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Original Article

Bafilomycin A1 Inhibits Chloroquine-Induced Death of Cerebellar Granule Neurons

Department of Pathology, Division of Neuropathology (J.J.S., B.J.K., K.A.R.) and Department of Medicine (G.D.), University of Alabama at Birmingham, Birmingham, Alabama; Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, Osaka, Japan (M.S., Y.U.); and Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, St. Louis, Missouri (R.E.S.)

Abstract

Treatment of cells with the macrolide antibiotic bafilomycin A1, an inhibitor of vacuolar (V)-ATPase, or with the lysosomotropic agent chloroquine, has been shown to pharmacologically inhibit autophagy as evidenced by an accumulation of autophagosomes, which in turn causes Bax-dependent apoptosis. However, bafilomycin A1 has also been reported to inhibit chloroquine-induced apoptosis, suggesting a complex interrelationship between these two inhibitors of autophagy. To determine whether the cytoprotective effect of bafilomycin A1 on chloroquine-treated cells was dependent on inhibition of V-ATPase, we examined the single and combined effects of bafilomycin and chloroquine on cultured cerebellar granule neurons. When added separately, chloroquine or high concentrations of bafilomycin A1 (10 nM) induced a dose-dependent inhibition of autophagy (as measured by an increase in LC3-II, a marker specific for autophagosomes), followed by caspase-3 activation and cell death. When added in combination, bafilomycin A1 potently inhibited chloroquine-induced caspase-3 activity and cell death at concentrations (1 nM) that neither altered vacuolar acidification nor inhibited autophagy. The neuroprotective effects of bafilomycin A1 against chloroquine were substantially greater than those produced by Bax deficiency. Bafilomycin A1-induced neuroprotection seemed to be stimulus-specific, in that staurosporine-induced death was not attenuated by coaddition of bafilomycin A1. Together, these data suggest that in addition to promoting death via inhibition of V-ATPase and autophagy, bafilomycin A1 possesses novel, neuroprotective properties that inhibit Bax-dependent activation of the intrinsic apoptotic pathway resulting from the pharmacological inhibition of autophagy.

Address correspondence to: Dr. Kevin A. Roth, Department of Pathology, Division of Neuropathology, University of Alabama at Birmingham, SC961, 1530 3rd Ave South, Birmingham, AL 35294-0017. E-mail: kroth{at}path.uab.edu

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