Superoxide Dismutase Family of Enzymes in Brain Neurogenesis and Radioprotection

Abstract

The family of superoxide dismutases (SODs) have an almost ubiquitous presence in living organisms. Their importance in maintaining normal cellular functions and fate decisions has been demonstrated in a large number of studies since their discovery in 1968. Studies of pathological conditions resulting from naturally occurring SOD mutations in human populations or from altered SOD levels created in animal models further highlighted the critical roles of SODs in maintaining the redox balance for normal tissue functions. The production of adult-born neurons in the hippocampus is important for the neuronal plasticity of learning and memory, and yet the process is exquisitely sensitive to changes in the redox balance in its microenvironment. Consequently, mutant mice deficient in CuZnSOD or MnSOD showed altered progenitor cell differentiation towards the astroglial, instead of the neuronal, lineage, while EC-SOD deficient mice exhibited a significant reduction in the production of newborn neurons. Similarly, ionizing radiation, even at low doses, led to persistent perturbation of the tissue redox environment and suppression of hippocampal neurogenesis. The defects in hippocampal neurogenesis resulting from EC-SOD deficiency or ionizing irradiation also correlated with impairments in hippocampal-dependent functions of learning and memory. To correct the persistent redox imbalance following irradiation, enhanced EC-SOD levels in mature hippocampal neurons were achieved by transgenic approach. The transgenic mice were able to minimize irradiation-induced suppression of hippocampal neurogenesis and the associated cognitive defects, suggesting that SOD-based antioxidant supplementation may be an efficacious therapeutic approach to CNS defects following ionizing radiation therapy. The new generation Mn-containing porphyrins had been demonstrated to possess high SOD-like activities, and some of them were able to cross the blood brain barrier. Their radioprotective capacity had been demonstrated in a number of tissues in radiation animal models. Application of Mn porphyrins for the preservation of hippocampal neurogenesis and cognitive functions in experimental models will increase their potential relevance towards human radiation therapy of the CNS.