Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo.

Irradiation-induced brain injury, leading to cognitive impairment several months to years after whole brain irradiation (WBI) therapy, is a common health problem in patients with primary or metastatic brain tumor and greatly impairs quality of life for tumor survivors. Recently, it has been demonstrated that a rapid and sustained increase in activated microglia following WBI led to a chronic inflammatory response and a corresponding decrease in hippocampal neurogenesis. Tamoxifen, serving as a radiosensitizer and a useful agent in combination therapy of glioma, has been found to exert anti-inflammatory response both in cultured microglial cells and in a spinal cord injury model. In the present study, we investigated whether tamoxifen alleviated inflammatory damage seen in the irradiated microglia in vitro and in the irradiated brain. Irradiating BV-2 cells (a murine microglial cell line) with various radiation doses (2-10 Gy) led to the increase in IL-1 beta and TNF-alpha expression determined by ELISA, and the conditioned culture medium of irradiated microglia with 10 Gy radiation dose initiated astroglial activation and decreased the number of neuronal cells in vitro. Incubation BV-2 cells with tamoxifen (1 microM) for 45 min significantly inhibited the radiation-induced microglial inflammatory response. In the irradiated brain, WBI induced the breakdown of the blood-brain barrier permeability at day 1 post irradiation and tissue edema formation at day 3 post-radiation. Furthermore, WBI led to microglial activation and reactive astrogliosis in the cerebral cortex and neuronal apoptosis in the CA1 hippocampus at day 3 post-radiation. Tamoxifen administration (i.p., 5 mg/kg) immediately post radiation reduced the irradiation-induced brain damage after WBI. Taken together, these data support that tamoxifen can decrease the irradiation-induced brain damage via attenuating the microglial inflammatory response.