Chronic exposure to drugs of abuse will give rise to persistent structural and functional changes in the central nervous system. These phenomena are usually referred as ′drug-induced neuroplasticity′ and depend on c...Chronic exposure to drugs of abuse will give rise to persistent structural and functional changes in the central nervous system. These phenomena are usually referred as ′drug-induced neuroplasticity′ and depend on changes in gene expression. The cAMP response element binding protein(CREB),as a downstream molecule in mediating the actions of cAMP is an important transcriptional factor in establishing and maintaining addiction to drugs of abuse. Application of a PDE4 inhibitor attenuates the rewarding properties of cocaine and morphine. Given the fact that PDE10A is specifically located in striatum,an important structure involved in the reward circuit,we thus investigated the PDE10A inhibitormodulated the behavioral reinforcement exerted by morphine. The results show that MP-10 2.5 mg·kg^(-1),administered subcutaneously,significantly inhibited the acquisition of morphine-induced CPP. Moreover,MP-10 did not alter the expression of morphine-induced CPP,but did accelerate the extinction of morphine-induced CPP. Additionally,chronic treatment with MP-10 2.5 mg·kg^(-1)decreased expression of phosphorylated CREB(pC REB) in dorsomedial striatum,in shell of NAc,and in anterior cingulate cortex(ACC) as well as decreased expression of ΔFos B in the shell of NAc and ACC. These data indicate that PDE10A inhibition may have a potential therapeutic effect on addiction. Since the MP-10 has relative short metabolic Stability,we also developed a few novel potent new PDE10A selective inhibitor with improved stability and brain exposure. The new compound exhibited promising potential in schizophrenia and addiction treatment.展开更多
Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration.There is currently no effective treatment for retinitis pigmentosa.Although a mixture of lutein and other antioxidant agents has sh...Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration.There is currently no effective treatment for retinitis pigmentosa.Although a mixture of lutein and other antioxidant agents has shown promising effects in protecting the retina from degeneration,the role of lutein alone remains unclear.In this study,we administered intragastric lutein to Pde6brd10 model mice,which display degeneration of retinal photoreceptors,on postnatal days 17(P17)to P25,when rod apoptosis reaches peak.Lutein at the optimal protective dose of 200 mg/kg promoted the survival of photoreceptors compared with vehicle control.Lutein increased rhodopsin expression in rod cells and opsin expression in cone cells,in line with an increased survival rate of photoreceptors.Functionally,lutein improved visual behavior,visual acuity,and retinal electroretinogram responses in Pde6brd10 mice.Mechanistically,lutein reduced the expression of glial fibrillary acidic protein in Müller glial cells.The results of this study confirm the ability of lutein to postpone photoreceptor degeneration by reducing reactive gliosis of Müller cells in the retina and exerting anti-inflammatory effects.This study was approved by the Laboratory Animal Ethics Committee of Jinan University(approval No.LACUC-20181217-02)on December 17,2018.展开更多
文摘Chronic exposure to drugs of abuse will give rise to persistent structural and functional changes in the central nervous system. These phenomena are usually referred as ′drug-induced neuroplasticity′ and depend on changes in gene expression. The cAMP response element binding protein(CREB),as a downstream molecule in mediating the actions of cAMP is an important transcriptional factor in establishing and maintaining addiction to drugs of abuse. Application of a PDE4 inhibitor attenuates the rewarding properties of cocaine and morphine. Given the fact that PDE10A is specifically located in striatum,an important structure involved in the reward circuit,we thus investigated the PDE10A inhibitormodulated the behavioral reinforcement exerted by morphine. The results show that MP-10 2.5 mg·kg^(-1),administered subcutaneously,significantly inhibited the acquisition of morphine-induced CPP. Moreover,MP-10 did not alter the expression of morphine-induced CPP,but did accelerate the extinction of morphine-induced CPP. Additionally,chronic treatment with MP-10 2.5 mg·kg^(-1)decreased expression of phosphorylated CREB(pC REB) in dorsomedial striatum,in shell of NAc,and in anterior cingulate cortex(ACC) as well as decreased expression of ΔFos B in the shell of NAc and ACC. These data indicate that PDE10A inhibition may have a potential therapeutic effect on addiction. Since the MP-10 has relative short metabolic Stability,we also developed a few novel potent new PDE10A selective inhibitor with improved stability and brain exposure. The new compound exhibited promising potential in schizophrenia and addiction treatment.
基金supported by Aier Eye Hospital Group,Nos.AF2019001 and AF2019002(to SBT,KFS,YX and XSM)the National Natural Science Foundation of China,No.82074169(to XSM)+3 种基金Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology of China,No.20200730009(to YX)Guangdong Grant Key Technologies for Treatment of Brain Disorders,China,No.2018B030332001(to YX)Natural Science Foundation of Guangdong Province of China,No.2021A1515012473(to XSM)Project of Administration of Traditional Chinese Medicine of Guangdong Province,No.20202045(to XSM)。
文摘Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration.There is currently no effective treatment for retinitis pigmentosa.Although a mixture of lutein and other antioxidant agents has shown promising effects in protecting the retina from degeneration,the role of lutein alone remains unclear.In this study,we administered intragastric lutein to Pde6brd10 model mice,which display degeneration of retinal photoreceptors,on postnatal days 17(P17)to P25,when rod apoptosis reaches peak.Lutein at the optimal protective dose of 200 mg/kg promoted the survival of photoreceptors compared with vehicle control.Lutein increased rhodopsin expression in rod cells and opsin expression in cone cells,in line with an increased survival rate of photoreceptors.Functionally,lutein improved visual behavior,visual acuity,and retinal electroretinogram responses in Pde6brd10 mice.Mechanistically,lutein reduced the expression of glial fibrillary acidic protein in Müller glial cells.The results of this study confirm the ability of lutein to postpone photoreceptor degeneration by reducing reactive gliosis of Müller cells in the retina and exerting anti-inflammatory effects.This study was approved by the Laboratory Animal Ethics Committee of Jinan University(approval No.LACUC-20181217-02)on December 17,2018.
