The antiapoptotic and neuroprotective activity of irreversible monoamine oxidase (MAO) B inhibitor, rasagiline [R(+)-N-propargyl-1-aminioindan], its S-isomer (TVP1022) and TV 3219, a novel anti-Alzheimer cholinesterase-MAO inhibitor drug derived from rasagiline were examined in PC12 cells cultures and in vivo. We found that these drugs have potent antiapoptotic and neuroprotective activities in response to serum and NGF withdrawal in partially neuronally differentiated PC12 cells and prevent the fall in mitochondrial membrane potential, the first step in cell death. Closed head injury studies in mice have shown that both rasagiline and TVP1022 are neuroprotective. All these compounds possess a propargyl moiety, which normally is responsible for irreversible inactivation of MAO, as is seen with rasagiline. However, neither TVP1022 nor TV3219 are MAO inhibitors, both share the antiapoptotic and neuroprotective actions of rasagiline, indicating that MAO inhibition is not a prerequisite for neuroprotection and that the propargyl moiety exhibits intrinsic neuroprotective pharmacological activity that requires identification.

译文

在PC12细胞培养和体内检测了不可逆单胺氧化酶 (MAO) B抑制剂雷沙吉兰 [R(+)-N-propargyl-1-aminioindan],其S-异构体 (TVP1022) 和来自雷沙吉兰的新型抗阿尔茨海默氏胆碱酯酶-MAO抑制剂药物TV 3219的抗凋亡和神经保护活性。我们发现,这些药物对部分神经分化的PC12细胞的血清和NGF戒断具有有效的抗凋亡和神经保护活性,并防止线粒体膜电位下降,这是细胞死亡的第一步。在小鼠中进行的闭合性颅脑损伤研究表明,雷沙吉兰和TVP1022均具有神经保护作用。所有这些化合物都具有炔丙基部分,这通常是MAO不可逆失活的原因,如雷沙吉兰所见。然而,TVP1022和TV3219都不是MAO抑制剂,都具有雷沙吉兰的抗凋亡和神经保护作用,表明抑制MAO不是神经保护的先决条件,并且炔丙基部分表现出需要鉴定的内在神经保护药理活性。

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