Age and energy intake interact to modify cell stress pathways and stroke outcome

Abstract

Objective-Age and excessive energy intake/obesity are risk factors for cerebrovascular disease, but it is not known if and how these factors affect the extent of brain damage and outcome in ischemic stroke. We therefore determined the interactions of age and energy intake on the outcome of ischemic brain injury, and elucidated the underlying mechanisms.Methods-We utilized a novel microchip-based immunoaffinity capillary electrophoresis technology to measure a panel of neurotrophic factors, cytokines and cellular stress resistance proteins in brain tissue samples from young, middle age and old mice that had been maintained on control or energy restricted diets prior to middle cerebral artery occlusion and reperfusion (I/R).Results-Mortality from focal ischemic stroke was increased with advancing age and reduced by an intermittent fasting (IF) diet. Brain damage and functional impairment were reduced by IF in young and middle age mice, but not in old mice. The basal and post-stroke levels of neurotrophic factors (BDNF and bFGF), protein chaperones (HSP70 and GRP78) and the antioxidant enzyme HO-1 were decreased, while levels of inflammatory cytokines were increased in the cerebral cortex and striatum of old mice compared to younger mice. IF coordinately increased levels of protective proteins and decreases inflammatory cytokines in young, but not in old mice.Interpretation-Reduction in dietary energy intake differentially modulates neurotrophic and inflammatory pathways to protect neurons against ischemic injury, and these beneficial effects of IF are compromised during aging resulting in increased brain damage and poorer functional outcome.

Heat shock proteins in neurodegenerative disorders and aging

“…Using immunohistochemical and stereological tools, GRP78 levels have also been shown to be increased in the substantia nigra of older Asian Indians, suggestive of age-related compensatory changes in the endoplasmic reticulum (Alladi et al 2010). Contrary to the immunohistochemical findings in the human nigra, GRP78 levels are lowered in homogenates of the cortex and striatum in the aged mouse brain (Arumugam et al 2010), suggestive of differences across brain regions, species, and/or assay techniques. Many other studies have similarly shown that GRP78 is decreased in aged tissue, such as the cerebral cortex and hippocampus (Hussain and Ramaiah 2007;Naidoo et al 2008;Paz Gavilan et al 2006).…”

Blockage of cytosolic phospholipase A2 alpha by monoclonal antibody attenuates focal ischemic brain damage in mice

“…The area of infarction was evaluated with TTC staining as described previously (16). Two-mm brain sections were incubated with 2% TTC at 37℃ for 30 min with gentle shaking and then fixed with 10% formalin in PBS.…”

Impaired Adaptive Cellular Responses to Oxidative Stress and the Pathogenesis of Alzheimer's Disease

“…Similar events occur in many neurons during exercise and when dietary energy intake is low. Normally, neurons respond to this mild stress adaptively, as indicated at the molecular level by their upregulation of expression of genes encoding neurotrophic factors such as BDNF and FGF2, protein chaperones such as HSP70 and GRP78, and antioxidant enzymes such as HO-1 (11). The mechanisms by which these cellular defenses are mobilized are beginning to be understood and are described below (Fig.…”

“…Not only does expression of HSPs increase in muscle after exercise (58,120), but increased expression also occurs in neurons in response to exercise (31) and dietary energy restriction (11,182). In an animal model of heat stroke-induced hyperthermia, 3 weeks of exercise induced HSP72 expression in the brain and protected neurons against damage and also increased the survival of the animals (31).…”