Reversible Oxidative Damage to Behavior During Aging

Larry Hunter hunter at
Thu Feb 27 20:36:37 EST 1992

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

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

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
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 (internet)

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