Interleukin-4 and Interleukin-13 Exacerbate Neurotoxicity of Prothrombin Kringle-2 in Cortex In Vivo via Oxidative Stress

The present study investigated the effects of activated microglia-derived interleukin-4 (IL-4) and IL-13 on neurodegeneration in prothrombin kringle-2 (pKr-2)-treated rat cortex. pKr-2 was unilaterally injected into the Sprague-Dawley rat cerebral cortex and IL-4 and IL-13 neutralizing antibody was used to block the function of IL-4 and IL-13. Immunohistochemical analysis showed a significant loss of NeuN(+) and Nissl(+) cells and an increase of OX-42(+) cells in the cortex at seven days post pKr-2. The levels of IL-4 and IL-13 expression were upregulated in the activated microglia as early as 12 hours post pKr-2 and sustained up to seven days post pKr-2. Neutralization by IL-4 or IL-13 antibodies (NA) significantly increased neuronal survival in pKr-2-treated rat cortex in vivo by suppressing microglial activation and the production of reactive oxygen species, as analyzed by immunohisotochemistry and hydroethidine histochemistry. These results suggest that IL-4 and IL-13 that were endogenously expressed from reactive microglia may play a critical role on neuronal death by regulating oxidative stress during the neurodegenerative diseases, such as Alzheimer's disease and dementia.