The purpose of this study was to determine if the substituted pyrimidine, CXB-909 (formerly known as KP544) which has been shown to amplify the effects of nerve growth factor in elevating choline-acetyltransferase act...The purpose of this study was to determine if the substituted pyrimidine, CXB-909 (formerly known as KP544) which has been shown to amplify the effects of nerve growth factor in elevating choline-acetyltransferase activity in vitro, could attenuate memory deficits in the mu-p-75 saporin injected mouse model of Alzheimer’s disease (AD). Seventy-one, seven-week old C57/BL6 mice received daily oral intubation of 10, 15, or 20 mg/kg CXB-909, or vehicle (0.5% methylcellulose solution), which continued for 32 days. At postnatal week nine, mice received bilateral intra-cerebroventricular injections of mu-p-75 saporin, or sterile phosphate buffered saline. Seven days after surgery, mice were trained for two days, on a cued-platform version of the Morris water maze task, and then tested on a four-day hidden-platform version, followed by a one-day probe version of this task. Mice injected with mu-p-75 saporin, had increased latency to find the hidden-platform compared to sham mice. Furthermore, mice treated with CXB-909 at the 10, and 15 mg/kg doses, significantly reduced their latency to reach the hidden-platform, compared to vehicle-treated mice given mu-p-75 saporin. These results suggest that CXB-909 can attenuate memory deficits in the mu-p-75 saporin injected mouse model of AD.展开更多
Gradual degeneration and loss of dopaminergic neurons in the substantia nigra,pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s dis...Gradual degeneration and loss of dopaminergic neurons in the substantia nigra,pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s disease(PD).In addition,half of the PD patients also exhibit frontostriatal-mediated executive dysfunction,including deficits in attention,short-term working memory,speed of mental processing,and impulsivity.The most commonly used treatments for PD are only partially or transiently effective and are available or applicable to a minority of patients.Because,these therapies neither restore the lost or degenerated dopaminergic neurons,nor prevent or delay the disease progression,the need for more effective therapeutics is critical.In this review,we provide a comprehensive overview of the current understanding of the molecular signaling pathways involved in PD,particularly within the context of how genetic and environmental factors contribute to the initiation and progression of this disease.The involvement of molecular chaperones,autophagy-lysosomal pathways,and proteasome systems in PD are also highlighted.In addition,emerging therapies,including pharmacological manipulations,surgical procedures,stem cell transplantation,gene therapy,as well as complementary,supportive and rehabilitation therapies to prevent or delay the progression of this complex disease are reviewed.展开更多
文摘The purpose of this study was to determine if the substituted pyrimidine, CXB-909 (formerly known as KP544) which has been shown to amplify the effects of nerve growth factor in elevating choline-acetyltransferase activity in vitro, could attenuate memory deficits in the mu-p-75 saporin injected mouse model of Alzheimer’s disease (AD). Seventy-one, seven-week old C57/BL6 mice received daily oral intubation of 10, 15, or 20 mg/kg CXB-909, or vehicle (0.5% methylcellulose solution), which continued for 32 days. At postnatal week nine, mice received bilateral intra-cerebroventricular injections of mu-p-75 saporin, or sterile phosphate buffered saline. Seven days after surgery, mice were trained for two days, on a cued-platform version of the Morris water maze task, and then tested on a four-day hidden-platform version, followed by a one-day probe version of this task. Mice injected with mu-p-75 saporin, had increased latency to find the hidden-platform compared to sham mice. Furthermore, mice treated with CXB-909 at the 10, and 15 mg/kg doses, significantly reduced their latency to reach the hidden-platform, compared to vehicle-treated mice given mu-p-75 saporin. These results suggest that CXB-909 can attenuate memory deficits in the mu-p-75 saporin injected mouse model of AD.
文摘Gradual degeneration and loss of dopaminergic neurons in the substantia nigra,pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s disease(PD).In addition,half of the PD patients also exhibit frontostriatal-mediated executive dysfunction,including deficits in attention,short-term working memory,speed of mental processing,and impulsivity.The most commonly used treatments for PD are only partially or transiently effective and are available or applicable to a minority of patients.Because,these therapies neither restore the lost or degenerated dopaminergic neurons,nor prevent or delay the disease progression,the need for more effective therapeutics is critical.In this review,we provide a comprehensive overview of the current understanding of the molecular signaling pathways involved in PD,particularly within the context of how genetic and environmental factors contribute to the initiation and progression of this disease.The involvement of molecular chaperones,autophagy-lysosomal pathways,and proteasome systems in PD are also highlighted.In addition,emerging therapies,including pharmacological manipulations,surgical procedures,stem cell transplantation,gene therapy,as well as complementary,supportive and rehabilitation therapies to prevent or delay the progression of this complex disease are reviewed.
