Matrix-derived inflammatory mediator N-acetyl proline-glycine-proline is neurotoxic and upregulated in brain after ischemic stroke

Jeff W. Hill, Edwin M. Nemoto

N-acetyl proline-glycine-proline (ac-PGP) is a matrix-derived chemokine produced through the proteolytic destruction of collagen by matrix metalloproteinases (MMPs). While upregulation and activation of MMPs and concomitant degradation of the extracellular matrix are known to be associated with neurological injury in ischemic stroke, the production of ac-PGP in stroke brain and its effects on neurons have not been investigated. We examined the effects of ac-PGP on primary cortical neurons and found that it binds neuronal CXCR2 receptors, activates extracellular signal-regulated kinase 1/2 (ERK1/2), and induces apoptosis associated with caspase-3 cleavage in a dose-dependent manner. After transient ischemic stroke in rats, ac-PGP was significantly upregulated in infarcted brain tissue. The production of ac-PGP in brain in ischemia/reperfusion injury and its propensity to induce apoptosis in neurons may link MMP-mediated destruction of the extracellular matrix and opening of the blood-brain barrier to progressive neurodegeneration associated with the initiation and propagation of inflammation. Ac-PGP may be a novel neurotoxic inflammatory mediator involved in sustained inflammation and neurodegeneration in stroke and other neurological disorders associated with activation of MMPs.