Alzheimer＇s disease （AD）, a fatal, progressive, neurodegener- ative disorder, is the most common cause of old-age demen- tia, accounting for 50-75% of dementia patients. Early stages of AD are marked by vocabulary ...Alzheimer＇s disease （AD）, a fatal, progressive, neurodegener- ative disorder, is the most common cause of old-age demen- tia, accounting for 50-75% of dementia patients. Early stages of AD are marked by vocabulary shrinkage, spatial disori- entation, depression, apraxia, and deterioration of recent forms of declarative memory. In course of time, the patients require close supervision due to the loss of cognitive and functional abilities, and at the terminal stages of the disease, all forms of memory are severely impaired with the patients needing nursing home care （World Alzheimer Report, 2013）.展开更多
AIM: To determine the effect of different concentrations of the acetylcholinesterase (AChE) inhibitors tacrine and donepezil on retinal protection in AChE(+/-) mice (AChE knockout mice) of various ages. METHODS: Cultu...AIM: To determine the effect of different concentrations of the acetylcholinesterase (AChE) inhibitors tacrine and donepezil on retinal protection in AChE(+/-) mice (AChE knockout mice) of various ages. METHODS: Cultured ARPE -19 cells were treated with hydrogen peroxide (H2O2) at concentrations of 0, 250, 500, 1000 and 2000 mu mol/L and protein levels were measured using Western blot. Intraperitoneal injections of tacrine and donepezil (0.1 mg/mL, 0.2 mg/mL and 0.4 mg/mL) were respectively given to AChE4- mice aged 2mo and 4mo and wild-type S129 mice for 7d; phosphate buffered saline (PBS) was administered to the control group. The mice were sacrificed after 30d by cardiac perfusion and retinal samples were taken. AChE(+/-) deficient mice were identified by polymerase chain reaction (PCR) analysis using specific genotyping protocols obtained from the Jackson Laboratory website. H&E staining, immunofluorescence and Western blot were performed to observe AChE protein expression changes in the retinal pigment epithelial (RPE) cell layer. RESULTS: Different concentrations of H2O2 induced AChE expression during RPE cell apoptosis. AChE(+/-) mice retina were thinner than those in wild -type mice (P< 0.05); the retinal structure was still intact at 2mo but became thinner with increasing age(P <0.05); furthermore, AChE'l- mice developed more slowly than wild-type mice (P <0.05). Increased concentrations of tacrine and donepezil did not significantly improve the protection of the retina function and morphology (P >0.05). CONCLUSION: in viva, tacrine and donepezil can inhibit the expression of AChE; the decrease of AChE expression in the retina is beneficial for the development of the retina.展开更多
With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses a...With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses are commonly used to develop reliable therapeutic agents. The multitarget-directed ligand (MTDL) approach was taken in this work to develop multi-functional agents, which can mainly serve as dual BACE 1 and AChE inhibitors. Depending on the scaffolds of (+)-(S)- dihydro-ar-tumerone and (-)-gallocatechin gallate, 3 series of new compounds have been designed, synthesized and evaluated, from which we have identified 2-(2-(3-methylbenzoyl)-3-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl) isoindoline-1,3-dione (3d) as a new cholinesterase and β-secretase dual inhibitor without toxicity. Furthermore, 3d also exhibits hydrogen peroxide scavenging activity which could help to reduce the reactive oxygen species (ROS) in the brain of AD patients.展开更多
基金in part supported by the German Ministry for Education and Research (BMBF) special network program KMU-Innovativ-2
文摘Alzheimer＇s disease （AD）, a fatal, progressive, neurodegener- ative disorder, is the most common cause of old-age demen- tia, accounting for 50-75% of dementia patients. Early stages of AD are marked by vocabulary shrinkage, spatial disori- entation, depression, apraxia, and deterioration of recent forms of declarative memory. In course of time, the patients require close supervision due to the loss of cognitive and functional abilities, and at the terminal stages of the disease, all forms of memory are severely impaired with the patients needing nursing home care （World Alzheimer Report, 2013）.
基金Supported by National Natural Science Foundation of China(No.81160118,81400372)Clinical Medicine Research Special-purpose Foundation of China(No.L2012052)+5 种基金Jiangxi Province Sailing Engineering(No.2014022)Science Technology Foundation of Jiangxi Province(No.20151BBG70223)Youth Science Foundation of Jiangxi Province(No.20151BAB215016)Education Department Youth Scientific Research Foundation(No.GJJ14170)Health Development Planning Commission Science Foundation of Jiangxi Province(NO:20155154)Health Department Tradition Chinese Medicine Science and Technology Foundation(No.2010A015,2012A139,2013A073)
文摘AIM: To determine the effect of different concentrations of the acetylcholinesterase (AChE) inhibitors tacrine and donepezil on retinal protection in AChE(+/-) mice (AChE knockout mice) of various ages. METHODS: Cultured ARPE -19 cells were treated with hydrogen peroxide (H2O2) at concentrations of 0, 250, 500, 1000 and 2000 mu mol/L and protein levels were measured using Western blot. Intraperitoneal injections of tacrine and donepezil (0.1 mg/mL, 0.2 mg/mL and 0.4 mg/mL) were respectively given to AChE4- mice aged 2mo and 4mo and wild-type S129 mice for 7d; phosphate buffered saline (PBS) was administered to the control group. The mice were sacrificed after 30d by cardiac perfusion and retinal samples were taken. AChE(+/-) deficient mice were identified by polymerase chain reaction (PCR) analysis using specific genotyping protocols obtained from the Jackson Laboratory website. H&E staining, immunofluorescence and Western blot were performed to observe AChE protein expression changes in the retinal pigment epithelial (RPE) cell layer. RESULTS: Different concentrations of H2O2 induced AChE expression during RPE cell apoptosis. AChE(+/-) mice retina were thinner than those in wild -type mice (P< 0.05); the retinal structure was still intact at 2mo but became thinner with increasing age(P <0.05); furthermore, AChE'l- mice developed more slowly than wild-type mice (P <0.05). Increased concentrations of tacrine and donepezil did not significantly improve the protection of the retina function and morphology (P >0.05). CONCLUSION: in viva, tacrine and donepezil can inhibit the expression of AChE; the decrease of AChE expression in the retina is beneficial for the development of the retina.
文摘With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses are commonly used to develop reliable therapeutic agents. The multitarget-directed ligand (MTDL) approach was taken in this work to develop multi-functional agents, which can mainly serve as dual BACE 1 and AChE inhibitors. Depending on the scaffolds of (+)-(S)- dihydro-ar-tumerone and (-)-gallocatechin gallate, 3 series of new compounds have been designed, synthesized and evaluated, from which we have identified 2-(2-(3-methylbenzoyl)-3-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl) isoindoline-1,3-dione (3d) as a new cholinesterase and β-secretase dual inhibitor without toxicity. Furthermore, 3d also exhibits hydrogen peroxide scavenging activity which could help to reduce the reactive oxygen species (ROS) in the brain of AD patients.
