RESUMEN
BACKGROUND AND AIM OF THE STUDY: The symptoms of Parkinson's disease are alleviated by dopamine D2 agonists, which are classified as ergot dopamine D2 agonists and non-ergot D2 agonists. Among the former, pergolide has been associated with valvular heart disease, since it has both potent D2 receptor and serotonin 5-HT(2B) receptor agonistic properties. Among the latter, pramipexole has few incidences of heart valve disease onset, since it has an absence of 5-HT(2B) receptor agonism. METHOD: A [3H]thymidine incorporation assay was performed to monitor function, and microarray global analysis to monitor gene expression, on porcine heart valve interstitial cells (VICs) treated with pergolide or pramipexole. RESULTS: The 5-HT(2B) receptor was abundantly expressed in porcine VICs. The 5-HT(2B) receptor agonist pergolide induced an increase in [3H]thymidine incorporation, accompanied by a decrease in 5-HT(2B) receptor mRNA expression. [3H]thymidine incorporation was blocked by lisuride, a 5-HT(2B) receptor antagonist, and also by LY-294002, a specific inhibitor of PI3K and Akt. Moreover, type 2 iodothyronine deiodinase (Dio2) expression in porcine VICs treated with pergolide was shown, by a global analysis of mRNA, to be markedly increased compared to that induced by pramipexole. Such changes in VICs may correlate with the mechanism of heart valve disease pathogenesis. CONCLUSION: There were substantial differences (increased [3H]thymidine incorporation, and Dio2 expression) between pergolide and pramipexole, which might correlate with the mechanism of heart valve disease onset.
Asunto(s)
Benzotiazoles/toxicidad , Agonistas de Dopamina/toxicidad , Válvula Mitral/efectos de los fármacos , Pergolida/toxicidad , Receptores de Dopamina D2/agonistas , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Válvula Mitral/metabolismo , Válvula Mitral/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Pramipexol , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor de Serotonina 5-HT2B/efectos de los fármacos , Receptor de Serotonina 5-HT2B/genética , Receptor de Serotonina 5-HT2B/metabolismo , Receptores de Dopamina D2/metabolismo , Reproducibilidad de los Resultados , Agonistas del Receptor de Serotonina 5-HT2/toxicidad , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Increasing evidence suggests that the elevation of beta-amyloid (Abeta) peptides in the brain is central to the pathogenesis of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, enhances cAMP/protein kinase A/extracellular signal-regulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates Abeta-induced memory impairment in AD model rats. For the first time, we report that this natural compound improves memory deficits in amyloid precursor protein (APP) transgenic mice that overexpress human APP695 harboring the double Swedish and London mutations [APP-SL 7-5 transgenic (Tg) mice]. Our enzyme-linked immunosorbent assay (ELISA) also showed that administration of nobiletin to the transgenic mice for 4 months markedly reduced quantity of guanidine-soluble Abeta(1-40) and Abeta(1-42) in the brain. Furthermore, consistent with the results of ELISA, by immunohistochemistry with anti-Abeta antibody, it was evidently shown that the administration of nobiletin decreased the Abeta burden and plaques in the hippocampus of APP-SL 7-5 Tg mice. These findings suggest that this natural compound has potential to become a novel drug for fundamental treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/fisiología , Modelos Animales de Enfermedad , Flavonas/uso terapéutico , Flavonoides/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/biosíntesis , Péptidos beta-Amiloides/genética , Animales , Citrus , Flavonas/química , Flavonoides/química , Trastornos de la Memoria/genética , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Recent studies have indicated that learning-induced activation of extracellular signal-regulated kinase (ERK) signaling via N-methyl-D-aspartate (NMDA) receptors is required for consolidation of the resultant learning. These findings raise an idea that control of ERK signaling may be a potential target for treatment of cognitive dysfunction. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from Citrus depressa, enhances cAMP/protein kinase A/ERK signaling in cultured rat hippocampal neurons and PC12D cells. Here, we, for the first time, present the evidence that this natural compound reverses learning impairment associated with NMDA receptor antagonism by activation of ERK in the hippocampus. Treatment with 50 mg/kg nobiletin reversed the NMDA receptor antagonist MK-801 (dizocilpine maleate)-induced learning impairment in mice. Western blot analysis also showed that nobiletin reversed MK-801-induced inhibition of learning-associated ERK activation in the hippocampus of the animals. Furthermore, consistent with these results, in cultured rat hippocampal neurons, nobiletin restored MK-801-induced impairment of NMDA-stimulated phosphorylation of ERK in a concentration-dependent manner. Taken together, the present study suggests that compounds that activate ERK signaling improve cognitive deficits associated with NMDA receptor hypofunction and that nobiletin may give us a new insight into therapeutic drug development for neurological disorders exhibiting cognitive impairment accompanied by a hypofunction of NMDA receptor-ERK signaling.