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

Considerable attention has focused on the therapeutic transfer of genes wit h viral vectors into neurons for the purpose of protecting against neurolog ical insults. A number of papers have reported that overexpression of the a nti-apoptotic protein Bcl-2 can protect neurons both in vitro and in vivo a gainst a variety of necrotic insults. An emerging literature suggests that the availability of energy tends to modulate a neuron towards dying apoptot ically, rather than necrotically, in the aftermath of an insult. This sugge sts that an anti-apoptotic protein such as Bcl-2 should be minimally protec tive, at best, against purely energetic insults. In support of this idea, w e report that overexpression of Bcl-2 with a herpes simplex viral vector fa ils 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 ac id. This finding supports the view that neurotoxicity induced by 3AP is lik ely to have only minimal apoptotic facets. On a broader level, it suggests some limitations in the neuroprotective potential of gene therapy with Bcl- 2. (C) 2000 Elsevier Science B.V. All rights reserved.