Prevention of cognitive deficits and brain oxidative stress with superoxide dismutase/catalase mimetics in aged mice.
rs1...@yahoo.com
Prevention of cognitive deficits and brain oxidative stress with
superoxide dismutase/catalase mimetics in aged mice.
Clausen A, Doctrow S, Baudry M.
Neuroscience Program, University of Southern California, Los Angeles,
CA 90089, USA.
Continuous decline in cognitive performance accompanies the natural
aging process in humans, and multiple studies in both humans and
animal models have indicated that this decrease in cognitive function
is associated with an age-related increase in oxidative stress.
Treating aging mammals with exogenous free radical scavengers has
generally been shown to attenuate age-related cognitive decline and
oxidative stress. The present study assessed the effectiveness of the
superoxide dismutase/catalase mimetics EUK-189 and EUK-207 on age-
related decline in cognitive function and increase in oxidative
stress. C57/BL6 mice received continuous treatment via osmotic
minipumps with either EUK-189 or EUK-207 for 6 months starting at 17
months of age. At the end of treatment, markers for oxidative stress
were evaluated by analyzing levels of free radicals, lipid
peroxidation and oxidized nucleic acids in brain tissue. In addition,
cognitive performance was assessed after 3 and 6 months of treatment
with fear conditioning. Both EUK-189 and EUK-207 treatments resulted
in significantly decreased lipid peroxidation, nucleic acid oxidation,
and reactive oxygen species (ROS) levels. In addition, the treatments
also significantly improved age-related decline in performance in the
fear-conditioning task. Our results thus confirm a critical role for
oxidative stress in age-related decline in learning and memory and
strongly suggest a potential usefulness for salen-manganese complexes
in reversing age-related declines in cognitive function and oxidative
load.
PMID: 18571288 [PubMed - as supplied by publisher]
Paul Antonik Wakfer
From the full paper:
"the calculated drug infusion rates were ≈9 nmol/day for the 1.5 mM
doses of EUK-compounds and ≈0.9 nmol/day for the 0.15 mM doses of EUK
compounds. The lower concentration is equivalent to a dose of 15 and
16 μg/kg/day for EUK-189 and EUK-207, respectively (assuming a 30 g
mouse). This is a much lower dose than has ever been tested for
efficacy in previous studies."
Discussion Section
"Both compounds appeared to significantly decrease the deficits in
learning and memory that take place between 16 and 23 months of age,
and reverse the increases in brain lipid peroxidation, ROS content,
and oxidized guanine occurring during this time period. Chronic
treatment with either EUK-189 or EUK-207 also significantly reduced
the increased cognitive decline that occurred between 20 and 23 months
of age. Moreover, our results indicate that oxidative load in aged
mice accounts for about 50–60% of the variance in learning ability.
Interestingly, while treatment with either EUK-189 or EUK-207 produced
almost complete reversal of age-related increase in oxidative load, it
decreased decline in performance in fear conditioning by about 50–60%.
This result suggests that some factors other than oxidative load
account for the remaining of the decline in cognitive function with
aging.
Both concentrations of EUK-189 and EUK-207 were equally effective in
preventing age-associated cognitive decline and oxidative stress in
aged mice. However, previous work done in our laboratory suggested
that the effectiveness of theses compounds might decrease at high
concentrations. Like in this present study, 1.5 mM of both compounds
inhibited age-dependent cognitive deficits and oxidative stress in
middle-aged mice (Liu et al., 2003). However, in the previous study,
we also showed that at higher concentrations (15 mM), EUK-207 was less
effective than at 1.5 mM (Liu et al., 2003). In the current study, in
an attempt to eliminate potentially deleterious doses as well as to
better characterize dose-dependency of the compounds, we repeated the
1.5 mM dose and added a ten-fold lower dose group. In this study,
while not yet identifying a suboptimal dose, we report for the first
time in any in vivo system that EUK-189 and EUK-207 are active at a
dose of 0.15 mM, that is approximately 15 μg/kg/day.
