Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor beta 1

Serine proteases play a key role in the fundamental biology of the central nervous system (CNS), and recent data suggest their involvement in the path ophysiology of neurodegenerative diseases, Little is known about the physio logical regulation of these proteases in the CNS, Among the multiple growth factors present in the brain, transforming growth factor beta 1 (TGF-beta 1) has been described as an injury-related growth factor. However, its bene ficial or deleterious role remains unclear. In the present study, we invest igated the influence of TGF-beta 1 in apoptosis and necrosis, two mechanism s involved in ischemic neuronal death. We show that TGF-beta 1 exerts a neu roprotective role restricted to necrosis induced by N-methyl-D-aspartate. T his effect is observable only in the obligatory presence of TGF-beta 1-resp onsive astrocytes, We demonstrate that this neuroprotective activity is med iated through an up-regulation of a serine protease inhibitor (PAI-1) in as trocytes, These results underline the involvement of serine proteases and e xtracellular matrix components such as the PAI-1/t-PA axis in the excitotox ic cascade, Moreover, regardless of the underlying mechanisms of t-PA invol vement in excitotoxic injury, our observations might warn against the use o f tissular plasminogen activator as an alternative therapy for the treatmen t of hypoxic-ischemic injury in the brain.