Kharlamov A, Zivkovic I, Polo A, Armstrong D M, Costa E, Guidotti A
FIDIA-Georgetown Institute for the Neurosciences, Georgetown University Medical School, Washington, DC 20007.
Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6303-7. doi: 10.1073/pnas.91.14.6303.
A bilateral photochemically induced thrombotic lesion of rat sensorimotor cortex (approximately 3 mm in diameter and 25 mm3 in volume) is associated with a persistent cognition (learning and memory) deficit, which was evaluated with water maze tasks. The N-dichloroacetylsphingosine derivative of lysoGM1 (LIGA20) administered after the lesion either i.v. or per or reduces the infarct size by 30-40% and attenuates the associated cognition deficits, presumably by limiting the extent of damage of neurons at risk located in the surroundings of the infarcted core (i.e., area penumbra). The LIGA20 protection is dose and time dependent. Maximal protection is afforded by a single dose of LIGA20 of 34 mumol/kg i.v. 1 hr after lesion or by a dose of 270 mumol/kg per os when administered 1 hr and 24 hr after the lesion. The protective effect of LIGA20 can be observed when the drug is administered i.v. up to 6 hr after the lesion. The protective efficacy of the oral administration of LIGA20 is related to its physiochemical properties, which, unlike those of GM1, allow absorption from the gastrointestinal tract. LIGA20 given orally reaches the brain promptly and rapidly inserts into the neuronal membranes. Here, by an unknown molecular mechanism, LIGA20 selectively reduces the pathological amplification of Ca2+ signaling elicited by persistent stimulation of ionotropic glutamate receptors in the area penumbra.
大鼠感觉运动皮层的双侧光化学诱导血栓性损伤（直径约3毫米，体积25立方毫米）与持续的认知（学习和记忆）缺陷相关，该缺陷通过水迷宫任务进行评估。损伤后静脉内或经口给予溶血型神经节苷脂GM1的N - 二氯乙酰鞘氨醇衍生物（LIGA20）可使梗死面积减小30 - 40%，并减轻相关的认知缺陷，这可能是通过限制梗死核心周围（即半暗带）处于危险状态的神经元的损伤程度来实现的。LIGA20的保护作用具有剂量和时间依赖性。损伤后1小时静脉内给予34微摩尔/千克的单剂量LIGA20，或损伤后1小时和24小时经口给予270微摩尔/千克的剂量可提供最大保护。当在损伤后6小时内静脉内给药时，可观察到LIGA20的保护作用。LIGA20口服给药的保护效果与其理化性质有关，与GM1不同，其理化性质使其能够从胃肠道吸收。口服给予的LIGA20能迅速到达大脑并快速插入神经元膜。在此，通过未知的分子机制，LIGA20选择性地减少了半暗带中离子型谷氨酸受体持续刺激引发的Ca2+信号的病理性放大。
