Carney JM Floyd RA
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.
In: J Mol Neurosci (1991) 3(1):47-57
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.
Institutional address:
Department of Pharmacology
Chandler Medical Center
University of Kentucky
Lexington 40536.
PS: PBN is patented in Europe as a hair-growth
stimulator. Does make it a bit relevant.
Peter H. Proctor, PhD, MD
(713) 960-1616
