Increased sensitivity to oxidative stress and the loss of muscarinic receptor responsiveness in senescence.
Although there are numerous findings which suggest that the pathogenesis of age-related neurodegenerative disorders (e.g., AD and PD) may involve oxidative stress (OS), relationships between functional age-related neuronal deficits, especially those with behavioral correlates, and OS have been difficult to establish. We have attempted to establish such relationships by determining the role of OS in the loss of muscarinic receptor (mAChR) sensitivity in aging. These decrements are expressed as age-related reductions in oxotremorine enhancement of K(+)-evoked dopamine release (K(+)-ERDA) from superfused striatal slices. Using this model we have found that: a) The reductions can be restored with in vivo administration of the free-radical trapping agent, N-tert-butyl-alpha-phenylnitrone (PBN); b) Striatal slices from old animals showed increased sensitivity (e.g., reduced DA release or oxo-enhancement of K(+)-ERDA) to the in vitro application of sodium nitroprusside, a potent NO generator or to H2O2 which treatment of striatal slices from young animals with these agents or exposure of young animals to low doses of whole-body 56Fe irradiation decreased mAChR sensitivity and signal transduction (ST). Protection from the NO- or H2O2-induced deficits could be prevented with Trolox, PBN or cholesterol pretreatment. Evidence derived from PC-12 cells suggests that OS may directly affect ST by decreasing Ca2+ flux and increasing the length of the recovery period (i.e., return to baseline Ca2+ levels) after KCI (30 mM) depolarization.
Joseph
J A
JA
USDA-ARS Human Nutrition Research Center, Boston, Massachusetts 02111, USA.
Villalobos-Molina
R
R
Denisova
N
N
Erat
S
S
Jimenez
N
N
Strain
J
J
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology; D018384:Oxidative Stress; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012680:Sensitivity and Specificity
D011976:Receptors, Muscarinic; D009569:Nitric Oxide; D002784:Cholesterol