目的基于cAMP-CREB-BDNF通路探讨柴胡-白芍药对抗抑郁的作用机制。方法建立慢性温和不可预知应激(CUMS)大鼠抑郁模型,ELISA法测定大鼠海马组织中环磷酸腺苷(cAMP)、磷酸化环磷腺苷效应元件结合蛋白(p-CREB)、脑源性神经营养因子(BDNF)...目的基于cAMP-CREB-BDNF通路探讨柴胡-白芍药对抗抑郁的作用机制。方法建立慢性温和不可预知应激(CUMS)大鼠抑郁模型,ELISA法测定大鼠海马组织中环磷酸腺苷(cAMP)、磷酸化环磷腺苷效应元件结合蛋白(p-CREB)、脑源性神经营养因子(BDNF)和磷酸二酯酶抑制剂(PDE4)以及血浆中cAMP水平的变化,采用RT-PCR法测定海马、下丘脑和皮质中的BDNF mRNA的表达。结果与模型组相比,阳性药组、柴胡-白芍药对给药组可以不同程度地逆转大鼠海马组织及血浆中cAMP水平和大鼠海马组织中p-CREB、BDNF水平的降低。同时阳性药组、柴胡-白芍药对给药组能够增加大鼠海马、皮质和下丘脑中BDNF m RNA的表达。结论柴胡-白芍药对对CUMS大鼠模型具有明显的抗抑郁作用,并可以通过调节cAMP-CREB-BDNF通路而达到抗抑郁的作用。展开更多
Cyclic AMP (cAMP), as a second messenger, plays a critical role in cellular signaling transduction. However, it is not clear how this apparently identical cAMP signal induces divergent physiological re- sponses. The p...Cyclic AMP (cAMP), as a second messenger, plays a critical role in cellular signaling transduction. However, it is not clear how this apparently identical cAMP signal induces divergent physiological re- sponses. The potential explanation that cAMP signaling is compartmentalized was proposed by Buxton and Brunton twenty years ago. Compartmentalization of cAMP signaling allows spatially distinct pools of protein kinase A (PKA) to be differently activated. Research on cAMP signaling has regained impetus in many fields of life sciences due to the progress in understanding cAMP signaling complexity and functional diversity. The cAMP/PKA signaling compartments are maintained by A-kinase anchoring proteins (AKAPs) which bind PKA and other signaling proteins, and by PDEs which hydrolyse cAMP and thus terminate PKA activity. PDE4 enzymes belong to PDE superfamily and stand at a crossroad that allows them to integrate various signaling pathways with that of cAMP in spatially distinct com- partments. In the current review, the nomenclature, taxonomy and gene expression of PDE4, and the system and region of its effect are described. In addition, the idiographic molecules, mechanisms, and regulation models of PDE4 are summarized. Furthermore, the important roles PDE4 plays in the matu- ration of rat granulosa cells and cAMP signaling compartmentalization are discussed.展开更多
BACKGROUND： Long-term exposure to drugs of abuse causes an upregulation of the cAMP-signaling pathway in the nucleus accumbens and other forebrain regions, this common neuroadaptation is thought to underlie aspects o...BACKGROUND： Long-term exposure to drugs of abuse causes an upregulation of the cAMP-signaling pathway in the nucleus accumbens and other forebrain regions, this common neuroadaptation is thought to underlie aspects of drug tolerance and dependence. Phosphodiesterase 4 （PDE4） is an enzyme that the selective hydrolyzes intracellular cAMP. It is expressed in several brain regions that regulate the reinforcing effects of drugs of abuse. OBJECTIVE： Here, we review the current knowledge about central nervous system （CNS） distribution of PDE4 isoforms and the effects of systemic and brain-region specific inhibition of PDE4 on behavioral models of drug addiction. METHODS： A systematic literature search was performed using the Pubmed. RESULTS： Using behavioral sensitization, conditioned place preference and drug self-administration as behavioral models, a large number of studies have shown that local or systemic administration of PDE4 inhibitors reduce drug intake and/or drug seeking for psychostimulants, alcohol, and opioids in rats or mice. CONCLUSIONS： Preclinical studies suggest that PDE4 could be a therapeutic target for several classes of substance use disorder. We conclude by identifying opportunities for the development of subtype-selective PDE4 inhibitors that may reduce addiction liability and minimize the side effects that limit the clinical potential of non-selective PDE4 inhibitors. Several PDE4 inhibitors have been clinically approved for other diseases. There is a promising possibility to repurpose these PDE4 inhibitors for the treatment of drug addiction as they are safe and well-tolerated in patients.展开更多
