Entacapone,a catechol-O-methyltransferase inhibitor,can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease.However,few studies are reported on whether entacapone can affect hippoca...Entacapone,a catechol-O-methyltransferase inhibitor,can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease.However,few studies are reported on whether entacapone can affect hippocampal neurogenesis in mice.To investigate the effects of entacapone,a modulator of dopamine,on proliferating cells and immature neurons in the mouse hippocampal dentate gyrus,60 mice(7 weeks old)were randomly divided into a vehicle-treated group and the groups treated with 10,50,or 200 mg/kg entacapone.The results showed that 50 and 200 mg/kg entacapone increased the exploration time for novel object recognition.Immunohistochemical staining results revealed that after entacapone treatment,the numbers of Ki67-positive proliferating cells,doublecortin-positive immature neurons,and phosphorylated cAMP response element-binding protein(pCREB)-positive cells were significantly increased.Western blot analysis results revealed that treatment with tyrosine kinase receptor B(TrkB)receptor antagonist significantly decreased the exploration time for novel object recognition and inhibited the expression of phosphorylated TrkB and brain-derived neurotrophic factor(BDNF).Entacapone treatment antagonized the effects of TrkB receptor antagonist.These results suggest that entacapone treatment promoted hippocampal neurogenesis and improved memory function through activating the BDNF-TrkB-pCREB pathway.This study was approved by the Institutional Animal Care and Use Committee of Seoul National University(approval No.SNU-130730-1)on February 24,2014.展开更多
Of the eleven families of cyclic nucleotide phosphodiesterases(PDEs) present in the human body,PDE4s represent the most widely expressed family of PDEs. A large body of work has been published on the expression and fu...Of the eleven families of cyclic nucleotide phosphodiesterases(PDEs) present in the human body,PDE4s represent the most widely expressed family of PDEs. A large body of work has been published on the expression and function of these PDEs,which preferentially hydrolyze cAMP in all cells studied,including neurons and supporting cells of the CNS. Four distinct genes termed PDE4 A,PDE4B,PDE4C and PDE4D encode PDE4 proteins. However,the number of PDE4s identified in different tissues and cells is estimated to be more than 30. Differences in regulation and localization explain this extreme heterogeneity. PDE4 hydrolytic activity is regulated by phosphorylation,and protein kinase A(PKA) was the first kinase identified. This PKA-dependent regulation establishes a feedback loop where cAMP regulates its own degradation to control the intensity and localization of the hormone and neurotransmitter signal. In addition,numerous additional kinases phosphorylate PDE4s to modulate the PKA-dependent activation and fine tune cAMP levels by growth factors and other extracellular cues. Thus,PDE4 can be considered a coincidence detector that integrates multiple signaling pathways. Finally,different PDE4s are involved in numerous macromolecular complexes targeting the cAMP hydrolytic activity to different subcellular domains. Thus,PDE4s function in different subcellular compartments,and inhibition of different isoforms affects cAMP levels in different subdomains with consequently different functions. The dyad space and the control of excitation/contraction will be used as examples of these localized regulations.展开更多
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea Government(MSIP)(NRF-2016R1A2B4009156)the Promising-Pioneering Researcher Program through Seoul National University(SNU)in 2015 and by the Research Institute for Veterinary Science,Seoul National University.
文摘Entacapone,a catechol-O-methyltransferase inhibitor,can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease.However,few studies are reported on whether entacapone can affect hippocampal neurogenesis in mice.To investigate the effects of entacapone,a modulator of dopamine,on proliferating cells and immature neurons in the mouse hippocampal dentate gyrus,60 mice(7 weeks old)were randomly divided into a vehicle-treated group and the groups treated with 10,50,or 200 mg/kg entacapone.The results showed that 50 and 200 mg/kg entacapone increased the exploration time for novel object recognition.Immunohistochemical staining results revealed that after entacapone treatment,the numbers of Ki67-positive proliferating cells,doublecortin-positive immature neurons,and phosphorylated cAMP response element-binding protein(pCREB)-positive cells were significantly increased.Western blot analysis results revealed that treatment with tyrosine kinase receptor B(TrkB)receptor antagonist significantly decreased the exploration time for novel object recognition and inhibited the expression of phosphorylated TrkB and brain-derived neurotrophic factor(BDNF).Entacapone treatment antagonized the effects of TrkB receptor antagonist.These results suggest that entacapone treatment promoted hippocampal neurogenesis and improved memory function through activating the BDNF-TrkB-pCREB pathway.This study was approved by the Institutional Animal Care and Use Committee of Seoul National University(approval No.SNU-130730-1)on February 24,2014.
文摘Of the eleven families of cyclic nucleotide phosphodiesterases(PDEs) present in the human body,PDE4s represent the most widely expressed family of PDEs. A large body of work has been published on the expression and function of these PDEs,which preferentially hydrolyze cAMP in all cells studied,including neurons and supporting cells of the CNS. Four distinct genes termed PDE4 A,PDE4B,PDE4C and PDE4D encode PDE4 proteins. However,the number of PDE4s identified in different tissues and cells is estimated to be more than 30. Differences in regulation and localization explain this extreme heterogeneity. PDE4 hydrolytic activity is regulated by phosphorylation,and protein kinase A(PKA) was the first kinase identified. This PKA-dependent regulation establishes a feedback loop where cAMP regulates its own degradation to control the intensity and localization of the hormone and neurotransmitter signal. In addition,numerous additional kinases phosphorylate PDE4s to modulate the PKA-dependent activation and fine tune cAMP levels by growth factors and other extracellular cues. Thus,PDE4 can be considered a coincidence detector that integrates multiple signaling pathways. Finally,different PDE4s are involved in numerous macromolecular complexes targeting the cAMP hydrolytic activity to different subcellular domains. Thus,PDE4s function in different subcellular compartments,and inhibition of different isoforms affects cAMP levels in different subdomains with consequently different functions. The dyad space and the control of excitation/contraction will be used as examples of these localized regulations.
