Autophagy, bafilomycin and cell death - The "A-B-Cs" of plecomacrolide-induced neuroprotection

Bafilomycin Al (BafAl), which is a member of the plecomacrolide sub-class of macrolide antibiotics, has differential, concentration-dependent effects on neuronal cell viability. When used at high concentrations, BafAl inhibits vacuolar ATPase (V-ATPase), promotes the accumulation of autophagic vacuoles and triggers Bax-dependent apoptosis. These effects are similar to those induced by the lysosomotropic agent chloroquine. Conversely, at concentrations below its reported ability to completely inhibit V-ATPase, BafAl dramatically attenuates chloroquine-induced apoptosis. The protective effects of BafAl appear to be independent of the chloroquine-induced accumulation of autophagosomes. Rather, BafAl appears to inhibit events downstream of chloroquine-induced autophagosome accumulation, such as the loss of mitochondrial or lysosomal integrity. Our finding that BafAl inhibits the death of neurons induced by autophagic stress/inhibition suggests a potentially novel mechanism of action apart from its ability to inhibit V-ATPase. Here we provide further evidence of neuroprotection against chloroquine-induced death by plecomacrolide antibiotics that are structurally similar to BafAl, including bafilomycin Bl and concanamycin A, and discuss potential mechanism(s) of neuroprotection against autophagic stress.