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 (A β) peptides A β 40 and Aβ42. We tested the hypotheses that 1) IHT limits EW-induced activation of the p38-PS1 axis, thereby attenuating γ-secretase activation and A β 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 A β 40 and A β 42 contents by enzyme-linked immunosorbent assay. IHT attenuated the EW-associated increases in PS1, p-p38, A β 40, A β 42, and protein carbonyl contents, but not that of PS1 messenger RNA, while preserving functionally competent HSP25 dimers in EW rats. Collectively, these findings suggest that IHT may attenuate EW-induced γ-secretase overactivation by suppressing activation of the p38-PS1 axis and by preventing oxidative protein damage.
|Journal||American Journal of Physiology - Regulatory Integrative and Comparative Physiology|
|Publication status||Published - 1 Jan 2017|
- Amyloid- β
- Ethanol withdrawal
- Heat shock protein 25
- Intermittent hypoxia training
- Presenilin 1