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The Journal of Neuroscience, April 1, 2003, 23(7):2735

Inhibition of Bax-Induced Cytochrome c Release from Neural Cell and Brain Mitochondria by Dibucaine and Propranolol

Brian M. Polster^{1, 2}, Gorka Basañez³, Michael Young¹, Motoshi Suzuki⁴, and Gary Fiskum¹

¹  Department of Anesthesiology and ²  Neuroscience Program, University of Maryland School of Medicine, Baltimore, Maryland 21201, ³  Unidad de Biofísica (Centro Mixto Consejo Superior de Investigaciones Científicas-Universidad del País Vasco/Euskal Herriko Unibertsitatea) y Departamento de Bioquímica y Biología Molecular, Universidad del País Vasco, 48080 Bilbao, Spain, and ⁴  Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892

BH3 (Bcl-2 homology 3)-only proteins of the Bcl-2 family activate Bax or Bak during apoptosis to promote the release of pro-death factors sequestered in the mitochondrial intermembrane space. Previous results demonstrated that a synthetic BH3 peptide mimics the ability of the BH3-only protein Bid to promote Bax insertion and cytochrome c (cyt c) release from neural cell mitochondria. However, the BH3 peptide was deficient in promoting cyt c release from mitochondria without associated Bax, such as adult rat brain mitochondria. This study tested the hypothesis that the amphiphilic membrane-active cationic drugs dibucaine and propranolol block BH3 peptide-initiated cyt c efflux by preventing the integration of Bax into the mitochondrial outer membrane. BH3 peptide-initiated release of cyt c from GT1-7 neural cell mitochondria was inhibited by dibucaine and propranolol at concentrations of 100-300 µM. Recombinant Bax (100 nM) alone did not release cyt c from adult rat brain mitochondria; however, when BH3 peptide or caspase-8 cleaved Bid (cBid) was added, robust cyt c release was achieved that was inhibited completely by 200 µM dibucaine or propranolol. These drugs at similar concentrations also inhibited release of entrapped 10 kDa dextrans from protein-free liposomes treated with Bax and cBid. Contrary to the hypothesis that dibucaine and propranolol act by inhibiting the insertion of Bax into the mitochondrial outer membrane, membrane insertion of Bax was not inhibited in mitochondria or liposomes, indicating a mechanism of drug action downstream from this event. These results suggest that dibucaine and propranolol inhibit Bax-induced permeability changes through a direct interaction with the lipid membrane and present a novel target for the development of neuroprotective, antiapoptotic therapeutics.

Key words: Bax; BH3; Bid; brain mitochondria; cytochrome c; dibucaine; propranolol; apoptosis; permeability transition

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2372735-09$05.00/0

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