Gopal P V, Sriram A V, Sharma D, Singh R
School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
Gerontology. 2000 Jan-Feb;46(1):7-11. doi: 10.1159/000022126.
Lipid peroxidation increases during ageing and has been implicated in the pathogenesis of degenerative processes associated with ageing. Despite the importance of the enzyme glutathione-S-transferase (GST) in the biotransformation and detoxification of lipid peroxidation products, there have been extremely limited studies of GST in the ageing brain. The drug chlorpromazine is known to have an activating influence on the activities of certain antioxidant enzymes (glutathione peroxidase, superoxide dismutase, etc.) and it also has anti-lipid peroxidative and anti-lipofuscin influences. Therefore, information about the age-related changes in brain GST and the effect of chlorpromazine on it in the ageing brain will be of further interest. We have, therefore, studied the effect of age on the activity of GST in the whole homogenate and cytosol fractions from the cerebral hemispheres of rats aged 1, 2, 3, 6, 12, 18 and 24 months. The effect of chlorpromazine treatment (10 mg/kg i.p. on alternate days for 6 months) was examined in the whole homogenate and cytosol fraction from the cerebral hemispheres of 6-, 12-, 18- and 24-month-old rats. The results showed that the values for GST specific activities in the cytosol fraction from all the age groups were higher then those in the whole homogenate; and the pattern of age changes in the whole homogenate differed from that in the cytosol. In the cytosol fraction the enzyme activity showed several phases of alterations: a progressive increase at 3 months of age, followed by a steady level up to 12 months of age; this phase was followed by a fall in the activity (at 18 months of age) then turned to a gradual increase. In the whole homogenate there were two phases of alterations: a progressive increase up to 12 months of age, which then turned to a somewhat gradual decrease with ageing. Thus, the decline in GST activity during ageing was evident in both the whole homogenate and cytosol. The results from chlorpromazine experiments showed that the drug elevated the GST activity in 12-, 18-, and 24-month-old animals but not in the 6-month-old animals. The drug's effects were most profound in 12-month-old animals. In conclusion, this study demonstrated an impairment of brain GST activity during ageing and the results further showed that the drug chlorpromazine attenuated the age-related impairment in the enzyme activity. The enhancement of the GST status of the ageing brain following chlorpromazine treatment is indicative of an additional antioxidative property of this drug.
脂质过氧化在衰老过程中会增加，并且与衰老相关的退行性病变的发病机制有关。尽管谷胱甘肽 - S - 转移酶（GST）在脂质过氧化产物的生物转化和解毒过程中具有重要作用，但关于衰老大脑中GST的研究极其有限。已知药物氯丙嗪对某些抗氧化酶（谷胱甘肽过氧化物酶、超氧化物歧化酶等）的活性有激活作用，并且它还具有抗脂质过氧化和抗脂褐素的作用。因此，有关大脑GST与年龄相关的变化以及氯丙嗪对衰老大脑中GST的影响的信息将更受关注。因此，我们研究了年龄对1、2、3、6、12、18和24月龄大鼠大脑半球全匀浆和胞质溶胶组分中GST活性的影响。在6、12、18和24月龄大鼠大脑半球的全匀浆和胞质溶胶组分中检测了氯丙嗪治疗（腹腔注射10mg/kg，隔日一次，共6个月）的效果。结果表明，所有年龄组胞质溶胶组分中GST的比活性值均高于全匀浆中的值；并且全匀浆中年龄变化模式与胞质溶胶中的不同。在胞质溶胶组分中，酶活性呈现几个变化阶段：3月龄时逐渐增加，随后在12月龄前保持稳定水平；此阶段之后活性下降（18月龄时），然后又逐渐增加。在全匀浆中有两个变化阶段：12月龄前逐渐增加，然后随着衰老略有逐渐下降。因此，衰老过程中GST活性的下降在全匀浆和胞质溶胶中均很明显。氯丙嗪实验结果表明，该药物提高了12、18和24月龄动物的GST活性，但对6月龄动物没有影响。该药物在12月龄动物中的作用最为显著。总之，本研究证明了衰老过程中大脑GST活性受损，结果进一步表明药物氯丙嗪减轻了与年龄相关的酶活性损害。氯丙嗪治疗后衰老大脑中GST状态的增强表明该药物具有额外的抗氧化特性。
