The emergence of proteinase-activated receptor-2 as a novel target for the treatment of inflammation-related CNS disorders

Abstract

The signalling molecules that are involved in inflammatory pathways are now thought to play a part in many disorders of the central nervous system (CNS). In common with peripheral chronic inflammatory diseases such a rheumatoid arthritis and ulcerative colitis, evidence now exists for the involvement of inflammatory cytokines, for example tumour necrosis factor (TNF) and interleukins (IL), in neurological disorders. A common factor observed with the up-regulation of these cytokines in peripheral inflammatory diseases, is the increased expression of the proteinase-activated receptor (PAR) subtype PAR-2. Indeed, recent evidence suggests that targeting PAR-2 helps reduce joint swelling observed in animal models of arthritis. So could targeting this receptor prove to be useful in treating those CNS disorders where inflammatory processes are thought to play an intrinsic role? The aim of this review is to summarize the emerging data regarding the role of PAR-2 in neuroinflammation and ischaemic injury and discuss its potential as an exciting new target for the prevention and/or treatment of CNS disorders.

Figure 1. Schematic representation of PAR-2 activation

Cleavage of the N-terminus by a serine proteinase such as trypsin, reveals a ‘tethered ligand’ which binds to the second extracellular loop of the receptor leading to receptor activation of signalling pathways. The identification of the tethered ligand amino acid sequence has led to the development of PAR-2-activating peptides, e.g. SLIGKV for PAR-2 that has enhanced our understanding of the physiological roles of the receptor.

Figure 2. Up-regulation of inflammatory cytokines and PAR-2 in brains of HAD patients

A–C, up-regulation of mRNA for TNF-α, IL-1β and PAR-2 in brains from HAD patients when compared with ND patients. D, no change in mRNA levels of the potential endogenous activator of PAR-2, Trypsinogen. E, PAR-2 immunoreactivity in ND (inset shows Ab absorbed with immunogen peptide) brain. F, PAR-2 immunoreactivity is increased in HAD (inset shows co-localization with neuronal marker, Neu-N) compared with ND brains. G and H, similar trypsinogen IV immunoreactivity in both ND and HAD (inset shows co-localization with neuronal marker, Neu-N) patients. Reproduced with permission from J Immunol174, 7320–7329.

Figure 3. Flow chart illustrating the disease states and experimental conditions that have led to the increased expression of PAR-2

It remains to be determined whether PAR-2 has a duality of function depending of the levels of expression and/or cell type in which the up-regulation is seen.