Shukitt-Hale B, Erat S A, Joseph J A
USDA-ARS, Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.
Free Radic Biol Med. 1998 May;24(7-8):1149-58. doi: 10.1016/s0891-5849(97)00399-7.
Administration of buthionine sulfoximine (BSO) selectively inhibits glutathione (GSH) biosynthesis and induces a GSH deficiency. Decreased GSH levels in the brain may result in less oxidative stress (OS) protection, because GSH contributes substantially to intracellular antioxidant defense. Under these conditions, administration of the pro-oxidant, dopamine (DA), which rapidly oxidizes to form reactive oxygen species, may increase OS. To test the cognitive behavioral consequences of decreased GSH, BSO (3.2 mg in 30 microliters, intracerebroventricularly) was administered to male Fischer 344 rats every other day for 4 days. In addition, DA (15 microliters of 500 microM) was administered every day [either 1 h after BSO (BSO + DA group) or 1 h before BSO (DA + BSO group), when given on the same day as BSO] and spatial learning and memory assessed (Morris water maze, six trials/day). BSO + DA rats, but not DA + BSO rats, demonstrated cognitive impairment compared to a vehicle group, as evidenced by increased latencies to find the hidden platform, particularly on the first trial each day. Also, the BSO + DA group utilized non-spatial strategies during the probe trials (swim with no platform): i.e., less time spent in the platform quadrant, fewer crossings and longer latencies to the previous platform location, and more time spent in the platform quadrant, fewer crossings and longer latencies to the previous platform location, and more time spent around the edge of the pool rather than in the platform zone. Therefore, the cognitive behavioral consequences of decreasing GSH brain levels with BSO in conjunction with DA administration depends on the order of administration. These findings are similar to those seen previously on rod and plank walking performance, as well as to those seen in aged rats, suggesting that the oxidation of DA coupled with a reduced capacity to respond to oxidative stress may be responsible for the induction of age-related cognitive deficits.
给予丁硫氨酸亚砜胺（BSO）可选择性抑制谷胱甘肽（GSH）的生物合成并导致GSH缺乏。大脑中GSH水平降低可能导致氧化应激（OS）保护作用减弱，因为GSH对细胞内抗氧化防御起重要作用。在这些条件下，给予促氧化剂多巴胺（DA）（其迅速氧化形成活性氧）可能会增加OS。为了测试GSH降低的认知行为后果，每隔一天给雄性Fischer 344大鼠脑室内注射BSO（30微升中含3.2毫克），共4天。此外，每天给予DA（15微升，500微摩尔）[在BSO注射后1小时（BSO + DA组）或BSO注射前1小时（DA + BSO组），与BSO在同一天给药]，并评估空间学习和记忆（莫里斯水迷宫，每天6次试验）。与溶媒组相比，BSO + DA组大鼠（而非DA + BSO组大鼠）表现出认知障碍，表现为找到隐藏平台的潜伏期增加，尤其是在每天的第一次试验中。此外，BSO + DA组在探索试验（无平台游泳）期间采用非空间策略：即在平台象限花费的时间减少、穿越次数减少以及到先前平台位置的潜伏期延长，并且在泳池边缘而不是平台区域花费更多时间。因此，用BSO降低GSH脑水平并联合给予DA的认知行为后果取决于给药顺序。这些发现与先前在杆和木板行走性能方面的发现相似，也与老年大鼠的发现相似，表明DA的氧化以及对氧化应激反应能力的降低可能是导致与年龄相关的认知缺陷的原因。
