RESUMEN
In the adult mammalian brain, newborn granule cells are continuously integrated into hippocampal circuits, and the fine-tuning of this process is important for hippocampal function. Thus, the identification of factors that control adult neural stem cells (NSCs) maintenance, differentiation and integration is essential. Here we show that the deletion of the iron trafficking protein lipocalin-2 (LCN2) induces deficits in NSCs proliferation and commitment, with impact on the hippocampal-dependent contextual fear discriminative task. Mice deficient in LCN2 present an increase in the NSCs population, as a consequence of a G0/G1 cell cycle arrest induced by increased endogenous oxidative stress. Of notice, supplementation with the iron-chelating agent deferoxamine rescues NSCs oxidative stress, promotes cell cycle progression and improves contextual fear conditioning. LCN2 is, therefore, a novel key modulator of neurogenesis that, through iron, controls NSCs cell cycle progression and death, self-renewal, proliferation and differentiation and, ultimately, hippocampal function.
Asunto(s)
Discriminación en Psicología/fisiología , Lipocalina 2/metabolismo , Neurogénesis/fisiología , Animales , Diferenciación Celular/fisiología , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Giro Dentado/metabolismo , Miedo/fisiología , Hipocampo/citología , Hipocampo/metabolismo , Lipocalina 2/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/fisiología , Neurogénesis/genética , Neuronas/citología , Neuronas/metabolismoRESUMEN
The production, accumulation and aggregation of amyloid beta (Aß) peptides in Alzheimer's disease (AD) are influenced by different modulators. Among these are iron and iron-related proteins, given their ability to modulate the expression of the amyloid precursor protein and to drive Aß aggregation. Herein, we describe that lipocalin 2 (LCN2), a mammalian acute-phase protein involved in iron homeostasis, is highly produced in response to Aß1-42 by choroid plexus epithelial cells and astrocytes, but not by microglia or neurons. Although Aß1-42 stimulation decreases the dehydrogenase activity and survival of wild-type astrocytes, astrocytes lacking the expression of Lcn2 are not affected. This protection results from a lower expression of the proapoptotic gene Bim and a decreased inflammatory response. Altogether, these findings show that Aß toxicity to astrocytes requires LCN2, which represents a novel mechanism to target when addressing AD.
Asunto(s)
Proteínas de Fase Aguda/genética , Péptidos beta-Amiloides/farmacología , Proteínas Reguladoras de la Apoptosis/biosíntesis , Astrocitos/metabolismo , Lipocalinas/biosíntesis , Lipocalinas/genética , Proteínas de la Membrana/biosíntesis , Proteínas Oncogénicas/genética , Proteínas Proto-Oncogénicas/biosíntesis , Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Astrocitos/citología , Proteína 11 Similar a Bcl2 , Células Cultivadas , Células Epiteliales/metabolismo , Hemo Oxigenasa (Desciclizante)/biosíntesis , Inflamación/inmunología , Hierro/metabolismo , Lipocalina 2 , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Neuronas/metabolismo , RatasRESUMEN
AIMS: The in vitro activity of ciclopirox olamine was evaluated against Cryptococcus spp. obtained from the cerebrospinal fluid (CSF) of immunocompromised patients. METHODS AND RESULTS: The antifungal activity of ciclopirox olamine was tested against Cryptococcus spp. obtained from the CSF of immunocompromised patients, using amphotericin B and fluconazole as controls. The minimal inhibitory concentration was determined following the microdilution method indicated by the Clinical and Laboratory Standards Institute. The minimal fungicide concentration was determined by the absence of growth on Sabouraud dextrose agar. The data obtained showed that antifungal activity of ciclopirox olamine ranged from 0·25 to 1 µg ml(-1) . CONCLUSIONS: This paper underscores the importance of the antifungal potential of ciclopirox olamine against Cryptococcus spp. as an alternative treatment against systemic cryptococosis. In vivo experiments are essential for future medical use. SIGNIFICANCE AND IMPACT OF THE STUDY: This was the first time that ciclopirox olamine was tested against Cryptococcus spp. using the reference method. The antifungal activity of this drug against this species suggests an applicable potential for systemic cryptococcosis therapy.
Asunto(s)
Antifúngicos/farmacología , Criptococosis/microbiología , Cryptococcus/efectos de los fármacos , Piridonas/farmacología , Líquido Cefalorraquídeo/microbiología , Ciclopirox , Criptococosis/tratamiento farmacológico , Cryptococcus/crecimiento & desarrollo , Cryptococcus/aislamiento & purificación , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
Sao revistos os apectos neurologicos da espondilartrose cervical. E estudada em seguida a incidencia dessa patologia no decenio 1971-80 no Hospital da Clinicas da Univesidade de Pernambuco, comparando-se os achados clinicos desse material com o estudado por Maia, na mesma regiao, na decada de 50