Oxidative stress and age-related neuronal deficits.
Research from our laboratory has indicated that the loss of sensitivity that occurs in several receptor systems as a function of age may be an index of an increasing inability to respond to oxidative stress (OS). This loss occurs partially as a result of altered signal transduction (ST). Assessments have involved determining the nature of age-related reductions in oxotremorine enhancement of K(+)-evoked dopamine release (K(+)-ERDA) from superfused striatal slices. Using this model, we have found that 1. Reductions can be restored with in vivo administration of the free-radical trapping agent, N-tert-butyl-alpha-phenylnitrone (PBN); 2. Decrements in DA release induced by NO or H2O2 from striatal slices from both young and old animals could be restored with alpha-tocopherol or PBN; 3. ST decrements, such as those seen in aging, could be induced with radiation exposure; and 4. Pre-incubation of the striatal slices with cholesterol decreased subsequent deleterious effects of NO or OH. on DA release. Thus, cholesterol, which increases in neuronal membranes as a function of age, may function as a potent antioxidant and protectant against neuronal damage. These results suggest that therapeutic efforts to restore cognitive deficits in aging and age-related disease might begin with antioxidant reversal of ST decrements.
Joseph
J A
JA
USDA-ARS Human Nutrition Research Center on Aging, Boston, MA 02111, USA.
Denisova
N
N
Villalobos-Molina
R
R
Erat
S
S
Strain
J
J
D000375:Aging / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D003497:Cyclic N-Oxides; D004298:Dopamine / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009589:Nitrogen Oxides / Q000494:pharmacology; D018384:Oxidative Stress; D010095:Oxotremorine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013113:Spin Labels; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D002839:Chromans; D003497:Cyclic N-Oxides; D009589:Nitrogen Oxides; D013113:Spin Labels; D014810:Vitamin E; C029217:phenyl-N-tert-butylnitrone; D010095:Oxotremorine; D006861:Hydrogen Peroxide; D011188:Potassium; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D004298:Dopamine