Our results also indicate that the age-associated deficits in learning
and memory we observed might be brought on by oxidative damage to
hippocampus, amygdala, or both. Contextual fear conditioning is a
learning and memory task that is dependent on both amygdala and
hippocampus ([Maren et al., 1997] and [Phillips and LeDoux, 1992]),
and our data show that increased levels of markers for oxidative
stress coincides with deficits in contextual fear conditioning.
Furthermore, chronic treatment with either EUK-189 or EUK-207
significantly alleviates these age-associated deficits in contextual
fear conditioning. These results are also in agreement with a similar
study in middle-aged mice (Liu et al., 2003). While it might have been
interesting to determine changes in oxidative load in hippocampus and
amygdala, the small size of these structures and the need for
relatively large amounts of tissues for all the biochemical assays
compelled us to limit our tissue samples to the combined forebrain and
midbrain.
This body of work and previous studies by others suggest that
antioxidant compounds could prove to be beneficial in treating age-
dependent cognitive deficits in humans. However, compounds that mimic
SOD and catalase might prove to be even more beneficial in humans
because, unlike antioxidants, they do not react on a stoichiometric
basis. Earlier work with a carboxyfullerene SOD mimetic showed a
dramatic decrease in age-dependent learning and memory deficits and
oxidative stress in mice (Quick et al., 2008). The multiple catalytic
activities of EUK-189 and EUK-207 might prove to be even more
beneficial, and could account for the very low efficacious doses, as
compared to that of the carboxyfullerene tested. Thus, a dose of the
EUK compounds of about 15 μg/kg/day was as potent as a dose of 10 mg/
kg/day of carboxyfullerene. In addition, it is important to note that
the carboxyfullerene is only an SOD mimetic whereas the EUK compounds
tested can also protect against damage caused by hydrogen peroxide,
and through catalase-like mechanisms (Doctrow et al., 2002 S.R.
Doctrow, K. Huffman, C.B. Marcus, G. Tocco, E. Malfroy, C.A. Adinolfi,
H. Kruk, K. Baker, N. Lazarowych, J. Mascarenhas and B. Malfroy, Salen–
manganese complexes as catalytic scavengers of hydrogen peroxide and
cytoprotective agents: structure-activity relationship studies,
[Doctrow et al., 2002] and [Sharpe et al., 2002]), reactive nitrogen
species.
Chronic treatment with EUK-189 or EUK-207 was initiated at a
relatively late stage in the lives of these mice, but our 6 month-long
treatments were still able to provide protection against cognitive
declines that occurred between 16 and 23 months of age. Thus, our
results suggest that these compounds might prove to be beneficial in
preventing further cognitive impairment in relatively old individuals
that already exhibit mild cognitive impairment. In addition, while
this study was not intended to address chronic toxicity, it is well
worth noting that long term, sustained treatment with these compounds
was beneficial to the mice without showing any indications of
toxicity. Similar observations have been made in other long-term
treatment studies, for example, chronic administration of EUK-189 in a
mouse Alzheimer's disease model (Melov et al., 2005).
Previous work done using SOD2 knock-out mice provided indirect
evidence that salen–manganese compounds such as EUK-8, EUK-134, or
EUK-189 are able to cross the blood brain barrier and to be mito-
protective (Melov et al., 2001). EUK-207 is as equally effective as
EUK-189 in extending the lifespan of SOD2 knock-out mice (unpublished
data), but its ability to alleviate the neurological phenotype has not
been characterized.
In conclusion, our data demonstrate that chronic treatment with the
superoxide dismutase/catalase mimetics EUK-189 or EUK-207
significantly reduces age-related cognitive impairment and age-
associated oxidative stress in mice. These findings add support to the
hypothesis that oxidative stress plays a critical role in age-related
learning and memory dysfunction. Furthermore, they suggest that
EUK-189 or EUK-207 have potential value as a treatment for age-related
cognitive dysfunction."
--Paul Wakfer
MoreLife for the rational - http://morelife.org
Reality based tools for more life in quantity and quality
The Self-Sovereign Individual Project - http://selfsip.org
Self-sovereignty, rational pursuit of optimal lifetime happiness,
individual responsibility, social preferencing & social contracting
jc101
Re dosages, keep in mind this was sc via implanted miniosmotic pumps,
not oral.
JLC