title: Autophagy, bafilomycin and cell death: the "a-B-cs" of plecomacrolide-induced neuroprotection.
abstract: Bafilomycin A1 (BafA1), 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, BafA1 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, BafA1 dramatically attenuates chloroquine-induced apoptosis. The protective effects of BafA1 appear to be independent of the chloroquine-induced accumulation of autophagosomes. Rather, BafA1 appears to inhibit events downstream of chloroquine-induced autophagosome accumulation, such as the loss of mitochondrial or lysosomal integrity. Our finding that BafA1 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 BafA1, including bafilomycin B1 and concanamycin A, and discuss potential mechanism(s) of neuroprotection against autophagic stress.
authors.affiliation: Department of Pathology, Neuropathology Division, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA. shacka@uab.edu
authors.forename: John J
authors.initials: JJ
authors.lastname: Shacka
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Klocke
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D018942:Macrolides / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D018942:Macrolides; D018696:Neuroprotective Agents; C040929:bafilomycin A1