Trimethyltin-induced expression of protease-activated receptor-1 in rat microglia

Neuroinflammation is a prominent feature shared by various neurodegenerative diseases and it is important to identify the signal pathways that control the initiation, progression and termination of the inflammatory reaction since a well-regulated inflammatory process is essential for tissue homeostasis. Protease-activated receptors (PARs) are cleaved and activated by thrombin and other extracellular proteaseswhich are released during tissue trauma and inflammation. PAR-1 is the prototypic member of the PAR family and has been shown to be upregulated in several brain pathologies being expressed by neurons and glial cells. Our previous results show that PAR-1 expression is increased in astrocytes both in vivo and in vitro after treatment with the neurotoxic compound trimethyltin (TMT). Administration of TMT to the rat results in loss of hippocampal neurons and an ensuing gliosis without blood-brain barrier compromise. TMT caused pyramidal cell damage within 3 days and a substantial loss of these neurons by 21 days post dosing. Marked microglial activation and astrogliosis are evident over the same time period. TMT causes large increase of PAR-1 immunoreactivity in microglia by day 7 while in untreated controls this receptor is barely detectable. In vitro data show that the administration of the PAR-1 activating peptides (TRAP6 and TFLLR) inhibits the production of the pro-inflammatory cytokines TNF-alpha and IL-6 in microglial cells treated with lipopolysaccharide (LPS) while promoting the release of the anti-inflammatory cytokine IL-10. Our results suggest that PAR-1 may be involved in the regulation of the inflammatory response in the brain.