Upregulation of bax protein levels in neurons following cerebral ischemia

Abstract

The patterns of expression of the bcl-2, bax, and bci-X genes were examined immunohistochemically in neurons of the adult rat brain before and after 10 min of global ischemia induced by transient cardiac arrest. High levels of the cell death promoting protein Bax and concomitant low levels of the apoptosis-blocking protein Bcl-2 were found in some populations of neurons that are particularly sensitive to cell death induced by transient global ischemia, such as the CA1 sector of the hippocampus and the Purkinje cells of the cerebellum. Moreover, within 0.5 to 3 hr after an ischemic episode, immunostaining for Bax was markedly increased within neurons with morphological features of degeneration in many regions of the brain. Use of a two-color staining method for simultaneous analysis of Bax protein and in situ detection of DNA-strand breaks revealed high levels of Bax immunoreactivity in many neurons undergoing apoptosis. Postischemic elevations in Bax protein levels in the hippocampus, cortex, and cerebellum were also demonstrated by immunoblotting. At early times after transient ischemia, regulation of Bcl-2 and Bcl-x protein levels varied among neuronal subpopulations, but from 3 hr on, those neurons with morphological evidence of degeneration uniformly contained reduced levels of Bci-2 and particularly Bci-X immunoreactivity. The findings suggest that differential expression of some members of the bcl-2 gene family may play an important role in determining the relative sensitivity of neuronal subpopulations to ischemia and that postischemic alterations in the expression of bax, bcl-2, and bcl-x may contribute to the delayed neuronal cell death that occurs during the repurfusion phase after a transient ischemic episode.

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

“…This study suggests that the control of the level of Bcl-x L expression may be therapeutically bene®cial for the treatment of vascular disease. In addition, because many tumors have increased Bcl-x L expression (Olopade et al, 1997;Kirsh et al, 1998;Krajewski et al, 1996Krajewski et al, , 1997Kondo et al, 1996), this approach may provide a powerful approach to treating cancer. In support of this hypothesis, a recent study examined the e cacy of using Bcl-2 antisense inhibitors to treat non-Hodgkin's lymphoma in the clinic (Webb et al, 1997).…”

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

“…Bax-like proteins, which include Bak and Bok, possess three BH domains and are critical mediators of mitochondrial dysfunction during apoptosis. Bax is widely expressed in the brain (Krajewski et al, 1995b), while Bok is present only in CA3 neurons (Lein et al, 2004). Fulllength Bak is present only in nonneuronal cells in brain, whereas neurons express an unusual BH3-only splice variant of Bak which has antiapoptotic activity (Sun et al, 2001).…”

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

“…Increases in Bax are found specifically in neurons that undergo cell death in ischemia-sensitive regions of the brain such as the CA1 sector of the hippocampus, in rat, hamster, and dog models of global cerebral ischemia. [26][27][28] Bax protein and mRNA levels also rapidly increase in neurons within the penumbra region of focal infarcts, in rodent models of middle cerebral artery occlusion. 29 Moreover, evidence suggesting a cause-and-effect relation between increases in Bax expression and ischemia-associated neuronal cell death has come from experiments using baxÀ/À mice generated by Korsmeyer et al 30 Elevations in Bax protein and mRNA levels were described in neurons in vivo after excitotoxic lesion with the N-methyl-D-aspartate receptor agonist, quinolinic acid, 31 as well as after systemic administration of kainic acid.…”