Abstract

The relationship between inflammation and neurogenesis in stroke is currently not well understood. Focal ischemia enhances cell proliferation and neurogenesis in the neurogenic regions including the subventricular zone (SVZ), dentate gyrus (DG) as well as non-neurogenic striatum, cortex in the ischemic hemisphere. Myeloperoxidase (MPO) is a potent oxidizing enzyme secreted during inflammation by activated leukocytes and its enzymatic activity is highly elevated after stroke. In this study, we investigated whether inhibition of MPO activity by a specific irreversible inhibitor, 4-aminobenzoic acid hydrazide (ABAH) or MPO-/- mice can increase neurogenesis after transient middle cerebral artery occlusion (tMCAO) in mice. ABAH administration increased the number of proliferating 5-bromo-2' deoxyuridine (BrdU)-positive cells expressing markers for neural stems cells, astrocytes, neuroprogenitors (Nestin), and neuroblasts (doublecortin) in the ischemic SVZ, anterior SVZ (aSVZ), striatum and cortex. MPO inhibition also increased levels of brain-derived neurotrophic factor (BDNF), phospho-cAMP response element-binding protein (pCREB Ser133), acetylated H3 (AcH3), and NeuN to promote neurogenesis in the ischemic SVZ. ABAH treatment also increased chemokine CXC receptor 4 (CXCR 4) expression in the ischemic SVZ. MPO-deficient mice treated with vehicle or ABAH both showed similar effects on the number of BrdU+ cells in the ischemic hemisphere, demonstrating that ABAH is specific to MPO. Taken together, our results underscore a detrimental role of MPO activity to post-ischemia neurogenesis and that a strategy to inhibit MPO activity can increase cell proliferation and improve neurogenesis after ischemic stroke.