Osteopontin mediates neuroprotection via inhibition of inducible nitric oxide synthase

Abstract

Neurodegeneration following ischemic stroke extends from the ischemic infarct to nonischemic subcortical regions such as the ipsilateral thalamus. At both sites, inflammation with activation of resident microglia/brain macrophage ensues and may exacerbate the degenerative process. Osteopontin (OPN) is a macrophage-derived secreted glycoprotein with cytokine-like and chemoattractant properties mediated via RGD-binding integrin receptors and CD44. OPN exerts proinflammatory effects in autoimmune conditions, but also participates in beneficial wound healing responses. Here, we addressed the role of OPN in ischemic brain injury using OPN knock-out (KO) mice in models of cortical stroke. Compared to wild-type (WT) animals, OPN KO mice exhibited unaltered infarct development at the primary injury site but greatly increased secondary neurodegeneration of the ipsilateral thalamus. Thalamic neurodegeneration in OPN-deficient mice was associated with excessive microglia activation and inflammatory gene expression and could be attenuated via pharmacologic blockade of the inducible nitric oxide synthase (iNOS). Thus, OPN provided neuroprotection through down-regulation of microglia activation and iNOS. OPN-dependent pathways may represent a new target of neuroprotective therapy in neurodegenerative diseases and stroke.