K. Kitani

deprenyl induces activities of both superoxide dismutase and catalase but not of glutathione peroxidase in the striatum of young male rats

Daily s.c. injection of (-)deprenyl (2.0 mg/kg/day) for three weeks in young male rats caused a threefold increase in superoxide dismutase (SOD) activity in the striatum of the brain compared with the value in saline-injected control rats. Furthermore, the activity of catalase (but not of glutathione peroxidase) was also increased significantly by deprenyl treatment. The results confirmed the previous findings of Knoll on SOD activity and furthermore provided evidence that the activity of catalase is also significantly induced by the drug, which was not found in the previous study.

Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat

Rasagiline [N-propargyl-l(R)-aminoindan] is a selective irreversible MAO-B inhibitor as is (-)deprenyl. The effect of the drug on antioxidant enzyme activities on dopaminergic tissue was examined in male F-344 rats (8.5-months-old). Two experimental groups were infused subcutaneously with rasagiline saline solutions by means of osmotic minipumps implanted subcutaneously in the back of the rats. Control animals were also similarly implanted with saline filled mini-pumps. Three-and-one-half weeks later, animals were sacrificed and selected tissue samples removed from brain, kidney and heart. Two doses of rasagiline (0.5 mg/kg/day, 1.0 mg/kg/day, both for 3.5 weeks) significantly increased catalase activities about 2-fold in substantia nigra and striatum but not in hippocampus. Interestingly, in both renal cortex and medulla. catalase (CAT) activities were significantly increased. Both Mn- and Cu,Zn-superoxide dismutase (SOD) activities were increased 2 to 4 fold in substantia nigra, striatum and renal cortex and heart. Several groups, including our own have reported an extension of survival of deprenyl-treated animals of different species. Although the mechanism(s) of the life extension by deprenyl remains unresolved, it would be interesting to investigate the effect of rasagiline on the survival of animals, since deprenyl also was shown to increase antioxidant enzyme activities in brain dopaminergic regions.

Chronic treatment of (-)deprenyl prolongs the life span of male fischer 344 rats. Further evidence

Seventy male Fischer 344 (F-344) rats were treated with s.c. injection of (-)deprenyl (0.5 mg/kg, n = 35) or physiological saline (n = 35) 3 times a week from the age of 18 months until the time of their natural death. The fifty percent survival time was 28 months in control animals and 30 months in the deprenyl treated group. The mean survival time after the start of treatment (18 months) and after 24 months were 378.3 +/- 97.4 days (mean +/- SD) and 196.3 +/- 97.4 days, respectively, in deprenyl treated rats and 328.7 +/- 108.8 days and 146.7 +/- 108.7 days in control rats. The increases in average life expectancies caused by deprenyl treatment (15% from 18 months and 34% from 24 months) were both statistically significant (P < 0.05, two-tailed t-test). The average body weights were comparable for both groups but the variation of body weight was greater in control groups, thus excluding the possibility that the life prolonging effect of deprenyl results from reduced dietary intake. The results confirm those of two previous studies (1,2) which reported a significant life prolonging effect of deprenyl in aged rats and lend added support to the results of a study on male F-344 rats where the effect was only marginally significant (16% increase after 24 months, P = 0.048 by one-tailed t test) (2).

The ability of (-)deprenyl to increase superoxide dismutase activities in the rat is tissue and brain region selective

In a previous study we have shown that chronic administration of (-)deprenyl increases activities of superoxide dismutase (SOD) and catalase (CAT) in rat striatum (1). The present study attempted to clarify how specific the effect of deprenyl is to certain tissues and brain regions in the rat. Two mg/kg/day of deprenyl was continuously infused s.c. in young male Fischer-344 rats. On the 22nd day, rats were sacrificed and enzyme activities of SOD and CAT were determined in several different brain regions and the liver. Activities of both SOD and CAT were significantly increased in striatum and substantia nigra but not in hippocampus, cerebellum or liver. Both types of SOD (i.e. Cu Zn-SOD and Mn-SOD) were significantly increased in striatum, substantia nigra. Interestingly, in cerebral cortices of three different regions, activities also tended to increase (especially those of Mn-SOD), although the increase was not so striking as in substantia nigra and striatum. The results confirm the previous observation that (-)deprenyl can increase free radical scavenger enzyme activities in striatum and provide further evidence that this effect is selective to certain brain regions and tissue types.

The effect of a long term (6 months) treatment with (−)deprenyl on antioxidant enzyme activities in selective brain regions in old female fischer 344 rats

The effect of long term treatment with (-)deprenyl (s.c. injection three times a week for 6 months) on superoxide dismutase (SOD) and catalase (CAT) in selective brain regions was examined in old (22 months) female Fischer 344 rats. The three doses of deprenyl used (0.1, 0.25 and 0.5 mg/kg/day) increased the activities of both enzymes in substantia nigra, striatum and cerebral cortices essentially in a dose dependent manner. However, for CAT activities in cerebral cortices, the smallest dose of 0.1 mg/kg/day was most effective, while the highest dose (0.5 mg/kg/day) had no effect. In contrast to these brain regions, there were no significant differences in enzyme activities between control and deprenyl-treated groups in the hippocampus and cerebellum. If the effect of deprenyl on the life span of female F-344 rats is causally related to its effect on antioxidant enzyme activities in selective brain regions as shown in this study, then a dose of 0.25 or 0.5 mg/kg/day appears to be most appropriate. Since this dose is much lower than the dose suggested by our previous short term (3 week) experiments, an even longer term experiment is necessary to determine the optimal dose of deprenyl to increase free radical scavenging and thus possibly extend lifespan.

deprenyl increases activities of superoxide dismutase and catalase in certain brain regions in old male mice.

