Amelioration of ionizing radiation induced cell death in lymphocytes redox reaction by Baicalein

The radioprotective, immunomodulatory and anti-tumor properties of a plant derived flavonoid, baicalein were evaluated using in vitro and in vivo model systems. The detailed molecular mechanism of action of baicalein was studied using murine splenic lymphocytes and lymphoma cells.It was observed that baicalein offered complete protection to lymphocytes against 4Gy ionizing radiation (IR) induced cell death. Baicalein induced phosphorylation of ERK, via inhibition of corresponding dual specificity phosphatase MKP3 and nuclear translocation of redox sensitive pro-survival transcription factor Nrf-2. Baicalein administration protected bone marrow cells and splenic lymphocytes against whole body irradiation (WBI 4 Gy) induced cell death. Baicalein administration resulted in significant increase in the frequency of hematopoietic stem cells, rescued mice against (WBI 7.5Gy) induced mortality and induced phosphorylation of Nrf-2 in bonemarrow cells. Interestingly, administration of Nrf-2 inhibitor abolished in vivo radioprotective effects of baicalein. IR induced inflammation contributes to late effects after IR exposure, hence anti-inflammatory property of baicalein was evaluated. It was observed that baicalein suppressed mitogen induced T cell responses in vitro and suppressed graft versus host disease associated mortality. Interestingly, baicalein did not suppress concanavalin A induced NF-KB but suppressed its transactivation by blocking thioredoxin activity. Radioprotector should not offer survival advantage to tumors hence studies were conducted pertaining to tumor radiosensitivity. Tumor radiosensitivity was significantly enhanced by inhibition of ERK or Nrf-2 or thioredoxin. Baicalein induced cell death in murine T cell lymphoma via inhibition of thioredoxin system. This thesis demonstrates the prophylactic radio-protective potential of baicalein and underlying mechanism. (author)