I just came across an "perspectives" article in the 13 Dec 1991
Science (vol 254, p. 1597) by Robert Floyd that makes a pretty
startling point (typos and [] comments are mine):
"The results of new experiments in Mongolian gerbils indicate that
the accumulation of oxidatively damaged proteins during aging may be
the cause of behavioral deficits in aging experimental animals and
that this chronic oxidation may be reversible with compounds that
react with and stabilize free radicals."
"Daily administration of PBN [N-tert-butyl-alpha-phenyl nitrone] to
old gerbils causes a decrease in the the amount of oxidized protein
and an increase in both glutamine synthetase and neural protease
activity in brain, as well as a decrease in the number of errors
made in a radial-arm maze test for memory.... Furthermore, after the
cessation of PBN administration, the amount of both oxidized protein
as well as glutamine synthetase and neutral protease activity
gradually returned to the values found in normal, older gerbils
(fig. 1 [omitted]). PBN did not have these effects in young
gerbils."
Here are Medline abstracts from some other recent articles from the
same lab (The Molecular Toxicology Research Program, Oklahoma Medical
Research Foundation). Does anyone out there know more about this
research, or know of other relevant evidence on ageing, behavior and
free radicals?
TI - Protection against oxidative damage to CNS by
alpha-phenyl-tert-butyl nitrone (PBN) and other spin-trapping
agents: a novel series of nonlipid free radical scavengers.
SO - J Mol Neurosci 1991;3(1):47-57
AB - Brain is extremely susceptible to oxidative damage. Utilizing a
series of novel approaches, we have demonstrated that oxidative
damage occurs during an ischemia/reperfusion insult (IRI) to
brain. Thus, we have demonstrated that an IRI to Mongolian gerbil
brain results in: (1) an enhanced rate of salicylate
hydroxylation, implicating an increased flux of hydroxyl free
radicals; (2) an enhanced flux of free radicals as determined by
spin-trapping; (3) an enhanced level of endogenous protein
oxidation; (4) a decrease in glutamine synthetase (GS) activity,
an enzyme very sensitive to oxidative damage; and (5)
demonstration of protection from an IRI by administering the
spin-trapping agent alpha-phenyl-tert-butyl nitrone (PBN). The
novel observation that PBN offers protection from the lethality
brought on by a brain IRI appears to be clearly linked to the
ability of the administered spin-trap to inhibit oxidative damage
as evidenced by the decreased amount of brain protein oxidation
and the prevention of an IRI-mediated loss of GS activity in
treated animals. Aged gerbils are more sensitive to the lethal
action of a brain IRI than younger animals, but they are
protected by PBN administration as are the younger animals. Older
gerbils have a significantly higher level of oxidized protein in
the brain. Older gerbils have decreased activities of GS and
neutral protease, the enzyme that removes oxidized protein, than
younger animals. Chronic twice daily administration of PBN (32
mg/kg) for 14 days to older animals significantly lowered brain
oxidized protein levels and raised GS and neutral protease
activity to those observed in younger animals. Cessation of PBN
administration resulted in a time-dependent restoration of
protein oxidation levels and enzyme activities back to those
observed prior to spin-trap administration. Older gerbils exhibit
significantly higher errors in a radial arm maze than younger
animals, but older gerbils that had received chronic daily
treatments of PBN (32 mg/kg) for 14 days committed significantly
less errors than untreated controls. The errors committed in
PBN-treated animals was decreased down to the level of those
observed in younger animals. Clearly the spin-trapping agent,
PBN, appears to have promise in: (1) elucidation of the role of
oxidative damage in normal brain function during aging, (2)
understanding the development of pathological conditions, and (3)
development of treatment regimens for prevention of damage that
occurs during the development of pathological conditions and in
aging.
TI - Reversal of age-related increase in brain protein oxidation,
decrease in enzyme activity, and loss in temporal and spatial
memory by chronic administration of the spin-trapping compound
N-tert-butyl-alpha-phenylnitrone.
SO - Proc Natl Acad Sci U S A 1991 May 1;88(9):3633-6
AB - Oxygen free radicals and oxidative events have been implicated as
playing a role in bringing about the changes in cellular function
that occur during aging. Brain readily undergoes oxidative
damage, so it is important to determine if aging-induced changes
in brain may be associated with oxidative events. Previously we
demonstrated that brain damage caused by an ischemia/reperfusion
insult involved oxidative events. In addition, pretreatment with
the spin-trapping compound N-tert-butyl-alpha-phenylnitrone (PBN)
diminished the increase in oxidized protein and the loss of
glutamine synthetase (GS) activity that accompanied
ischemia/reperfusion injury in brain. We report here that aged
gerbils had a significantly higher level of oxidized protein as
assessed by carbonyl residues and decreased GS and neutral
protease activities as compared to young adult gerbils. We also
found that chronic treatment with the spin-trapping compound PBN
caused a decrease in the level of oxidized protein and an
increase in both GS and neutral protease activity in aged
Mongolian gerbil brain. In contrast to aged gerbils, PBN
treatment of young adult gerbils had no significant effect on
brain oxidized protein content or GS activity. Male gerbils,
young adults (3 months of age) and retired breeders (15-18 months
of age), were treated with PBN for 14 days with twice daily
dosages of 32 mg/kg. If PBN administration was ceased after 2
weeks, the significantly decreased level of oxidized protein and
increased GS and neutral protease activities in old gerbils
changed in a monotonic fashion back to the levels observed in
aged gerbils prior to PBN administration. We also report that old
gerbils make more errors than young animals and that older
gerbils treated with PBN made fewer errors in a radial arm maze
test for temporal and spatial memory than the untreated aged
controls. These data can be interpreted to indicate that
oxidation of cellular proteins may be a critical determinant of
brain function. Moreover, it also implies that there is an
age-related increase in vulnerability of tissue to oxidation that
can be modified by free radical trapping compounds.
TI - Excess brain protein oxidation and enzyme dysfunction in normal
aging and in Alzheimer disease.
SO - Proc Natl Acad Sci U S A 1991 Dec 1;88(23):10540-3
AB - The relationship between Alzheimer disease (AD) and aging is not
currently known. In this study, postmortem frontal- and
occipital-pole brain samples were obtained from 16 subjects with
AD, 8 age-matched controls, and 5 young controls. These samples
were analyzed both for protein oxidation products (carbonyl) and
the activities of two enzymes vulnerable to mixed-function
oxidation, glutamine synthetase and creatine kinase. Glutamine
synthetase is more sensitive to mixed-function oxidation than
creatine kinase. Carbonyl content rises exponentially with age,
at double the rate in the frontal pole compared with the
occipital pole. Compared with young controls, both aged groups
(AD and age-matched controls) have increased carbonyl content and
decreased glutamine synthetase and creatine kinase activities,
which are more marked in the frontal than occipital pole in all
instances. We conclude that protein oxidation products accumulate
in the brain and that oxidation-vulnerable enzyme activities
decrease with aging in the same regional pattern (frontal more
affected than occipital). However, only glutamine synthetase
activity distinguishes AD from age-matched controls: Because
glutamine synthetase activity is differentially reduced in the
frontal pole in AD, we suggest that AD may represent a specific
brain vulnerability to age-related oxidation.
--
Lawrence Hunter, PhD.
National Library of Medicine
Bldg. 38A, MS-54
Bethesda. MD 20894
(301) 496-9300
(301) 496-0673 (fax)
hunter at nlm.nih.gov (internet)
