Transforming growth factor alpha-induced expression of type-1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity
FASEB j.. 2002-12-17; 17(2): 277-279
DOI: 10.1096/fj.02-0403fje
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Although transforming growth factor (TGF)-alpha, a member of the epidermal growth
factor (EGF) family, has been shown to protect neurons against excitotoxic and
ischemic brain injuries, its mechanism of action remains unknown. In the present
study, we used in vitro models of apoptotic or necrotic paradigms demonstrating
that TGF-alpha rescues neurons from N-methyl-D-aspartate (NMDA)-induced
excitotoxic death, with the obligatory presence of astrocytes. Because neuronal
tissue-type plasminogen activator (t-PA) release was shown to potentiate
NMDA-induced excitotoxicity, we observed that TGF-alpha treatment reduced
NMDA-induced increase of t-PA activity in mixed cultures of neurons and
astrocytes. In addition, we showed that although TGF-alpha induces activation of
the extracellular signal-regulated kinases (ERKs) in astrocytes, it failed to
activate p42/p44 in neurons. Finally, we showed that TGF-alpha, by an
ERK-dependent mechanism, stimulates the astrocytic expression of PAI-1, a t-PA
inhibitor, which mediates the neuroprotective activity of TGF-alpha against
NMDA-mediated excitotoxic neuronal death. Taken together, we indicate that
TGF-alpha rescues neurons from NMDA-induced excitotoxicity in mixed cultures
through inhibition of t-PA activity, involving PAI-1 overexpression by an
ERK-dependent pathway in astrocytes.