Protease-activated receptor-2 regulates trypsin expression in the brain and protects against seizures and epileptogenesis

Protease-activated receptor-2 (PAR2), primarily involved in inflammation, is highly expressed in limbic regions of the brain such as the hippocampus. Although extracellular proteolysis is involved in normal and stress-related neuronal plasticity associated with learning, memory and inflammatory disease states, little is known about the role of PAR2 and its physiological agonist, trypsin, in the brain. We show immunohistochemically that trypsin co-localises with tissue plasminogen activator within granular-like structures in PAR2-positive pyramidal neurons of the rat hippocampus. Central administration of the PAR2 peptide agonist, SLIGRL, inhibited electrical amygdala kindling-induced epileptogenesis and abolished kindling-induced over-expression of trypsin in the hippocampus. SLIGRL similarly attenuated kindling when administered subcutaneously. Non-enzymatic activation of neuronal PAR2 using SLIGRL may thus activate feedback mechanisms to inhibit the over-production of trypsin and possibly other proteases during brain insults and thereby attenuate pathogenesis. Prophylactic systemic administration of non-proteolytic PAR2 agonists may therefore represent a novel approach to protect against epileptogenic brain insults.