats. Bilateral lesions to the ventral hippocampus (VH) in rat pups were made using the excitotoxin ibotenic acid. We investigated 5-HT2A-receptor and SERT binding sites in cortical and subcortical areas in post-pubertal NVHL and sham-lesioned rats, using quantitative receptor autoradiography. We compared a 5-HT-dependent behavior in NVHL and sham animals, the wet-dog shake response (WDSr) to a 5-HT2A receptor agonist DOI. In addition, we studied prepulse inhibition (PPI) of startle responses in NVHL and Sham-lesioned animals treated with antipsychotic drugs haloperidol, risperidone and clozapine and 5-HT2A antagonists ketanserin or MDL100907. The WDSr elicited by DOI was enhanced in post-pubertal NVHL rats compared to sham-lesioned controls. Moreover, post-pubertal NVHL rats exhibited PPI deficits which was reversed by atypical antipsychotics, ketanserin and MDL100907. A significant increase in 5-HT2A-like receptor binding was observed in the medial prefrontal cortex (mPFC) in post-pubertal NVHL rats without any significant change in the striatum and ventral pallidum. A significant increase in SERT-like binding was also observed in the mPFC and striatum of NVHL rats at pre-pubertal period; however, at post-pubertal age, the binding remained elevated in mPFC only. These data suggest that increased prefrontal cortical 5-HT transmission may play a role in the behavioral deficits observed in this neurodevelopmental model of schizophrenia.
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Antipsicóticos/farmacología , Conducta Animal/fisiología , Hipocampo/patología , Corteza Prefrontal/metabolismo , Inhibición Prepulso/fisiología , Receptor de Serotonina 5-HT2A/metabolismo , Esquizofrenia , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Autorradiografía , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Corteza Prefrontal/efectos de los fármacos , Inhibición Prepulso/efectos de los fármacos , Ratas , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Maduración Sexual/fisiologíaRESUMEN
Altered levels of brain-derived neurotrophic factor (BDNF) have been reported in neurologically diseased human brains. Therefore, it is important to understand how the expression of BDNF is controlled under pathophysiological as well as physiological conditions. Here, we report a method to visualize changes in BDNF expression in the living mouse brain using bioluminescence imaging (BLI). We previously generated a novel transgenic mouse strain, Bdnf-Luciferase (Luc), to monitor changes in Bdnf expression; however, it was difficult to detect brain-derived signals in the strain using BLI with d-luciferin, probably because of incomplete substrate distribution and light penetration. We demonstrate that TokeOni, which uniformly distributes throughout the whole mouse body after systematic injection and produces a near-infrared bioluminescence light, was suitable for detecting signals from the brain of the Bdnf-Luc mouse. We clearly detected brain-derived bioluminescence signals that crossed the skin and skull after intraperitoneal injection of TokeOni. However, repeated BLI using TokeOni should be limited, because repeated injection of TokeOni on the same day reduced the bioluminescence signal, presumably by product inhibition. We successfully visualized kainic acid-induced Bdnf expression in the hippocampus and sensory stimulation-induced Bdnf expression in the visual cortex. Taken together, non-invasive near-infrared BLI using Bdnf-Luc mice with TokeOni allowed us to evaluate alterations in BDNF levels in the living mouse brain. This will enable better understanding of the involvement of BDNF expression in the pathogenesis and pathophysiology of neurological diseases.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Rayos Infrarrojos , Mediciones Luminiscentes , Animales , Hipocampo/metabolismo , Ácido Kaínico , Luciferasas/metabolismo , Ratones Transgénicos , Sensación , Corteza Visual/metabolismoRESUMEN
Brain-derived neurotrophic factor (BDNF) is a key player in synaptic plasticity, and consequently, learning and memory. Because of its fundamental role in numerous neurological functions in the central nervous system, BDNF has utility as a biomarker and drug target for neurodegenerative and neuropsychiatric disorders. Here, we generated a screening assay to mine inducers of Bdnf transcription in neuronal cells, using primary cultures of cortical cells prepared from a transgenic mouse strain, specifically, Bdnf-Luciferase transgenic (Bdnf-Luc) mice. We identified several active extracts from a library consisting of 120 herbal extracts. In particular, we focused on an active extract prepared from Ginseng Radix (GIN), and found that GIN activated endogenous Bdnf expression via cAMP-response element-binding protein-dependent transcription. Taken together, our current screening assay can be used for validating herbal extracts, food-derived agents, and chemical compounds for their ability to induce Bdnf expression in neurons. This method will be beneficial for screening of candidate drugs for ameliorating symptoms of neurological diseases associated with reduced Bdnf expression in the brain, as well as candidate inhibitors of aging-related cognitive decline.
