In the present study, we investigated the effects of
IL-13, a well-known anti-inflammatory
cytokine, on the
thrombin-treated hippocampus in vivo. NeuN immunohistochemistry and Nissl staining revealed significant loss of hippocampal CA1 neurons upon intrahippocampal injection of
thrombin. This neurotoxicity was accompanied by substantial microglial activation, as evident from OX-42 immunohistochemistry results. In parallel, Western blot analysis and
hydroethidine histochemistry disclosed activation of
NADPH oxidase, generation of
reactive oxygen species, and oxidative damage in the hippocampal CA1 area showing hippocampal
neuron degeneration. Interestingly, immunohistochemical and biochemical experiments showed that intrahippocampal injection of
thrombin increased
IL-13 immunoreactivity and
IL-13 levels as early
as 8 h after
thrombin, reaching a peak at 7 days, which was maintained up to 14 days. Moreover, double-label immunohistochemistry revealed
IL-13 immunoreactivity exclusively in activated microglia. IL-13-neutralizing Abs significantly rescued CA1 hippocampal neurons from
thrombin neurotoxicity. In parallel, neutralization of
IL-13 inhibited activation of
NADPH oxidase,
reactive oxygen species production, and oxidative damage. Additionally,
IL-13 neutralization suppressed the expression of inducible
NO synthase and several proinflammatory
cytokines. To our knowledge, the present study is the first to show that
IL-13 triggers microglial
NADPH oxidase-derived oxidative stress, leading to the degeneration of hippocampal neurons in vivo, as occurs in cases of
Alzheimer's disease.