Mitigation of radiation-induced hematopoietic injury via regulation of cellular MAPK/phosphatase levels and increasing hematopoietic stem cells

• Published in: Free radical biology & medicine 2014-03, Vol.68, p.52-64
• Main Authors: Patwardhan, R.S., Sharma, Deepak, Checker, Rahul, Sandur, Santosh K.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - metabolism; Baicalein; Cell Death - drug effects; Cell Death - radiation effects; Dual Specificity Phosphatase 6 - antagonists & inhibitors; Dual Specificity Phosphatase 6 - metabolism; ERK; Flavanones - administration & dosage; Free radicals; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - radiation effects; Hematopoietic System - metabolism; Hematopoietic System - pathology; Hematopoietic System - radiation effects; Lymphocytes - drug effects; Lymphocytes - radiation effects; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - radiation effects; Mice; MKP3; NF-E2-Related Factor 2 - metabolism; Nrf-2; Phosphorylation - radiation effects; Proto-Oncogene Proteins c-akt - metabolism; Radioprotector; Stem cells; Whole-Body Irradiation
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2013.11.004

Here we describe a novel strategy for mitigation of ionizing radiation-induced hematopoietic syndrome by suppressing the activity of MKP3, resulting in ERK activation and enhanced abundance of hematopoietic stem cells, using the antioxidant flavonoid baicalein (5,6,7-trihydroxyflavone). It offered complete protection to mouse splenic lymphocytes against radiation-induced cell death. Inhibitors of ERK and Nrf-2 could significantly abrogate baicalein-mediated radioprotection in lymphocytes. Baicalein inhibited phosphatase MKP3 and thereby enhanced phosphorylation of ERK and its downstream proteins such as Elk and Nrf-2. It also increased the nuclear levels of Nrf-2 and the mRNA levels of its dependent genes. Importantly, baicalein administration to mice before radiation exposure led to significant recovery of loss of bone marrow cellularity and also inhibited cell death. Administration of baicalein increased the hematopoietic stem cell frequency as measured by side-population assay and also by antibody staining. Further, baicalein offered significant protection against whole-body irradiation (WBI; 7.5Gy)-induced mortality in mice. Interestingly, we found that baicalein works by activating the same target molecules ERK and Nrf-2 both in vitro and in vivo. Finally, administration of all-trans-retinoic acid (inhibitor of Nrf-2) significantly abrogated baicalein-mediated protection against WBI-induced mortality in mice. Thus, in contrast to the generalized conception of antioxidants acting as radioprotectors, we provide a rationale that antioxidants exhibit pleiotropic effects through the activation of multiple cellular signaling pathways. [Display omitted] •Baicalein inhibited ionizing radiation-induced cell death in splenic lymphocytes.•It activated ERK/Nrf-2 by suppressing MKP3 activity and levels.•Baicalein administration rescued mice against radiation-induced mortality.•Administration of baicalein augmented hematopoietic stem cell abundance.•Baicalein-mediated radioprotection of mice was abrogated by an inhibitor of Nrf-2.