Marczynski T J, Artwohl J, Marczynska B
Department of Pharmacology, College of Medicine, University of Illinois, Chicago 60612.
Neurobiol Aging. 1994 Jan-Feb;15(1):69-84. doi: 10.1016/0197-4580(94)90146-5.
Under barrier condition and with ad lib access to food and water, 20 Fischer-344 rats were chronically treated for 10 months with the benzodiazepine (BDZ) antagonist, flumazenil (FL; 4 mg/kg/day in drinking water acidified to pH = 3.0), beginning at the age of 13 months, while the group of 20 control age-matched rats received plain acidified water. The life span of the first 8 deceased rats treated with FL was significantly longer than that of the first 8 deceased rats in the age-matched control group. In tests for spontaneous ambulation and exploratory behavior in the Holeboard apparatus, conducted during the 3rd and the 8th month of treatment, the FL group, relative to controls, had significantly higher scores for the ambulation and exploratory behavior. In tests for unrewarded spontaneous alternation in the T maze, conducted at days 7, 39, 42, and 47 through 54 after drug withdrawal, i.e., at the age of 24-25 months, the FL-exposed group, compared to age-matched controls, showed a significantly higher percent of alternating choices, a behavior that was statistically comparable to that of the "young" 6-month-old controls. In the Radial Maze tests conducted 2 months after drug withdrawal, the FL group made significantly less "working memory" errors and "reference memory" errors, relative to the age-matched 25-month-old control group, a performance that was comparable to that of the young 7-month-old control group. In conclusion, chronic FL significantly protected rats from age-related loss of cognitive functions. It is postulated that the age-related alterations in brain function may be attributable to the negative metabolic/trophic influences of the "endogenous" benzodiazepine (BDZ) ligands and/or those ingested with food. A BDZ/GABAergic hypothesis of brain aging has been formulated which assumes that age-related and abnormally strong BDZ/GABAergic influences promote neurodegeneration by suppressing trophic functions of the aminergic and peptidergic neurons through opening of chloride channels in soma membrane and axon terminals, causing excessive hyperpolarizing and depolarizing inhibition, respectively. The review of human clinical and animal data indicates that FL has nootropic actions by enhancing vigilance cognitive and habituation processes.
在屏障条件下，给予20只Fischer-344大鼠随意获取食物和水的机会，从13月龄开始，用苯二氮䓬（BDZ）拮抗剂氟马西尼（FL；在酸化至pH = 3.0的饮用水中，剂量为4 mg/kg/天）对其进行为期10个月的长期治疗，而另一组20只年龄匹配的对照大鼠则饮用普通酸化水。接受FL治疗的前8只死亡大鼠的寿命明显长于年龄匹配对照组中的前8只死亡大鼠。在治疗的第3个月和第8个月期间，在洞板装置中进行的自发走动和探索行为测试中，相对于对照组，FL组在走动和探索行为方面的得分显著更高。在停药后第7天、39天、42天以及47至54天（即24至25月龄时）进行的T迷宫无奖励自发交替测试中，与年龄匹配的对照组相比，接触FL的组表现出显著更高的交替选择百分比，这一行为在统计学上与6月龄“年轻”对照组相当。在停药2个月后进行的放射状迷宫测试中，相对于年龄匹配的25月龄对照组，FL组出现的“工作记忆”错误和“参考记忆”错误显著更少，其表现与7月龄年轻对照组相当。总之，长期使用FL能显著保护大鼠免受与年龄相关的认知功能丧失。据推测，与年龄相关的脑功能改变可能归因于“内源性”苯二氮䓬（BDZ）配体和/或随食物摄入的配体的负面代谢/营养影响。已经提出了一个关于脑衰老的BDZ/γ-氨基丁酸能假说，该假说认为与年龄相关且异常强烈的BDZ/γ-氨基丁酸能影响通过打开体膜和轴突终末的氯离子通道来抑制胺能和肽能神经元的营养功能，分别导致过度的超极化抑制和去极化抑制，从而促进神经退行性变。对人类临床和动物数据的综述表明，FL通过增强警觉性、认知和习惯化过程而具有促智作用。
