Overexpression of Bcl-xl protects septal neurons from prolonged hypoglycemia and from acute ischemia-like stress

• Published in: Neuroscience Vol. 135; no. 1; pp. 73 - 80
• Main Authors: Panickar, K.S., Nonner, D., Barrett, J.N.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 2005; Elsevier
• Subjects: Adenosine Triphosphate - metabolism; Animals; Antimetabolites; bcl-X Protein - biosynthesis; bcl-X Protein - genetics; Bcl-xl; Biological and medical sciences; Brain Ischemia - metabolism; Caspase 3; Caspases - metabolism; Cell Death - drug effects; Cells, Cultured; Deoxyglucose; Diagnostic Imaging; Gene Expression Regulation - physiology; Green Fluorescent Proteins - metabolism; hyperglycemia; hypoglycemia; Hypoglycemia - chemically induced; Hypoglycemia - metabolism; Hypoxia, Brain - metabolism; ischemia; Medical sciences; Neurology; neuron; Neurons - metabolism; Nitro Compounds - pharmacology; Propionates - pharmacology; Rats; Rats, Sprague-Dawley; Septum of Brain - cytology; Septum of Brain - metabolism; Stress, Physiological - metabolism; Succinate Dehydrogenase - metabolism; Transfection; Vascular diseases and vascular malformations of the nervous system; GFP; hyperglycemia; Bcl-xl; hypoglycemia; transfection; neuron; VDAC; PI; 3-NP; OGD; ischemia; Neuroprotection; Acute; Central nervous system; Gene overexpression; Cardiovascular disease; Metabolic diseases; Hypoglycemia; In vitro; Stress; Encephalon; Hyperglycemia; Neuron; Ischemia
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2005.02.052

Overexpression of Bcl-xl, a member of the Bcl-2 protein family, is reported to protect from a variety of stresses involving delayed cell death. We tested the ability of Bcl-xl overexpression to protect primary cultures of embryonic rat septal neurons subjected to one of four different stresses: 6 h of combined oxygen–glucose deprivation, which produces rapid cell death, or a 24 h exposure to hypoglycemia, hyperglycemia, or 1mM 3-nitropropionic acid (an inhibitor of mitochondrial respiration), which results in a more slowly-developing death. Prior to the stress neurons were transiently transfected to overexpress either green fluorescent protein only or green fluorescent protein along with wild-type Bcl-xl. Immediately after oxygen–glucose deprivation, many neurons expressing green fluorescent protein only showed process blebbing and disintegration, with only 49% of the initial cells remaining intact with processes. Neurons expressing both green fluorescent protein and Bcl-xl showed less damage (68% intact post-stress, P<0.05). This result indicates that Bcl-xl’s saving effects are not due solely to blocking delayed (apoptotic) death, because death following oxygen–glucose deprivation was rapid and was not accompanied by increased activation of caspase-3. Bcl-xl expression also significantly protected against the hypoglycemic stress (23% intact 24 h post-stress with green fluorescent protein only, compared with 70% with Bcl-xl and green fluorescent protein), but did not protect from hyperglycemia or 3-nitropropionic acid. Thus Bcl-xl does not protect against all forms of delayed death. Bcl-xl’s protective effects may include blocking early damaging events, perhaps by increasing mitochondrial function in the face of low levels of energy substrates. Bcl-xl’s protective effects may require an intact electron transport chain.