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Factor Neurotrófico Derivado del Encéfalo/genética , Corteza Cerebral/citología , Luciferasas/metabolismo , Tamizaje Masivo , Neuronas/metabolismo , Transcripción Genética , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dopamina/metabolismo , Ginsenósidos/farmacología , Ratones Transgénicos , Neuronas/efectos de los fármacos , Extractos Vegetales/farmacología , Ratas Sprague-Dawley , Receptores del Ácido Lisofosfatídico/metabolismo , Transducción de Señal , Transcripción Genética/efectos de los fármacosRESUMEN
AIMS: In order to clarify hepato-protective actions of estrogen, we examined the progress of carbon tetrachloride (CCl4)-induced acute liver injury (ALI) in sham and ovariectomized (ovx) mice and the effects of dimethylthiourea (DMTU), a hydroxyl radical scavenger, and meloxicam (Melo), a selective cox-2 inhibitor, on the development of CCl4-induced ALI. MAIN METHODS: Female C57BL/6â¯J mice weighing 15-20â¯g were performed sham or ovx operation at 8 weeks of age. Blood and liver samples were collected 15 and 24â¯h after CCl4 administration. Sham and ovx mice were given DMTU, Melo or saline intraperitoneally 30â¯min before CCl4 or corn oil administration. KEY FINDINGS: ALT levels in ovx mice were significantly increased compared to those in sham mice. DMTU reduced ALT levels in ovx mice to the same levels as those in sham mice after CCl4 injection. CCl4 upregulated TNF-α, IL-6, cox-2 and iNOS expression in ovx mice compared to the levels in sham mice. DMTU significantly reduced cox-2 and iNOS expression levels upregulated by CCl4 in ovx mice. However, pretreatment with Melo had no effects on ALT levels and the gene expression levels of TNF-α, IL-6 and HO-1 in either sham or ovx mice, indicating that cox-2 may not participate in increase of CCl4-induced ALI caused by estrogen deficiency. SIGNIFICANCE: Ovariectomy accelerated the development of CCl4-induced acute liver injury, and DMTU reduced liver injury. These results suggest that estrogen may act as an antioxidant in the development CCl4-induced acute liver injury.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Hígado/efectos de los fármacos , Tiourea/análogos & derivados , Alanina Transaminasa/metabolismo , Animales , Antioxidantes/metabolismo , Tetracloruro de Carbono/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Ciclooxigenasa 2/metabolismo , Femenino , Interleucina-6/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ovariectomía/métodos , Tiourea/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Unilateral ureteral obstruction (UUO) is a well-established method to study interstitial fibrosis of the kidney. In this study, we investigated the effects of a calcium channel blocker, amlodipine, on UUO-induced renal interstitial fibrosis in mice. UUO significantly increased the fibrotic area in the obstructed kidney, but this change was inhibited by amlodipine (6.7mg/kg/day in drinking water). mRNA expression of heat shock protein (HSP) 47 and type IV collagen was increased in the kidneys of UUO mice. Amlodipine reduced the expression of both HSP47 and type IV collagen mRNAs. Phosphorylation of c-jun-N-terminal kinase (JNK) was significantly increased by UUO, but the change was inhibited by amlodipine. Collectively, these results suggest that amlodipine may inhibit the expression of HSP47 and type IV collagen by reducing phosphorylation of JNK and ameliorating the renal interstitial fibrosis induced by UUO.
