title: Limitations in the neuroprotective potential of gene therapy with Bcl-2.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Stanford University, Stanford, CA, USA. rgphil@leland.stanford.edu
authors.forename: R G
authors.initials: RG
authors.lastname: Phillips
authors.forename: M S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: D Y
authors.initials: DY
authors.lastname: Ho
authors.forename: R M
authors.initials: RM
authors.lastname: Sapolsky
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D018929:Cell Culture Techniques; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; C010835:3-acetylpyridine