Many cognitive impairments occur in both old experimental animals and in humans. This suggests that the natural antioxidant defense mechanisms in the brain that act against oxidative stress are not enough to prevent the damage caused by this type of stress, resulting in impairment. The purpose of this study is to show that dietary intake of certain antioxidants, specifically the synthetic catalytic molecules (SOD) EUK-189 and EUK 207, would aid in preserving brain function.

This study used 105 C57BL/6N Sim female mice that were 8 months of age. Before any part of the experiment took place, the mice were placed 4 to a cage on a bed of sawdust in the same room on a 12 hour light/dark cycle with behavioral testing eventually taking place during the light cycle. The mice were allowed free access to food and water. The mice were then randomly assigned to one of five groups: vehicle control, low dose EUK-189, high dose EUK-189, low dose EUK-207, and high dose EUK-207. Each group contained 16-18 mice. The EUK groups had the antioxidants adminstered through a pump which was surgically implanted. The pumps delivered the dose depending on the group to which the mouse was assigned. The two groups of low dose EUK mice received 9 nmol/day for a total of 1.5 mM while the high dose EUK groups received .09 µmol/day for a total of 15 mM at the end of the three month treatment. (Liu et. al., 2003).

The behavioral testing used on the mice was fear conditioning. The mice were placed in a conditioning chamber which consisted of a plexiglass cage and a metal floor with stainless steel rods. On the first day of training, the mice were placed in the chamber for three minutes. After the third minute, they received three tone and foot-shock pairings. One minute after the final foot-shock, the mice were returned to their cages. On the second day of testing, the mice were placed into the same chamber for eight minutes, but there was no tone or foot-shock. On the third and final day of testing, the mice were placed in different chamber that contained different visual characteristics. After one minute in this chamber, the same tone was given for an eight minute test. The fear conditioning was measured by recording freezing behavior and calculating it into a percentage of time in which the mice displayed this behavior. (Liu et. al., 2003).

"The control group of 11-month-old-mice (treated with vehicle only) exhibited low levels of freezing with both tone and context presentation, suggesting that these middle-aged mice already had impaired learning and memory. Both EUK-189 and EUK-207 treatment dramatically increased tone-and-context-evoked freezing" (Liu et. al., 2003). When the 11 month old mice that were treated with EUK-207 were compared to the 8 month control mice, the EUK-207 appeared to reverse the age-related impairments.

"Chronic treatments with either EUK-189 or EUK-207 produced decreases in lipid peroxidation and protein oxidation. The effects of the low doses of mimetics were generally more significant than the effects of high doses and represented a 20-25% reduction in the levels of oxidative stress" (Liu et. al., 2003). Levels of both lipid peroxidation and protein oxidation increase in the brain of mice between the ages of 8-11 months. Treatment with the SOD/mimetics reversed the age-related increase in protein oxidation and reduced the lipid peroxidation by about 50%.

These results show that impairment in learning and memory increase with increasing levels of oxidative stress, which in turn is caused by increased levels of lipid peroxidation and protein oxidation. A previous study done by Leutner, Eckert, and Muller (2001) (as cited by Liu et. al., 2003) found that "oxidative stress increases almost linearly with age, by about 40% from 2-3 to 20-21 months of age in mice. This study shows that a complete reversal in protein oxidation and about a 50% decrease in lipid peroxidation is possible through a 3 month treatment of a SOD/catalase mimetic in mice from ages 8-11 months. The same low doses of the SOD/catalase mimetic that provided the best protection against age-related decline also had the greatest effect on learning and memory.

The researchers in this study hope that these results could provide a possible theraputic use for SOD/catalase mimetics for age-related cognitive impairments.



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