title: Bcl-2 protects neural cells from cyanide/aglycemia-induced lipid oxidation, mitochondrial injury, and loss of viability.
abstract: The protooncogene bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that the mechanism of action of Bcl-2 involves antioxidant activity. The involvement of free radicals in ischemia/reperfusion 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 the survival of control and bcl-2 transfectants of a hypothalamic tumor cell line, GT1-7, exposed to potassium cyanide in the absence of glucose (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 following 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 reenergization were similar in control and Bcl-2-expressing cells. Bcl-2-expressing cells were protected from oxidative damage resulting from this treatment, as indicated by significantly lower levels of oxidized lipids. Mitochondrial respiration in control but not Bcl-2-expressing cells was compromised immediately following hypoxic treatment. These results indicate that Bcl-2 can protect neural cells from delayed death resulting from chemical hypoxia and reenergization, and may do so by an antioxidant mechanism. The results thereby provide evidence that Bcl-2 or a Bcl-2 mimetic has potential therapeutic application in the treatment of neuropathologies involving oxidative stress, including focal and global cerebral ischemia.
authors.affiliation: Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Myers
authors.forename: G
authors.initials: G
authors.lastname: Fiskum
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: S J
authors.initials: SJ
authors.lastname: Simmens
authors.forename: D E
authors.initials: DE
authors.lastname: Bredesen
authors.forename: A N
authors.initials: AN
authors.lastname: Murphy
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005947:Glucose / Q000172:deficiency*; D050356:Lipid Metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011190:Potassium Cyanide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured
chemical_list: D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D005947:Glucose; D011190:Potassium Cyanide