Asunto(s)
Amlodipino/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Riñón/efectos de los fármacos , Riñón/patología , Animales , Fibrosis , Riñón/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Fosforilación/efectos de los fármacos , Obstrucción Ureteral/complicacionesRESUMEN
Malignant gliomas are characterized by their high level of resistance to chemo- and radiotherapy and new treatment options are urgently required. We previously demonstrated that brefelamide, an aromatic amide isolated from methanol extracts of cellular slime molds Dictyostelium brefeldianum and D. giganteum, had antiproliferative effects on 1321N1 human astrocytoma cells, a model of glioma. In this study, we investigated the mechanisms by which brefelamide inhibited 1321N1 and PC12 rat pheochromocytoma cell proliferation. When cells were cultured in serum-free medium, hepatocyte growth factor (HGF) increased survival of 1321N1 cells but not PC12 cells. HGF receptor, c-MET, was strongly expressed in 1321N1 cells, but not in PC12 cells. Pretreatment of 1321N1 cells with brefelamide inhibited both HGF-induced cell survival and expression of c-MET. Phosphorylation of extracellular signal-regulated kinase (ERK) and AKT was increased by HGF, but these changes were inhibited by brefelamide pretreatment. Moreover, HGF mRNA levels and secretion were reduced by brefelamide. These results suggest that brefelamide reduces survival of 1321N1 cells via multiple effects including suppression of HGF receptor expression and HGF secretion and inhibition of ERK and AKT phosphorylation.
Asunto(s)
Amidas/farmacología , Antineoplásicos/farmacología , Astrocitoma/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Factor de Crecimiento de Hepatocito/farmacología , Fenoles/farmacología , Amidas/química , Animales , Antineoplásicos/química , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Células PC12 , Fenoles/química , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , RatasRESUMEN
To determine the physiological role of estrogen in the development of liver injury, we examined the sensitivities of sham and ovariectomy (ovx) mice against doxycycline (DOXY)-induced acute liver injury. Ovx or sham operation was performed in C57BL/6J wild-type female mice of eight weeks of age. Sham mice and ovx mice were treated with DOXY (240 mg/kg ip) 8 weeks after the operation, 30 min after apocynin (5 mg/kg) or saline administration. Blood and liver samples were obtained at 3 and 6 h after DOXY administration. Liver dysfunction occurred soon after DOXY administration and became more severe in ovx mice than in sham mice. At early phase after DOXY injection, TNF-α and iNOS inductions upregulated almost the same levels in sham and ovx mice. On the other hand, expression levels of IL-6, IL-10, c-fos, cox-2 and HO-1, downstream genes of TNF-α, were significantly increased in ovx mice compared to those in sham mice, correlated with liver dysfunction. In addition, apocynin, a NADPH oxidase (Nox) inhibitor, totally improved DOXY-induced liver injury in both sham and ovx mice, indicating that reactive oxygen species generated through Nox activation by DOXY are responsible for development of acute liver injury.
RESUMEN
Unilateral ureteral obstruction (UUO) is a well-established model for the study of interstitial fibrosis in the kidney. In this study, we investigated the effects of a COX-2 inhibitor, meloxicam, on UUO-induced renal interstitial fibrosis in mice. Serum creatinine, blood urea nitrogen and urinary glucose were significantly increased by UUO. However, all of these changes were attenuated by meloxicam (1 mg/kg/day). Masson׳s trichrome staining showed that interstitial fibrosis was significantly increased by UUO, but that meloxicam also significantly diminished the area of UUO-induced fibrosis. Heat shock protein (HSP) 47 protein, a collagen-specific molecular chaperone essential for the biosynthesis of collagen molecules, and type IV collagen mRNA were increased in kidneys of UUO mice. Meloxicam reduced the expression of both HSP47 protein and type IV collagen mRNA. The phosphorylation of extracellular regulated kinase (ERK) and c-jun-N-terminal kinase (JNK) was increased by UUO, but these changes were inhibited by meloxicam. Collectively, these results suggest that COX-2 may be involved in the expression of HSP47 and type IV collagen through the phosphorylation of ERK and JNK, accelerating renal interstitial fibrosis.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/farmacología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Riñón/efectos de los fármacos , Tiazinas/farmacología , Tiazoles/farmacología , Animales , Colágeno/genética , Colágeno/metabolismo , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Fibrosis , Proteínas del Choque Térmico HSP47/metabolismo , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/tratamiento farmacológico , Masculino , Meloxicam , Ratones Endogámicos BALB C , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , ARN Mensajero/metabolismo , Tiazinas/uso terapéutico , Tiazoles/uso terapéuticoRESUMEN
In this study, we investigated the effects of the cyclooxygenase (COX)-2 selective inhibitor, meloxicam, on cisplatin-induced inflammation, oxidative stress and renal lesions in BALB/c mice. A single cisplatin injection (13 mg/kg, i.p.) significantly increased plasma creatinine, blood urea nitrogen and urinary glucose accompanied by a concomitant increase in COX-2 mRNA and COX-2 protein levels. These changes in renal lesion parameters were diminished by simultaneous treatment of meloxicam (0.7 mg/kg/day in drinking water). The expression of oxidative stress markers, p47(phox), p67(phox), hemoxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and 4-hydroxy-2-nonenal (4-HNE)-modified protein were increased with cisplatin injection. Simultaneous treatment of meloxicam with cisplatin significantly inhibited the increase in p47(phox), HO-1 and 4-HNE-modified protein. The phosphorylation of extracellular regulated kinase (ERK) and c-jun-N-terminal kinase (JNK) were increased with cisplatin injection, but these changes were inhibited by meloxicam. Moreover, concomitant meloxicam treatment also prevented the cisplatin-induced infiltration of macrophages to the tubulointerstitial area. These results suggest that meloxicam can ameliorate cisplatin-induced mouse renal lesions, potentially through the inhibition of inflammatory and oxidative stress responses.
