Brefeldin A-induced neurotoxicity in cultured spinal cord
neurons.
Kikuchi S, Shinpo K, Tsuji S, Yabe I, Niino M, Tashiro K.
Department of Neurology, Hokkaido University School of Medicine, Sapporo,
Hokkaido, Japan. skikuti@med.hokudai.ac.jp
Brefeldin A (BFA) is a fungus metabolite that is known to cause the disassembly
of the Golgi complex and apoptosis in exposed cells, both of which have been
suggested as playing roles in the pathogenesis of neurodegenerative diseases,
particularly amyotrophic lateral sclerosis (ALS). This study showed that BFA
caused neurotoxicity and apoptotic nuclear changes in cultured spinal neurons of
rat spinal cord in a dose- and time-dependent manner. The spinal motor neurons
were more vulnerable to this neurotoxicity. The cultured spinal neurons showed
irreversible disassembly of the Golgi apparatus as early as 1 hr after exposure
to BFA. BFA induced the expression and activation of caspase-12 beginning 8 hr
after exposure. The level of the cleaved form of caspase-3 had increased 12 hr
after the addition of BFA. Free radical generation and loss of mitochondrial
membrane potential were observed in the later stages of neurotoxicity caused by
BFA. Collectively, our data suggests that BFA is an excellent agent for
reproducing the pathophysiological features of ALS. This in vitro model may be
useful in attempts to study the mechanisms of this neurodegenerative disease and
to examine therapeutic potentials. Copyright 2002 Wiley-Liss, Inc.
