Endogenous Antioxidants and Three Paradoxes of Hypoxic Preconditioning

Abstract

Severe acute hypobaric hypoxia increases the expression of 4 endogenous antioxidant proteins (Cu,Zn-SOD, Mn-SOD, thioredoxin-1 [Trx-1], and thioredoxin-2 [Trx-2]) in rat hippocampus. This increase is a protective reaction, but it is not enough to prevent massive delayed neuronal death. A preconditioning by 3 episodes of mild hypoxia (3PC) significantly enhances and, in some cases, accelerates the increase of antioxidant expression after subsequent severe hypoxia. That prevents neuronal death and ameliorates functional disorders induced by severe hypoxia. It has been assumed that the effect of 3PC is associated with protective increase of “background” antioxidant levels even before severe hypoxia. The first paradox, however, is that 3PC itself (ie, without or before subsequent severe hypoxia) does not increase the expression of Trx-1, Trx-2, or Cu,Zn-SOD in any hippocampal area 24 hours after last session (ie, at the starting point of severe hypoxia). Moreover, in many cases, 3PC itself significantly reduces the hippocampal expression of these antioxidants. We have hypothesized that the neuroprotective effect of preconditioning bears on the reduced “background” levels of antioxidants, which facilitates reactive oxygen species–mediated signal transduction. The second paradox is that preconditioning by a single episode of mild hypoxia (1PC), in contrast to 3PC, does not have a neuroprotective effect against subsequent severe hypoxia. Nonetheless, the effects of 1PC itself on the expression of antioxidants are similar to the effects of 3PC. Thus, the neuroprotective effects of preconditioning in these cases appear not to be determined by any specific baseline level of antioxidant expression at the starting timepoint of subsequent severe hypoxia but, rather, are caused by dynamic changes of the expression, which switch the neuronal cells into a functional state of readiness for rapid and intense expression of antioxidants in response to severe hypoxia. The third paradox is that the 6-trial mild hypoxia (6PC) itself significantly amplifies the expression of Trx-1 and both SODs. In case of subsequent severe hypoxia, 6PC has a neuroprotective effect, albeit less efficient than 3PC. However, the mechanism of neuroprotection essentially differs. In 6PC, the neuroprotective effect is apparently caused by accumulation of a defensive pool of antioxidants by the starting point of severe hypoxia.