Greater resistance to inflammation at adulthood could contribute to extended life span of p66(Shc-/-) mice.
Evidence is mounting that reactive oxygen species (ROS) produced because of stressful challenges could interfere with the proper functioning of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in greater vulnerability to aging and neurodegeneration. Here we tested the hypothesis that p66(Shc-/-) mice, which have been described to have an extended life span and a high resistance to oxidative stress, might be less susceptible to the effects of inflammatory insults at adulthood. Although adrenocortical reactivity in response to bacterial endotoxin (lipopolysaccharide, LPS) did not differ as a function of the genotype, a hyperdrive of the HPA axis was revealed following treatment with a synthetic glucocorticoid agonist. When measuring changes in hippocampal oxidative status following LPS, only wild-type (WT) subjects showed increased levels of F(2)-isoprostanes, an index of lipid peroxidation and free radical formation. At the same time, the neurotrophin brain-derived neurotrophic factor was selectively increased in WT subjects, while levels of prostaglandin E(2) were decreased in the mutants. Overall, the greater resilience to inflammation-induced changes in the p66(Shc-/-) mutants might underlie the better health status and the longevity characterizing these mice.
Berry
Alessandra
A
Section of Behavioural Neurosciences, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
Carnevale
Daniela
D
Giorgio
Marco
M
Pelicci
Pier Giuseppe
PG
de Kloet
Edo Ronald
ER
Alleva
Enrico
E
Minghetti
Luisa
L
Cirulli
Francesca
F
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000032:analysis; D015232:Dinoprostone / Q000032:analysis; D007249:Inflammation / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008136:Longevity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D055765:Shc Signaling Adaptor Proteins / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D019208:Brain-Derived Neurotrophic Factor; D008070:Lipopolysaccharides; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C075750:8-epi-prostaglandin F2alpha; D003907:Dexamethasone; D015237:Dinoprost; D015232:Dinoprostone; D003345:Corticosterone