A subcutaneous continuous infusion of (-)deprenyl for 3 weeks in old C57BL male mice increased superoxide dismutase (SOD) and catalase (CAT) activities in s. nigra, striatum and cerebral cortex but not in hippocampus, cerebellum or liver. The doses of 0.5 and 1.0 mg/kg/day were most effective, while with a higher dose (2.0 mg/kg/day), deprenyl tended to lose its effect slightly and with a lower dose (0.25 mg/kg/day) deprenyl was clearly less effective. The results suggest that deprenyl can increase antioxidant enzyme activities in certain brain regions in mice as was previously demonstrated in rats of both sexes and different ages; this raises the possibility that deprenyl has this particular effect in animal species other than rats.

Deprenyl Increases the Life Span as Well as Activities of Superoxide Dismutase and Catalase but Not of Glutathione Peroxidase in Selective Brain Regions in Fischer Rats

(-)Deprenyl, a MAO-B inhibitor that is also known to be effective for symptoms of Parkinsons disease, when injected subcutaneously (sc) in male Fischer-344 rats at a dose of 0.5 mg/kg per day (3 times a week) from 18 months of age, significantly increased the remaining life expectancy. The average life span after 24 months was 34% greater in treated rats than in saline-treated control animals. Furthermore, a short-term (3 wk) continuous sc infusion of deprenyl significantly increased activities of superoxide dismutase and catalase but not of glutathione peroxidase in selective brain regions such as s. nigra, striatum, and cerebral cortex, but not in hippocampus or cerebellum, or the liver. The optimal dose for increasing these activities, however, differed greatly depending on the sex and age of animals, with a 10-fold lower value for young female than male rats. Interestingly, aging caused an increase and a decrease in the optimal dose in female and male rats, respectively. In addition, treatment for a longer term tended to reduce the optimal dosage in the same animal group. The results clearly demonstrate that deprenyl increases antioxidant enzyme activities in selective brain regions. If this effect of deprenyl is causally related to its life-prolonging effect, the dosage to be used for any life span study would be a critical factor, with the dosage differing widely depending on sex, age of animal, and mode and duration of drug administration.

The optimal dosage of (−)deprenyl for increasing superoxide dismutase activities in several brain regions decreases with age in male Fischer 344 rats

We previously reported that the optimal dosage of (-)deprenyl to increase superoxide dismutase (SOD) activities in striatum in rats differs 10 fold between young male and female rats (1). Furthermore, in female rats the optimal dosage increased with age (1). In the present study in order to clarify how the optimal dosage of this effect changes with age in male rats, we examined the effects of four different dosages of deprenyl on SOD enzyme activities in striatum and several other tissues in old (28-29-month-old) male Fischer 344 (F-344) rats. Continuous s.c. infusion of deprenyl for 3 wks increased activities of SOD and catalase (CAT) in striatum, substantia nigra and cortical regions but not in hippocampus, cerebellum or the liver. The dose of 0.5 mg/kg/day was found to be most effective, while higher (1.0, 2.0 mg/kg/day) or lower (0.1 mg/kg/day) dosages were less effective. This value of 0.5 mg/kg/day was 4 fold lower than the dosage of 2.0 mg/kg/day which was most effective in increasing SOD and CAT activities in young (5-7 month old) male rats of the same strain (1,2). The decline of the optimal dosage with age found in male rats is best explained by a possible decline with age in the hepatic microsomal monooxygenase enzyme activities that are involved with the metabolism of deprenyl. In view of the large differences in the optimal dosages shown among different sexes and ages of rats, future studies regarding the unique effect of this drug in prolonging the life span of rats must be carefully investigated with the caution in mind that the optimal dosage for the life prolonging effect may well differ depending on sex, age and possibly strain and species of animal model used.

deprenyl increases activities of Superoxide Dismutase (SOD) in striatum of dog brain

Seven beagle dogs were administered sucrose (control animals) or different doses of (-)deprenyl orally by means of capsules for 3 weeks. Activities of Cu Zn-SOD and Mn-SOD were determined in striatum and hippocampus in these animals. There was a significant dose-dependent increase in activities of total as well as in both types of SOD enzymes in striatum but not in hippocampus. The results suggest that this monoamine oxidase B inhibitor can increase antioxidant enzyme activities in striatum but not in hippocampus in the dog, thus showing brain region selectivity. These results are in accordance with previously published observations in rats.

Upregulation of Antioxidant Enzyme Activities by Deprenyl

In order to elucidate the exact role of antioxidant enzyme activities such as superoxide dismutase (SOD) in the aging process of animals, we compared various enzyme activities in different brain regions and in the liver of young (6-8 mo) and old (28-30 mo) Fischer-344 (F-344) rats. While Mn-SOD activities were elevated 3-5-fold in specific brain regions such as hippocampus, striatum and substantia nigra in brains of old male rats compared with the young, in females both forms of SOD (Cu, Zn- and Mn-) enzyme activities remained essentially unchanged with aging. Continued subcutaneous infusion of deprenyl for 3 weeks caused a 2-3-fold increase in activities of both Cu Zn- and Mn-SOD and a 50-60% increase in CAT activities in striatum and substantia nigra but not in hippocampus, cerebellum or the liver. Further, long-term treatment of old male rats with deprenyl caused a significant increase in the remaining life expectancy from 24 months of age by 34%. In conclusion, activities of antioxidant enzymes in these regions examined do not show any uniform age-associated change, suggesting that changes in these enzyme activities do not have any specific role in the life span of rodents in general terms. In contrast, the results of our deprenyl study suggests the possibility that the protection of catecholaminergic neurons by an upregulation of SOD and CAT activities plays a significant role in the life span of animals.