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Abstract: The patterns of expression of the Bcl-2, Bax, and Bcl-xL proteins were examined immunocytochemically in rat hippocampus and neocortex after severe hypobaric hypoxia (180 Torr for 3 h) and severe hypoxia preconditioned by intermittent mild hypoxia (360 Torr for 2 h daily, for 3 consecutive days, 24 h prior to severe hypoxia). As revealed by TUNEL assay, severe hypobaric hypoxia produced extensive apoptotic damage to the neurons of hippocampal CA1–CA4 and the neocortex but not the dentate gyrus granule cells. Remarkable posthypoxic up-regulation of Bax expression maximal at 24 h was detected in the CA1–CA4 areas of hippocampus and neocortex 3–72 h after severe hypoxia. The preconditioning to severe hypoxia protected neurons from the posthypoxic apoptotic transformations, the up-regulation of Bax expression, and resulted in persistent overexpression of Bcl-2 and Bcl-xL. We conclude that the protective action of hypoxic preconditioning is at least in part mediated by shifting of neuronal Bax/Bcl-2–Bcl-xL ratio to a favor of antiapoptotic proteins Bcl-2 and Bcl-xL. [Copyright &y& Elsevier]

Abstract: Severe hypoxia results in functional and structural injury of the brain. A preconditioning with repetitive episodes of mild hypoxia considerably ameliorates neuronal resistance to subsequent severe hypoxia. Activation of endogenous antioxidants including Cu, Zn-depending superoxide dismutase (Cu, Zn-SOD) (EC.1.15.1.1) is one of the main cell defense mechanisms against oxidative stress induced by hypoxia. Alterations of expression and enzyme activity of Cu, Zn-SOD 3 and 24h after severe hypobaric hypoxia in forebrain structures of preconditioned and non-preconditioned rats were investigated. We found that hypoxia without preconditioning suppressed the Cu, Zn-SOD enzyme activity at 3h time-point but preconditioning essentially modified the reaction to severe hypoxia by increasing the expression and activity of Cu, Zn-SOD during early stages of reoxygenation crucial for apoptosis initiation. [Copyright &y& Elsevier]

Induction of endogenous antioxidants is one of the key molecular mechanisms of cell resistance to hypoxia/ischemia. The effect of severe hypoxia on the expression of cytosolic antioxidant thioredoxin-1 (Trx) in hippocampus and neocortex was studied in preconditioned and non-preconditioned rats. The preconditioning consisted of three trials of mild hypobaric hypoxia (360Torr, 2h) spaced at 24h. Twenty-four hours after the last trial rats were subjected to severe hypobaric hypoxia (180Torr, 3h). Trx expression was studied by immunocytochemistry. In hippocampus severe hypobaric hypoxia rapidly induced Trx expression, which remained elevated still at 24h. In neocortex the enhanced expression appeared only at 24h. The preconditioning significantly augmented severe hypoxia-induced Trx-immunoreactivity at 3h but not at 24h. These findings point out that Trx contributes to mechanisms of brain tolerance to hypobaric hypoxia, especially in early periods after the exposure. [Copyright &y& Elsevier]

The impact of severe hypoxia and preconditioning on the expression of the mitochondrial antioxidant thioredoxin-2 (Trx-2) in rat hippocampus (CA1, CA2, CA3 fields, and dentate gyrus) and neocortex was studied by immunocytochemistry. The preconditioning consisted of three trials of mild hypobaric hypoxia (360 Torr, 2 hr) spaced at 24 hr. The last trial was followed by severe hypobaric hypoxia (180 Torr, 3 hr) 24 hr later. Both in hippocampus and in neocortex, severe hypobaric hypoxia resulted in enhanced Trx-2 expression at 3 hr, followed by a slight decline in Trx-2 levels, which nevertheless remained increased at 24 hr elsewhere except for the CA1 region. The preconditioning considerably augmented severe hypoxia-induced Trx-2 immunoreactivity, affecting both the number of immunoreactive cells and the intensity of immunostaining. The findings suggest a role for Trx-2 in the formation of brain hypoxic/ischemic tolerance accomplished by the preconditioning.