Asunto(s)
Cisplatino/efectos adversos , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Riñón/efectos de los fármacos , Tiazinas/farmacología , Tiazoles/farmacología , Animales , Ciclooxigenasa 2/genética , Dinoprostona/orina , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Meloxicam , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , Tromboxano B2/orinaRESUMEN
AIMS: We reported that interleukin-6 (IL-6) plays a protective role in the development of cisplatin-induced acute renal failure (ARF) through upregulation of anti-oxidative stress factors. In this study, we examined the effects of dimethylthiourea (DMTU), a hydroxyl radical scavenger, on the development of cisplatin-induced ARF in wild-type (WT) and IL-6(-/-) mice to determine how IL-6 contributes to modulation of oxidative stress caused by cisplatin. MAIN METHODS: WT and IL-6(-/-) male mice were given either cisplatin (30 mg/kg) or saline intraperitoneally. DMTU (100mg/kg) or saline was given 30 min before cisplatin or saline administration. Blood and kidney samples were collected on days 1 and 3 after cisplatin administration. KEY FINDINGS: In WT mice, DMTU markedly improved cisplatin-induced renal dysfunction and survival rate. DMTU reduced the expression levels of TNF-α, Bax and c-fos and increased the expression levels of IL-6, Bcl-xL and Nrf2 in WT mice. Reduced reactive oxygen species (ROS) by DMTU resulted in increases of IL-6, anti-apoptosis and anti-oxidant gene expression levels. In IL-6(-/-) mice, DMTU also improved cisplatin-induced renal dysfunction and reduced expression levels of TNF-α, Bax and c-fos, but not Bcl-xL and Nrf2. Since Nrf2 induces IL-6 expression, IL-6 and Nrf2 may influence each other during anti-oxidant responses. The basal level of HO-1 in IL-6(-/-) mice was higher than that in WT mice. SIGNIFICANCE: In IL-6(-/-) mice, overproduction of ROS by cisplatin results in upregulation of HO-1 expression in order to eliminate oxidative stress. IL-6 mediates the generation and elimination of ROS during cisplatin-induced ARF.
