Limitations in the neuroprotective potential of gene therapy with Bcl-2

• Published in: Brain research Vol. 859; no. 2; pp. 202 - 206
• Main Authors: Phillips, Russell G., Lawrence, Matthew S., Ho, Dora Y., Sapolsky, Robert M.
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 24-03-2000; Amsterdam Elsevier; New York, NY
• Subjects: 3-Acetylpyridine; Animals; Apoptosis - drug effects; Apoptosis - physiology; Apoptosis inhibitor; Biological and medical sciences; Biotechnology; Cell Culture Techniques; Energy Metabolism - drug effects; Energy Metabolism - physiology; Enzyme Inhibitors - pharmacology; Fetus; Fundamental and applied biological sciences. Psychology; Gene therapy; Gene transfer; Genetic Therapy - methods; Genetic Vectors; Health. Pharmaceutical industry; Hippocampus; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Industrial applications and implications. Economical aspects; Necrosis; Neurodegeneration; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - metabolism; Neurotoxins - pharmacology; Proto-Oncogene Proteins c-bcl-2 - genetics; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Simplexvirus; Apoptosis inhibitor; Gene transfer; Neurodegeneration; Hippocampus; Necrosis; Vertebrata; Mammalia; Rat; Rodentia; Central nervous system; Gene therapy; In vitro; Brain (vertebrata); Apoptosis; Genetic transfer
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(99)02453-1

Considerable attention has focused on the therapeutic transfer of genes with viral vectors into neurons for the purpose of protecting against neurological insults. A number of papers have reported that overexpression of the anti-apoptotic protein Bcl-2 can protect neurons both in vitro and in vivo against a variety of necrotic insults. An emerging literature suggests that the availability of energy tends to modulate a neuron towards dying apoptotically, rather than necrotically, in the aftermath of an insult. This suggests that an anti-apoptotic protein such as Bcl-2 should be minimally protective, at best, against purely energetic insults. In support of this idea, we report that overexpression of Bcl-2 with a herpes simplex viral vector fails to protect hippocampal neurons, either in vitro or in vivo, against the electron transport uncoupler 3-acetylpyridine (3AP). As a positive control, the same vector significantly protected against the excitotoxin kainic acid. This finding supports the view that neurotoxicity induced by 3AP is likely to have only minimal apoptotic facets. On a broader level, it suggests some limitations in the neuroprotective potential of gene therapy with Bcl-2.