Kim J S, Gutierrez M C, Giacobini E, Sundberg J P
Department of Pharmacology, Southern Illinois University, School of Medicine, Springfield 62708.
Int J Dev Neurosci. 1986;4(2):113-8. doi: 10.1016/0736-5748(86)90035-3.
Pipecolic acid represents the major metabolite of lysine in the CNS. This study aimed to mimic the known pathological condition of hyperpipecolatemia in human neonates by maintaining high and steady concentrations in the mouse brain both pre- and postnatally. Although histological observations did not reveal any abnormal findings in the brain, liver and kidney, the offsprings of mothers which were injected during pregnancy with 250 mg/kg PA presented a significant decrease in both cortical and whole brain DNA content. Protein, RNA and CNPase activity were not altered. The changes in DNA content are of particular interest since they demonstrate that a high and steady level of pipecolic acid, which is comparable to the level seen in human hyperpipecolatemic brain, can induce a neurotoxic effect in the fetal mouse brain. Mice injected with the same dose from day 1 to day 29 after birth did not show any change in DNA content in the cortex. These results suggest that the critical period from pipecolic acid neurotoxic effect is prenatal, probably due to a selective vulnerability of developing neurons to high levels of pipecolic acid. The decrease in DNA concentration induced by maternal hyperpipecolatemia suggests a neurotoxic effect of pipecolic acid on cell proliferation during fetal development which could be related to the neuronal damage observed in the brain of hyperpipecolatemic neonates.
哌啶酸是赖氨酸在中枢神经系统中的主要代谢产物。本研究旨在通过在小鼠出生前后维持其大脑中高浓度且稳定的哌啶酸水平，来模拟人类新生儿已知的高哌啶酸血症病理状况。尽管组织学观察未在脑、肝和肾中发现任何异常结果，但孕期注射250mg/kg哌啶酸的母鼠所产仔鼠的皮质和全脑DNA含量均显著降低。蛋白质、RNA和CNPase活性未发生改变。DNA含量的变化尤其令人关注，因为它们表明，与人类高哌啶酸血症大脑中所见水平相当的高浓度且稳定的哌啶酸水平，可在胎鼠大脑中诱导神经毒性作用。出生后第1天至第29天注射相同剂量哌啶酸的小鼠，其皮质中的DNA含量未显示任何变化。这些结果表明，哌啶酸产生神经毒性作用的关键时期是在产前，这可能是由于发育中的神经元对高水平哌啶酸具有选择性易损性。母体高哌啶酸血症诱导的DNA浓度降低表明，哌啶酸在胎儿发育过程中对细胞增殖具有神经毒性作用，这可能与高哌啶酸血症新生儿大脑中观察到的神经元损伤有关。