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Lesión Renal Aguda/inducido químicamente , Antineoplásicos/toxicidad , Cisplatino/toxicidad , Técnicas de Inactivación de Genes , Interleucina-6/genética , Riñón/efectos de los fármacos , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/genética , Lesión Renal Aguda/fisiopatología , Animales , Depuradores de Radicales Libres/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Hemo-Oxigenasa 1/genética , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Tiourea/análogos & derivados , Tiourea/uso terapéuticoRESUMEN
AIMS: Cisplatin, a major chemotherapeutic agent, accumulates in proximal tubules of the kidneys and causes acute renal failure dose-dependently. We previously reported that cisplatin induced more severe renal dysfunction in interleukin-6 (IL-6) knockout (IL-6(-/-)) mice than in wild-type (WT) mice. Expression of a pro-apoptotic protein was significantly increased with cisplatin in IL-6(-/-) mice compared to that in WT mice. IL-6, locally expressed in renal tubular cells after cisplatin administration, prevents the development of renal dysfunction at an early stage. In the present study, we focused on downstream signals of IL-6 and oxidative stress induced by cisplatin in order to evaluate the protective role of IL-6 in the development of acute renal failure. MAIN METHODS: WT and IL-6(-/-) mice were given either cisplatin (30 mg/kg) or saline intraperitoneally. Blood and kidney samples were collected at 24h and 72 h after cisplatin administration. The changes in expression of 4-hydroxy-2-nonenal protein (4-HNE, oxidative stress marker) and cyclooxygenase-2 (cox-2), activities of superoxide dismutases and caspase-3, and phosphorylation of extracellular signal-regulated kinase (ERK) were examined. KEY FINDINGS: Cisplatin increased the expression of 4-HNE and cox-2, and phosphorylation of ERK in IL-6(-/-) mice than in WT mice. On the other hand, activity of superoxide dismutase, an anti-oxidative enzyme, was significantly decreased in the kidney obtained from IL-6(-/-) mice after cisplatin administration. SIGNIFICANCE: Our findings suggest that IL-6 plays a protective role in the development of cisplatin-induced acute renal failure through upregulation of anti-oxidative stress factors.
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Lesión Renal Aguda/inducido químicamente , Antineoplásicos/efectos adversos , Antioxidantes/metabolismo , Cisplatino/efectos adversos , Interleucina-6/fisiología , Estrés Oxidativo/efectos de los fármacos , Lesión Renal Aguda/enzimología , Lesión Renal Aguda/inmunología , Lesión Renal Aguda/patología , Animales , Western Blotting , Ciclooxigenasa 2/biosíntesis , Inmunohistoquímica , Interleucina-6/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
p-Hydroxyamphetamine (p-OHA) has been shown to have a number of pharmacological actions, including causing abnormal behaviors such as increased locomotor activity and head-twitch response in rodents. We have recently reported that intracerebroventricular (i.c.v.) administration of p-OHA dose-dependently induces prepulse inhibition (PPI) disruption in mice, which is attenuated by pretreatment with haloperidol, clozapine or several dopaminergic agents. Haloperidol and clozapine have affinities for serotonergic (especially 5-HT(2A)) receptors. To investigate the involvement of the central serotonergic systems in p-OHA-induced PPI disruption, herein we tested several serotonergic agents to determine their effects on p-OHA-induced PPI disruption. p-OHA-induced PPI disruption was attenuated by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, a neurotoxin which targets serotonin-containing neurons) and p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor). p-OHA-induced PPI disruption was also attenuated by pretreatment with ketanserin (a 5-HT(2A/2C) receptor antagonist) and MDL100,907 (a selective 5-HT(2A) receptor antagonist). These data suggest that p-OHA-induced PPI disruption may involve increased serotonin release into the synaptic cleft, which then interacts with the post-synaptic 5-HT(2A) receptor.
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Inhibición Psicológica , Reflejo de Sobresalto/efectos de los fármacos , Serotonina/metabolismo , p-Hidroxianfetamina/farmacología , 5,7-Dihidroxitriptamina/efectos adversos , Estimulación Acústica/efectos adversos , Análisis de Varianza , Animales , Autorradiografía , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Fenclonina/farmacología , Fluorobencenos/farmacología , Ketanserina/farmacología , Masculino , Ratones , Piperidinas/farmacología , Serotoninérgicos/efectos adversos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Factores de TiempoRESUMEN
N-type voltage-dependent calcium channels (VDCCs) play an important role in neurotransmission, synaptic plasticity, and brain development. They are composed of several subunits named alpha(1), alpha(2), delta, beta and gamma. The alpha(1) subunit is essential for channel functions and determines fundamental channel properties. Since N-type VDCC are critically involved in the release of neurotransmitters and clinical relevance, we predicted that alpha(1) subunit KO mice would show several alterations in behavior. In the present study, we investigated neuronal functions in mice lacking the alpha(1B) (Ca(V)2.2) subunit of the N-type calcium channels. Ca(V)2.2(-/-) mice exhibited a significant increase in locomotion on an activity wheel during the dark phase. Furthermore, when challenged with apomorphine, mutant mice showed enhanced locomotor activity. Cognitive functions were examined using a Y-maze task for short-term memory and a passive avoidance task for long-term memory. The Y-maze revealed no differences in spontaneous alternation behavior between mutant and wild-type mice. The passive avoidance test revealed that the latency time in mutant mice was significantly decreased. The mutant mice showed prepulse inhibition deficits reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. Decreases in baseline levels of dopamine and serotonin within the striata and frontal cortices of mutant mice were also observed. These results suggest that Ca(2+) in the central nervous system modulates various neurophysiological functions, such as locomotor activity, long-term memory, and sensorimotor gating through the alpha(1B) subunit of the N-type calcium channels.
