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

Strathclyde Institute for Pharmacy & Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, G4 NR, UK.
The Journal of Physiology (Impact Factor: 5.04). 06/2007; 581(Pt 1):7-16. DOI: 10.1113/jphysiol.2007.129577
Source: PubMed


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.

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Available from: Trevor Bushell
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    • "PAR-2 is also expressed on the smooth muscles, neurons, microglia, astrocytes, and C6 glioma cells. Activated PAR-2 exert different effects on tissues such as gastrointestinal muscle relaxation, nervous system inflammation, nociception signaling, and neuronal cell death.27 However, physiological and pathological roles of PAR-2 receptors in regard to trypsin actions and astrocyte activities remain to be elucidated. "
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    ABSTRACT: Astrocytes are cells within the central nervous system which are activated in a wide spectrum of infections, and autoimmune and neurodegenerative diseases. In pathologic states, they produce inflammatory cytokines, chemokines, and nitric oxide (NO), and sometimes they induce apoptosis. Their protease-activated receptors (PARs) can be activated by proteases, e.g. thrombin and trypsin, which are important in brain inflammation. The current study aimed to investigate the effects of different concentrations of trypsin (1 to 100U/ml) on cultured astrocytes. In the present study, two-day rat infants' brains were isolated and homogenized after meninges removal, then cultivated in DMEM + 10% FBS medium. 10 days later, astrocytes were harvested and recultivated for more purification (up to 95%), using Immunocytochemistry method, in order to be employed for tests. They were affected by different concentrations of trypsin (1, 5, 10, 15, 20, 40, 60, 80, and 100 U/ml). To reveal the inflammation progress, NO concentrations (the Griess test) were assessed after 24 and 48 hours. The results showed that trypsin concentration up to 20 U/ml caused a significant increase in NO, in a dose-dependent manner, on cultured astrocytes (P < 0.001). Trypsin 20 U/ml increased NO production fivefold the control group (P < 0.001). At higher concentrations than 20 U/ml, NO production diminished (P < 0.001). At 100 U/ml, NO production was less than the control group (P < 0.001). Inflammatory effects of trypsin 5-20 U/ml are probably due to the stimulation of astrocytes' PAR-2 receptors and the increasing of the activation of NF-κB, PKC, MAPKs. Stimulation of astrocytes' PAR-2 receptors causes an increase in iNOS activation which in turn leads to NO production. However, higher trypsin concentration possibly made astrocyte apoptosis; therefore, NO production diminished. These assumptions need to be further investigated.
    Full-text · Article · Feb 2013 · Iranian Journal of Neurology
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    • "PARs are categorized into four types: PAR-1, PAR-3, and PAR-4 as thrombin receptors and PAR- 2 as the trypsin and tryptase receptors (Dery and Bunnett 1999; Kawabata and Kuroda 2000; Adams et al. 2011). PAR-2, the second member of the PAR family is expressed in a wide range of biological systems, such as the respiratory system (Cocks and Moffatt 2001; Jesmin et al. 2006), the cardiovascular system (Barnes et al. 2004; Steinberg 2005; Leger et al. 2006), the gastrointestinal tract (Kawabata 2002, 2003; Amadesi and Bunnett 2004), immune cells (Zhang et al. 2007), skin (Steinhoff et al. 2003; Rattenholl and Steinhoff 2008), and the nervous system (Bushell 2007; Greenwood and Bushell 2010). Many groups have found that activation of PAR-2 leads to multiple important biological functional responses, such as mitogenesis, proliferation, differentiation, inflammation, and apoptosis in many tissues and cell types under pathological and physiological conditions (Luo et al. 2007a, b; Vesey et al. 2007; Borensztajn et al. 2010; Zhou 2011). "
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    ABSTRACT: Hypoxia-induced apoptosis of retinal ganglion cells (RGCs) is regarded as a pivotal pathological process in various ocular diseases. Protease-activated receptor-2 (PAR-2) is involved in the regulation of cell inflammation, differentiation, and apoptosis in many cell types and tissues, but the role of PAR-2 in RGCs under pathological conditions remains unknown. The purpose of this study was to investigate the role of PAR-2 in the apoptosis of RGCs under hypoxic stress. An immortalized rat RGC line (RGC-5) was exposed to hypoxia (5 % O(2)). The expression and location of PAR-2 in RGC-5 cells under hypoxia stress were investigated using real-time PCR, western blotting and immunocytochemistry. Cell viability was determined using the Cell Counting Kit-8 assay. Apoptosis was detected using Hoechst 33342 staining and AnnexinV-FITC/PI assays. The role of Bcl-2, Bax, and the active subunit of caspase-3 was also investigated. The results showed that PAR-2 was functionally expressed in RGC-5 cells and up-regulated at both mRNA and protein levels under hypoxic stress. The PAR-2 selective agonist, SLIGRL, rescued RGC-5 cells from hypoxia-induced apoptosis through up-regulation of the Bcl-2/Bax ratio and down-regulation of caspase-3 activation. This study provides the first evidence that PAR-2 has a protective effect against the hypoxia-induced apoptosis of RGC-5 cells.
    Full-text · Article · Sep 2012 · Journal of Molecular Neuroscience
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    • "Our study, in accord with the above-mentioned studies, identifies PAR2 as a potential pharmacological target in the development of therapeutic strategies for neurodegenerative diseases. Several specific inhibitors of PAR2 have been described already (Severino et al., 2009; Sevigny et al., 2011), and their use for the treatment of various CNS disorders is being contemplated (Bushell, 2007). Fig. 3. Electrophoretic PrP TSE pattern, quantity and level of infectivity in PAR2 " / " and WT mouse brains. "
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    ABSTRACT: Proteinase-activated receptor 2 (PAR2) has recently been identified to be a possible modulator of neurodegeneration. To investigate whether PAR2 plays a role in prion infection, we inoculated PAR2-deficient (PAR2(-/-)) and wild-type (WT) mice intracerebrally with the Rocky Mountain Laboratory strain of scrapie. PAR2(-/-) mice demonstrated a delayed onset of clinical symptoms, including weight loss, and demonstrated moderate but highly significant prolongation of survival over WT controls. Concomitantly, no apparent differences in brain pathology, infectivity or features of brain prion protein between deceased WT and PAR2(-/-) mice were found. Our study suggests that PAR2 deletion modulates dynamics of the disease without gross perturbation of its pathogenesis.
    Full-text · Article · Jun 2012 · Journal of General Virology
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