中文摘要
镧是轻稀土元素的代表，可通过血脑屏障在脑内蓄积，影响智力发育和学习记忆能力、造成神经元损伤，但作用机制不清。D－丝氨酸是近年来新发现的一种神经胶质细胞递质，主要由星形胶质细胞内的丝氨酸消旋酶（SR）合成，能直接调控N－甲基－D－门冬氨酸受体（NMDAR）的活化程度。NMDAR过强表达可诱发兴奋性毒性，对神经元产生损害作用。本项目通过整体动物与体外试验相结合的方法，运用神经行为学、生物化学、分子生物学和病理组织学技术观察了镧暴露对大鼠学习记忆能力和大脑皮质、海马神经元的损害作用以及对大脑皮质和海马SR表达与活性、D－丝氨酸释放水平和神经元NMDAR表达的影响，证明了镧上调大脑皮质和海马SR-D－丝氨酸-NMDAR信号通路是其所致神经毒效应的关键机制。该研究对于全面阐述镧乃至稀土元素的神经毒作用机制以及有效干预镧乃至稀土元素引起的儿童智力低下和认知功能缺陷具有一定的理论意义和实际应用价值。
英文摘要
Lanthanum is the typical rare-earth element. It can pass through blood-brain barrier and accumulate in the brain, and therfore affect intelligence development and ability of learning and memory and cause neuronal damage. However, the mechanism underlying these effects isn't clear. D-serine is a new-found neurogliocyte transmitter, and it is synthesized by serine racemase (SR) in astrocytes. D-serine can directly control the activation of N-methyl-D-aspartate receptor (NMDAR). Over-expression of NMDAR can induce excitatory toxicity and lead to neuronal damage. By the experiments in vivo and studies in vitro, this study was conducted to explore the harmful effects of lanthanum on ability of learning and memory and neurons in the cerebral cortex and hippocampus and to study the effects of lanthanum on SR expression and activity, released D-serine level and neuronal NMDAR expression in the cerebral cortex and hippocampus with the techniques of neuroethology, biochemistry, molecular biology and pathohistology. The results confirmed that lanthanum interfered the SR-D-serine-NMDAR signal pathway which was probably the key mechanism underlying the neurotoxicity caused by lanthanum. This study has theoretical significance and practical application value for clarifing the mechanism underlying neurotoxicity and effectively treating children mental retardation and cognitive function defect caused by lanthanum and even rare-earth element.
结题摘要
镧是轻稀土元素的代表，可通过血脑屏障在脑内蓄积，影响智力发育和学习记忆能力、造成神经元损伤，但作用机制不清。D－丝氨酸是近年来新发现的一种神经胶质细胞递质，主要由星形胶质细胞内的丝氨酸消旋酶（SR）合成，能直接调控N－甲基－D－门冬氨酸受体（NMDAR）的活化程度。NMDAR过强表达可诱发兴奋性毒性，对神经元产生损害作用。本项目通过整体动物与体外试验相结合的方法，运用神经行为学、生物化学、分子生物学和病理组织学技术观察了镧暴露对大鼠学习记忆能力和大脑皮质、海马神经元的损害作用以及对大脑皮质和海马SR表达与活性、D－丝氨酸释放水平和神经元NMDAR表达的影响，证明了镧上调大脑皮质和海马SR-D－丝氨酸-NMDAR信号通路是其所致神经毒效应的关键机制。该研究对于全面阐述镧乃至稀土元素的神经毒作用机制以及有效干预镧乃至稀土元素引起的儿童智力低下和认知功能缺陷具有一定的理论意义和实际应用价值。