Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation

Abstract

Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in cancer survivors. Oxidative stress is considered a major cause of tissue injury from irradiation. However, in an earlier study mice deficient in the antioxidant enzyme extracellular superoxide dismutase (EC-SOD KO) showed reduced sensitivity to radiation-induced defects in hippocampal functions. To further dissect the role of EC-SOD in neurogenesis and in response to irradiation, we generated a bigenic EC-SOD mouse model (OE mice) that expressed high levels of EC-SOD in mature neurons in an otherwise EC-SOD-deficient environment. EC-SOD deficiency was associated with reduced progenitor cell proliferation in the subgranular zone of dentate gyrus in KO and OE mice. However, high levels of EC-SOD in the granule cell layer supported normal maturation of newborn neurons in OE mice. Following irradiation, wild-type mice showed reduced hippocampal neurogenesis, reduced dendritic spine densities, and defects in cognitive functions. OE and KO mice, on the other hand, were largely unaffected, and the mice performed normally in neurocognitive tests. Although the resulting hippocampalrelated functions were similar in OE and KO mice following cranial irradiation, molecular analyses suggested that they may be governed by different mechanisms: whereas neurotrophic factors may influence radiation responses in OE mice, dendritic maintenance may be important in the KO environment. Taken together, our data suggest that EC-SOD plays an important role in all stages of hippocampal neurogenesis and its associated cognitive functions, and that highlevel EC-SOD may provide protection against irradiation-related defects in hippocampal functions.

Cranial irradiation compromises neuronal architecture in the hippocampus

“…A recent study has reported irradiation to reduce dendritic spine density, an effect that could be ameliorated by manipulating the oxidative microenvironment (36). The capability of irradiation to induce an acute and persistent oxidative stress in vitro and in vivo (11) suggest changes in the microenvironmental redox state may play a role in the regulation of spine density and morphology.…”

Oxidative Stress and Adult Neurogenesis

“…Notably, the deficiency of different SOD family members (e.g., CuZnSOD, MnSOD and EC-SOD) also varies the effects of cranial irradiation [8,27,29,46]. Future studies are yet required to examine these effects at cellular levels to understand the direct contribution of these SODs to adult neurogenesis upon oxidative stress; moreover, specific pharmacological tools against different SODs will provide additional evidences for their different functions in NSCs/NPCs [10].…”

“…On the other hand, boosting SOD function or overexpression of SOD could act as Bneuroprotection^upon cranial irradiation, and preserve the cognition function dependent on hippocampus [46]. Interestingly, the SOD overexpression antagonizes the ageing induced spatial memory decreases, but did not prevent the ageing-related decline in neurogenesis in aged mice [11].…”

PRDX6 inhibits neurogenesis of neural precursor cells through downregulation of wdfy1 mediated TLR4 signal

“…Antioxidant reduces the deleterious activity of oxidative stress and potentially delays the development of neurodegenerative disease, the study of antioxidant enzyme in neurogenesis is very important for prevention of the development of neurodegenerative disease. The recent finding showed that when examined at 3-4 months of age, genetic deficiency of extracellular superoxide dismutase (SOD) was associated with a significant suppression of baseline neurogenesis and impaired hippocampal-dependent cognitive functions (Zou et al, 2012). Other study also demonstrated that lack of extracellular SOD in the microenvironment impacts radiation-induced changes in transgenic mice compared with non-tg mice.…”