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Conducta Animal/fisiología , Monoaminas Biogénicas/metabolismo , Encéfalo/metabolismo , Canales de Calcio Tipo N/deficiencia , Estimulación Acústica/métodos , Análisis de Varianza , Animales , Apomorfina/farmacología , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Conducta Animal/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Ritmo Circadiano/genética , Agonistas de Dopamina/farmacología , Conducta Exploratoria/fisiología , Inhibición Psicológica , Locomoción/efectos de los fármacos , Locomoción/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/genética , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/genética , Prueba de Desempeño de Rotación con Aceleración Constante/métodosRESUMEN
It is well known that amphetamine induces disrupted prepulse inhibition (PPI) in humans and rodents. We have previously reported that intracerebroventricular (i.c.v.) administration of p-hydroxyamphetamine (p-OHA) induces multiple behavioral responses, such as increased locomotor activity and head-twitch response in rodents. To reveal the characteristics of p-OHA on sensorimotor function in rodents, herein we tested the effects of p-OHA on PPI in mice. i.c.v. administration of p-OHA dose-dependently induced PPI disruptions for all prepulse intervals tested. This effect of p-OHA on PPI was attenuated by pretreatment with haloperidol or clozapine. p-OHA-induced PPI disruptions were also attenuated by pretreatment with L-741,626 (a selective D(2) receptor antagonist), L-745,870 (a selective D(4) receptor antagonist) or 6-hydroxydopamine (a neurotoxin which targets DA-containing neurons), but not by SCH 23390 (a selective D(1) receptor antagonist), eticlopride (a D(2)/D(3) receptor antagonist) or GBR 12909 (a DA-reuptake inhibitor). These results indicate that selective blockade of either the D(2) or D(4) receptor subtype may prevent disruption of PPI induced by p-OHA via presynaptic DA release.
Asunto(s)
Dopamina/fisiología , Filtrado Sensorial/efectos de los fármacos , Simpatomiméticos/farmacología , Transmisión Sináptica/efectos de los fármacos , p-Hidroxianfetamina/farmacología , Animales , Benzazepinas/farmacología , Clozapina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Haloperidol/farmacología , Indoles/farmacología , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos , Oxidopamina/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , Piridinas , Pirroles , Reflejo de Sobresalto/efectos de los fármacos , Salicilamidas/farmacología , Simpatomiméticos/administración & dosificación , p-Hidroxianfetamina/administración & dosificaciónRESUMEN
AIMS: Mood disorders including depression are more common in women than men, particularly in times of lower estradiol levels. In this study, we investigated the effect of estrogen on emotional behavior in mice in a stress environment. MAIN METHODS: Female mice were divided into four groups: two groups were ovariectomized (OVX) and two were sham-operated. One group each of OVX and sham mice was kept in a normal environment and the other groups were assigned to a daily stress (1 h/day) for 7 days from 5 days after operation. On the 14th day after operation, subjects were measured to assess behavioral specificity, locomotor activity, elevated plus-maze (EPM) behavior, passive avoidance (PA) behavior and forced swimming behavior. KEY FINDINGS: The OVX plus stress (OVX+S) group showed a significant prolongation of immobility compared with the other groups. In all the groups there were no changes in locomotor activity, EPM behavior or PA behavior. We further examined the effect of estrogen against depressive behavior in the OVX+S group. The vehicle or 17beta-estradiol (E2) was administered s.c. to OVX+S mice for 4 days beginning on post-operative day 11. Subchronic E2 treatment decreased the stress response and improved depressive behavior relative to the vehicle group. SIGNIFICANCE: These data have important implications regarding the prevention of depression in postmenopausal women undergoing estrogen therapy.