BCL-2 PROTECTS NEURAL CELLS FROM CYANIDE AGLYCEMIA-INDUCED LIPID OXIDATION, MITOCHONDRIAL INJURY, AND LOSS OF VIABILITY/

The protooncogene bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that the mechanism of action of Bcl-2 involve s antioxidant activity, The involvement of free radicals in ischemia/r eperfusion injury to neural cells has led us to investigate the effect of Bcl-2 in a model of delayed neural cell death, We have examined th e survival of control and bcl-2 transfectants of a hypothalamic tumor cell line, GT1-7, exposed to potassium cyanide in the absence of gluco se (chemical hypoxia/aglycemia). After 30 min of treatment, no loss of viability was evident in control or bcl-2 transfectants; however, Bcl -2-expressing cells were protected from delayed cell death measured fo llowing 24-72 h of reoxygenation. Under these conditions, the rate and extent of ATP depletion in response to treatment with cyanide in the absence of glucose and the rate of recovery of ATP during reenergizati on were similar in control and Bcl-2-expressing cells. Bcl-2-expressin g cells were protected from oxidative damage resulting from this treat ment, as indicated by significantly lower levels of oxidized lipids. M itochondrial respiration in control but not Bcl-2-expressing cells was compromised immediately following hypoxic treatment, These results in dicate that Bcl-2 can protect neural cells from delayed death resultin g from chemical hypoxia and reenergization, and may do so by an antiox idant mechanism, The results thereby provide evidence that Bcl-2 or a Bcl-2 mimetic has potential therapeutic application in the treatment o f neuropathologies involving oxidative stress, including focal and glo bal cerebral ischemia.