Intermittent hypoxia training blunts cerebrocortical presenilin 1 overexpression and amyloid-{beta} accumulation in ethanol-withdrawn rats

Abrupt cessation of chronic alcohol consumption triggers signaling cascades that harm vulnerable brain regions and produce neurobehavioral deficits. We have demonstrated that a program of intermittent, normobaric hypoxia training (IHT) in rats prevents brain damage and neurobehavioral impairment resulting from abrupt ethanol withdrawal (EW). Moreover, EW induced expression of stress-activated protein kinase p38 and presenilin 1 (PS1), the catalytic subunit of -secretase that produces the neurotoxic amyloid-β (Aβ) peptides Aβ40 and Aβ42. We tested the hypotheses that 1) IHT limits EW-induced activation of the p38-PS1 axis, thereby attenuating -secretase activation and Aβ accumulation, and 2) EW disables heat shock protein 25 (HSP25), a p38 substrate, molecular chaperone, and antioxidant, and provokes protein carbonylation in a manner suppressed by IHT. Adult male rats completed two cycles of a 4-wk ethanol diet (6.5% wt/vol) and a 3-wk EW or an isocaloric, dextrin-based control diet. A 20-day IHT program (5–8 daily cycles of 5–10 min of 9.5–10% fractional inspired O2 + 4 min of 21% fractional inspired O2) was administered during the first EW phase. After the second EW phase, the brain was excised and the prefrontal cortex extracted. PS1, phosphorylated p38 (p-p38), and HSP25 were analyzed by immunoblot, PS1 messenger RNA by quantitative polymerase chain reaction, protein carbonyl content by spectrometry, and Aβ40 and Aβ42 co...
Source: AJP: Regulatory, Integrative and Comparative Physiology - Category: Physiology Authors: Tags: Research Article Source Type: research