A CLINICALLY APPLIED DOSE OF (-)DEPRENYL CAN INCREASE ANTIOXIDANT ENZYME ACTIVITIES IN BRAIN AS WELL AS EXTRA-BRAIN TISSUES IN MONKEYS.
C. Minami 1, H. Maeda 2, T. Yamamoto 1, S. Satake 2. and K. Kitani *1
1National Institute for Longevity Sciences, 36-3, Gengo, Morioka-cho, Obu-shi, Aichi 474-8522, 2Shin Nippon Biomedical Laboratories, Ltd. 2438,Miyanoura, Yoshida-cho, Kagoshimagun, Kagoshima, Japan.
Several groups including our own have reported that (-)deprenyl treatment significantly prolonged life spans of different animal species including rats, mice, hamsters and dogs1-3. Although the mechanism(s) underlying this effect of the drug remains unknown, we have suggested that up-regulation of superoxide dismutase (SOD) and catalase (CAT) activities in brain dopaminergic regions induced by the drug may be causally related to the effect on the life span2,3. An important question which thus far has not been resolved is whether such changes in SOD & CAT activities occur in humans with a dose clinically used for treatment of ParkinsonŐs disease, since optimal doses found to be effective in maximally increasing SOD and CAT activities in dogs and rodents are 1 to 2 orders of magnitude greater than a clinically used dose in patients (10mg/day), and since this effect as well as the effect on life span of animals are highly dose dependent.
In order to access the answer to this question, we examined the effect of (-)deprenyl in brain as well as extra-brain tissues in monkeys.
Ten monkeys (Macaca mulata) aged 2 to 5 years were used in the study. Animals were treated with two different oral doses (0.17(n=4) or 1.0 mg(n=3)/kg/day)of the drug for 3.5 weeks. Control monkeys(n=3) were given saline solution. Under deep anesthesia, animals on a respirator were perfused with heparinized saline solution by means of cardiac puncture. After sacrificing the animals, we took tissue samples from various brain regions as well as from several extra-brain organs. CAT activities were determined on the day of sacrifice. SOD activities were determined later on homogenized tissues preserved at 80.
Blood samples were obtained before, during and after the treatment and SOD activities were also determined on lymphocytes prepared from blood samples.
Results
CAT activities were significantly increased in S.nigra, ascending aorta and kidneys. SOD activities were also significantly increased in striatum and S.nigra (but not in hippocampus) and ascending aorta. A smaller dose (0.17mg/kg/day) was generally more effective than a greater dose (1.0mg/kg/day). SOD activities in lymphocytes also tended to be increased in deprenyl treated animals and the increase tended to be higher with the longer treatment period. Again a smaller dose was more effective than the greater dose.
Conclusion: The results clearly demonstrated that (-)deprenyl treatment upregulates CAT and SOD activities in non-human primates, most importantly with the dose equivalent to a clinically used dose of the drug. These results suggest that the effect may most likely be observed in human patients with ParkinsonŐs disease treated with (-)deprenyl. The physiological significance of this effect on humans awaits further elucidation.
1)Kitani et al. Life Sci 52:281-288, 1993. 2)Kitani et al. Ann N Y Acad Sci 786:391-409, 1996. 3)Kitani et al. Ann N Y Acad Sci 854:291-306, 1998.
Key words:
Deprenyl, superoxide dismutase, catalase, monkeys
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