Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Mais filtros

Base de dados
Intervalo de ano de publicação
Cell Rep ; 29(10): 3223-3234.e6, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31801085


Major depression is a serious global health concern; however, the pathophysiology underlying this condition remains unclear. While numerous studies have focused on brain-specific mechanisms, few have evaluated the role of peripheral organs in depression. Here, we show that the liver activates an intrinsic metabolic pathway that can modulate depressive-like behavior. We find that chronic stress specifically increases the protein levels of monomeric and oligomeric soluble epoxide hydrolase (sEH), a key enzyme in epoxyeicosatrienoic acid (EET) signaling, in the liver. Hepatic deletion of Ephx2 (which encodes sEH) results in antidepressant-like effects, while the hepatic overexpression of sEH induces depressive phenotypes. The activity of sEH in hepatocytes modulates the plasma levels of 14,15-EET, which then interacts with astrocytes in the medial prefrontal cortex to mediate the effects of hepatic Ephx2 deletion. These results suggest that targeting mechanisms underlying the hepatic response to stress would increase our therapeutic options for the treatment of depression.

Stem Cells ; 31(8): 1633-43, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23630193


Astrocytes are key components of the niche for neural stem cells (NSCs) in the adult hippocampus and play a vital role in regulating NSC proliferation and differentiation. However, the exact molecular mechanisms by which astrocytes modulate NSC proliferation have not been identified. Here, we identified adenosine 5'-triphosphate (ATP) as a proliferative factor required for astrocyte-mediated proliferation of NSCs in the adult hippocampus. Our results indicate that ATP is necessary and sufficient for astrocytes to promote NSC proliferation in vitro. The lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficient ATP release from astrocytes. This deficiency led to a dysfunction in NSC proliferation that could be rescued via the administration of exogenous ATP. Moreover, P2Y1-mediated purinergic signaling is involved in the astrocyte promotion of NSC proliferation. As adult hippocampal neurogenesis is potentially involved in major mood disorder, our results might offer mechanistic insights into this disease.

Trifosfato de Adenosina/metabolismo , Astrócitos/citologia , Astrócitos/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Células-Tronco Neurais/metabolismo , Animais , Diferenciação Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Receptores de Inositol 1,4,5-Trifosfato/deficiência , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurogênese , Transdução de Sinais
J Neurosci ; 30(38): 12653-63, 2010 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-20861371


Increasing evidence indicates that stimulating hippocampal neurogenesis could provide novel avenues for the treatment of depression, and recent studies have shown that in vitro neurogenesis is enhanced by hypoxia. The aim of this study was to investigate the potential regulatory capacity of an intermittent hypobaric hypoxia (IH) regimen on hippocampal neurogenesis and its possible antidepressant-like effect. Here, we show that IH promotes the proliferation of endogenous neuroprogenitors leading to more newborn neurons in hippocampus in adult rats. Importantly, IH produces antidepressant-like effects in multiple animal models screening for antidepressant activity, including the forced swimming test, chronic mild stress paradigm, and novelty-suppressed feeding test. Hippocampal x-ray irradiation blocked both the neurogenic and behavioral effects of IH, indicating that IH likely produces antidepressant-like effects via promoting neurogenesis in adult hippocampus. Furthermore, IH stably enhanced the expression of BDNF in hippocampus; both the antidepressant-like effect and the enhancement of cell proliferation induced by IH were totally blocked by pharmacological and biological inhibition of BDNF-TrkB (tyrosine receptor kinase B) signaling, suggesting that the neurogenic and antidepressant-like effects of IH may involve BDNF signaling. These observations might contribute to both a better understanding of physiological responses to IH and to developing IH as a novel therapeutic approach for depression.

Hipocampo/fisiologia , Hipóxia/metabolismo , Atividade Motora/fisiologia , Neurogênese/fisiologia , Análise de Variância , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Atividade Motora/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/fisiologia , Estresse Psicológico/metabolismo