文摘目的基于cAMP-CREB-BDNF通路探讨柴胡-白芍药对抗抑郁的作用机制。方法建立慢性温和不可预知应激(CUMS)大鼠抑郁模型,ELISA法测定大鼠海马组织中环磷酸腺苷(cAMP)、磷酸化环磷腺苷效应元件结合蛋白(p-CREB)、脑源性神经营养因子(BDNF)和磷酸二酯酶抑制剂(PDE4)以及血浆中cAMP水平的变化,采用RT-PCR法测定海马、下丘脑和皮质中的BDNF mRNA的表达。结果与模型组相比,阳性药组、柴胡-白芍药对给药组可以不同程度地逆转大鼠海马组织及血浆中cAMP水平和大鼠海马组织中p-CREB、BDNF水平的降低。同时阳性药组、柴胡-白芍药对给药组能够增加大鼠海马、皮质和下丘脑中BDNF m RNA的表达。结论柴胡-白芍药对对CUMS大鼠模型具有明显的抗抑郁作用,并可以通过调节cAMP-CREB-BDNF通路而达到抗抑郁的作用。
基金Supported by the National Natural Science Foundation of China (Grant No. 30571335) a Grant-in-Aid for Innovatory Training of Graduated Students in Jiangsu Province, China
文摘Cyclic AMP (cAMP), as a second messenger, plays a critical role in cellular signaling transduction. However, it is not clear how this apparently identical cAMP signal induces divergent physiological re- sponses. The potential explanation that cAMP signaling is compartmentalized was proposed by Buxton and Brunton twenty years ago. Compartmentalization of cAMP signaling allows spatially distinct pools of protein kinase A (PKA) to be differently activated. Research on cAMP signaling has regained impetus in many fields of life sciences due to the progress in understanding cAMP signaling complexity and functional diversity. The cAMP/PKA signaling compartments are maintained by A-kinase anchoring proteins (AKAPs) which bind PKA and other signaling proteins, and by PDEs which hydrolyse cAMP and thus terminate PKA activity. PDE4 enzymes belong to PDE superfamily and stand at a crossroad that allows them to integrate various signaling pathways with that of cAMP in spatially distinct com- partments. In the current review, the nomenclature, taxonomy and gene expression of PDE4, and the system and region of its effect are described. In addition, the idiographic molecules, mechanisms, and regulation models of PDE4 are summarized. Furthermore, the important roles PDE4 plays in the matu- ration of rat granulosa cells and cAMP signaling compartmentalization are discussed.
文摘BACKGROUND： Long-term exposure to drugs of abuse causes an upregulation of the cAMP-signaling pathway in the nucleus accumbens and other forebrain regions, this common neuroadaptation is thought to underlie aspects of drug tolerance and dependence. Phosphodiesterase 4 （PDE4） is an enzyme that the selective hydrolyzes intracellular cAMP. It is expressed in several brain regions that regulate the reinforcing effects of drugs of abuse. OBJECTIVE： Here, we review the current knowledge about central nervous system （CNS） distribution of PDE4 isoforms and the effects of systemic and brain-region specific inhibition of PDE4 on behavioral models of drug addiction. METHODS： A systematic literature search was performed using the Pubmed. RESULTS： Using behavioral sensitization, conditioned place preference and drug self-administration as behavioral models, a large number of studies have shown that local or systemic administration of PDE4 inhibitors reduce drug intake and/or drug seeking for psychostimulants, alcohol, and opioids in rats or mice. CONCLUSIONS： Preclinical studies suggest that PDE4 could be a therapeutic target for several classes of substance use disorder. We conclude by identifying opportunities for the development of subtype-selective PDE4 inhibitors that may reduce addiction liability and minimize the side effects that limit the clinical potential of non-selective PDE4 inhibitors. Several PDE4 inhibitors have been clinically approved for other diseases. There is a promising possibility to repurpose these PDE4 inhibitors for the treatment of drug addiction as they are safe and well-tolerated in patients.
