Interleukin‐4‐mediated oxidative stress is harmful to hippocampal neurons of prothrombin kringle‐2‐ lesioned rat in vivo

Abstract

The present study investigated the effects of reactive microglia/macrophages‐derived interleukin‐4 (IL‐4) on hippocampal neurons in prothrombin kringle‐2 (pKr‐2)‐lesioned rats. pKr‐2 was unilaterally injected into hippocampus in the absence or presence of IL‐4 neutralizing antibody (IL‐4Nab). Immunohistochemical analysis showed a significant loss of Nissl+ and NeuN+ cells and activation of microglia/macrophages (increase in reactive OX‐42+ and OX‐6+ cells) in the hippocampus at 7 days after pKr‐2 injection. The levels of IL‐4 expression were upregulated in the reactive OX‐42+ microglia/macrophages as early as 1 day, maximal at 3 days and maintained up to 7 days after pKr‐2 injection. Treatment with IL‐4Nab significantly increased neuronal survival in pKr‐2‐treated CA1 layer of hippocampus in vivo. Accompanying neuroprotection, IL‐4 neutralization inhibited activation of microglia/macrophages, reactive oxygen species‐derived oxidative damages, production of myeloperoxidase‐ and inducible nitric oxide synthase‐derived reactive nitrogen species and nitrosative damages as analyzed by immunohistochemistry and hydroethidine histochemistry. These results suggest that endogenous IL‐4 expressed on reactive microglia/macrophages mediates oxidative/nitrosative stress and play a critical role on neurodegeneration of hippocampal CA1 layer in vivo.