Neuroprotection induced by protease-activated receptor 2 activation is independent of Gq signalling

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Moudio, Serge and Nuthall, Hugh N. and Bushell, Trevor J. (2025) Neuroprotection induced by protease-activated receptor 2 activation is independent of Gq signalling. Brain and Neuroscience Advances. ISSN 2398-2128 (In Press) (https://doi.org/10.1177/23982128251345673)

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Abstract

Protease-activated receptor 2 (PAR2) is proposed to be a novel target for several inflammation-related diseases but the role of PAR2 in the central nervous system remains unclear. PAR2 activation is protective in cell death and excitotoxicity assays whereas examination into the role of PAR2 in vivo has been hindered due to the lack of suitable pharmacological tools. Recently, a small molecule PAR2 activator, AC264613 (AC), was reported to be a potent and selective PAR2 activator that crosses the blood-brain barrier. Furthermore, peptide mimetic molecules e.g. GB88 were developed that were reported to act as PAR2 biased antagonists. Here, we examine their signalling pathways and neuroprotective properties in CNS preparations. AC induced significant increases in intracellular Ca2+ in both neurons and astrocytes of primary hippocampal cultures, whereas in contrast, GB88 induced a small but significant reduction in intracellular Ca2+ in both cell types. However, both AC and GB88 induced receptor internalisation when examined using fluorescently tagged PAR2. Both AC and GB88 did not induce neurotoxicity to organotypic hippocampal slice cultures (OHSCs) when applied alone but reduced neurotoxicity when co-applied with kainate (KA) in excitotoxicity assays. Furthermore, both AC and GB88 reduced neurotoxicity when applied post KA insult indicating they exhibit neuroprotective properties even after excitotoxicity is induced. These data indicate that PAR2 activation is neuroprotective but this is independent of Gq-induced Ca2+ activation. Given that AC crosses the BBB, this highlights its use as a novel tool to examine the protective properties of PAR2 in in vivo models of CNS disorders.

ORCID iDs

Moudio, Serge ORCID logoORCID: https://orcid.org/0000-0002-8983-1323, Nuthall, Hugh N. and Bushell, Trevor J. ORCID logoORCID: https://orcid.org/0000-0003-4145-9670;
CORE (COnnecting REpositories)