Intermittent hypoxia conditioning prevents behavioral deficit and brain oxidative stress in ethanol-withdrawn rats

Abstract

Jung ME, Simpkins JW, Wilson AM, Downey HF, Mallet RT. Intermittent hypoxia conditioning prevents behavioral deficit and brain oxidative stress in ethanol-withdrawn rats. J Appl Physiol 105: 510-517, 2008. First published May 22, 2008 doi:10.1152/japplphysiol.90317.2008.-Intermittent hypoxia (IH) has been found to protect brain from ischemic injury. We investigated whether IH mitigates brain oxidative stress and behavioral deficits in rats subjected to ethanol intoxication and abrupt ethanol withdrawal (EW). The effects of IH on overt EW behavioral signs, superoxide generation, protein oxidation, and mitochondrial permeability transition pore (PTP) opening were examined. Male rats consumed dextrin or 6.5% (wt/vol) ethanol for 35 days. During the last 20 days, rats were treated with repetitive (5-8 per day), brief (5-10 min) cycles of hypoxia (9.5-10% inspired O2) separated by 4-min normoxia exposures. Cerebellum, cortex, and hippocampus were biopsied on day 35 of the diet or at 24 h of EW. Superoxide and protein carbonyl contents in tissue homogenates and absorbance decline at 540 nm in mitochondrial suspensions served as indicators of oxidative stress, protein oxidation, and PTP opening, respectively. Although IH altered neither ethanol consumption nor blood ethanol concentration, it sharply lowered the severity of EW signs including tremor, tail rigidity, and startle response. Compared with dextrin and ethanol per se, in the three brain regions, EW increased superoxide and protein carbonyl contents and accelerated PTP opening in a manner ameliorated by IH. Administration of antioxidant N-acetylcysteine throughout the IH program abrogated the reductions in EW signs and superoxide content, implicating IHinduced ROS as mediators of the salutary adaptations. We conclude that IH conditioning during chronic ethanol consumption attenuates oxidative damage to the brain and mitigates behavioral abnormalities during subsequent EW. IH-induced ROS may evoke this powerful protection. mitochondrial permeability transition; superoxide; hippocampus; reactive oxygen species HYPOXIA, THE REDUCTION OF O 2 supply below physiological levels, is generally considered harmful, especially to tissues with high O 2 requirements (13). Hypoxia occurs naturally at high altitude, during strenuous exercise, and with various respiratory diseases. The fact that tissues survive such hypoxic stresses suggests that adaptive responses are mobilized to compensate for limitations in O 2 supply. Indeed, recent research demonstrates that cyclic exposure to moderate hypoxia with intervening periods of normoxia bolsters cellular resistance to ischemic stress in several organs (6, 7, 9, 25, 26, 31, 48), including brain (3, 33, 40). These studies suggest that intermittent hypoxia (IH) may stimulate endogenous defense mechanisms, affording significant cytoprotection.Brain mitochondria appear to be the principal targets of oxidative stress engendered by ethanol intoxication and withdrawal (20). The inner mitochondrial membrane's highly selective permeabil...

Ethanol withdrawal increases oxidative stress and reduces nitric oxide bioavailability in the vasculature of rats

“…Our findings demonstrating that ethanol withdrawal causes a significant increase in blood pressure are in accordance with previous observations in humans (Ceccanti et al, 2006;Clark & Friedman, 1985;King, Bernardy, Parsons, & Lovallo, 1996). Some studies suggested that the elevation in blood pressure observed during ethanol withdrawal is transitory (Ceccanti et al, 2006;Clark & Friedman, 1985).…”

“…Some studies suggested that the elevation in blood pressure observed during ethanol withdrawal is transitory (Ceccanti et al, 2006;Clark & Friedman, 1985). However, there is evidence that ethanol withdrawal induces a persistent alteration of blood pressure regulation even when resting pressures are normal, further suggesting that ethanol withdrawal may predict future cardiovascular abnormalities (King et al, 1996).…”

“…NAD(P)H oxidase is the major source of ROS in the cardiovascular system, and increased ROS generation or bioavailability has been implicated in the progression and/or onset of cardiovascular diseases, including hypertension (Touyz & Schiffrin, 2000). It has been previously described that ethanol withdrawal increases ROS generation and lipid peroxidation in the rat hippocampus and cerebellum (Jung, Rewal, Perez, Wen, & Simpkins, 2004;Jung, Simpkins, Wilson, Downey, & Mallet, 1985). However, whether ethanol withdrawal increases vascular production of ROS remains elusive.…”

“…The exact function of the vascular RAS remains elusive, but it may amplify the effects of the systemic RAS, particularly in pathological conditions, such as in hypertension (Nguyen Dinh Cat & Touyz, 2011). Ethanol withdrawal was found to activate the systemic RAS (Bezzegh et al, 1991;Clark & Friedman, 1985;King et al, 1991;Potter et al, 1983), but no information on the effects of ethanol withdrawal in the vascular RAS is available.…”

Hippocampal Hypertrophy and Sleep Apnea: A Role for the Ischemic Preconditioning?

“…It was suggested that biphasic, temporal change in DG proliferation may account for the partial recovery of clinical function in the later stages of IH exposure[31]. In accord, several other preclinical studies demonstrated protective nature of moderate IH suggesting that ischemic preconditioning-like processes may occur[4,32]. For example, in one rodent model, the IH intervention after the ischemic event lead to increased expression of brain derived neurotrophic factor (BDNF), increased hippocampal neurogenesis and functional synaptogenesis, as well as in improvement in spatial learning and long-term memory impairment[24,25].…”