The brain can be exposed to ionizing irradiation during cancer treatment, and the radiation dose that can be administered safely is dictated by the tolerance of normal tissues surrounding the tumor. Cranial irradiation can induce cognitive impairments that involve the hippocampus, a structure critical for learning and memory. The pathogenesis of cognitive impairment is poorly understood, but there are suggestions of a mechanistic link between such injury and altered hippocampal neurogenesis and/or disruption of neuronal function. Recent studies show that environmental influences such as oxidative stress are involved, suggesting that reactive oxygen species (ROS) may be critical environmental cues for the control of precursor cell survival and differentiation. Thus, oxidative stress and the maintenance of redox homeostasis may play an important role in altered neurogenesis and cognitive impairment after irradiation. The superoxide dismutase (SOD) isoforms mitigate the physiological and pathological effects of ROS. While the specific roles of the SODs are not completely understood, the extracellular isoform (EC-SOD, SOD3) has been shown to be associated with cognitive functions associated with the hippocampus. Alterations in EC- SOD expression impair learning, and hippocampal neurogenesis is reduced in animals deficient in EC-SOD (i.e., EC-SOD knockout (KO) mice). Additionally, when EC-SOD KO mice are exposed to a modest dose of x- rays, an expected decrease in neurogenesis does not occur. Thus, we hypothesize that an alteration in redox homeostasis can have beneficial effects in the context of radiation response in neurogenic populations. To understand how this protective effect works, and if it can ultimately be used to influence potential adverse effects of irradiation in patients, we will need to address issues related to redox homeostasis in the intact animal. Those issues deemed particularly important in this context include the determination of: a) whether EC-SOD deficiency can be turned on or off to affect the protective effects (Aim 1);b) if the protective effect changes with different degrees of oxidative insult (i.e. radiation dose) (Aim 2);c) if there are functional consequences (behavior) of EC-SOD deficiency after irradiation (Aim 3);d) if the protective effect is mediated by the presence of increased numbers endogenous inflammatory cells (microglia) (Aim 4);and e) if the protective effect is due to site specific (neuronal, endothelial) or systemic deficiency of EC-SOD (Aim 5). To address our hypothesis we have developed unique animal models in which we can selectively regulate the temporal expression of EC-SOD. The quantitative assessment of radiation effects will include quantification of neurogenesis, behavioral performance and a molecular determinant associated with learning and memory (the immediate early gene Arc). The ability to quantify and inter-relate these endpoints will provide novel insight about radiation brain injury, and may ultimately contribute to the development of strategies or approaches for the management of a very serious complication of cranial irradiation.

Public Health Relevance

Radiation exposure of the brain during cancer treatment can induce cognitive impairments, and often involves environmental influences such as oxidative stress. The manipulation of anti-oxidant molecules in normal brain tissues may impact critical events associated with behavioral performance. The ability to quantify and inter- relate measures of neurogenesis, neuronal activity and behavioral performance in animals deficient in a specific anti-oxidant gene will provide novel insight about radiation brain injury, and may ultimately contribute to the development of strategies or approaches for the management of a very serious complication of cranial irradiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046051-08
Application #
8206565
Study Section
Special Emphasis Panel (ZRG1-ONC-H (03))
Program Officer
Owens, David F
Project Start
2003-04-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
8
Fiscal Year
2012
Total Cost
$354,425
Indirect Cost
$102,765
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Belarbi, Karim; Jopson, Timothy; Arellano, Carla et al. (2013) CCR2 deficiency prevents neuronal dysfunction and cognitive impairments induced by cranial irradiation. Cancer Res 73:1201-10
Zou, Yani; Leu, David; Chui, Jennifer et al. (2013) Effects of altered levels of extracellular superoxide dismutase and irradiation on hippocampal neurogenesis in female mice. Int J Radiat Oncol Biol Phys 87:777-84
Fike, J R (2011) Physiopathology of radiation-induced neurotoxicity. Rev Neurol (Paris) 167:746-50
Raber, Jacob; Villasana, Laura; Rosenberg, Jenna et al. (2011) Irradiation enhances hippocampus-dependent cognition in mice deficient in extracellular superoxide dismutase. Hippocampus 21:72-80
Zou, Yani; Chen, Chih-Hsin; Fike, John R et al. (2009) A new mouse model for temporal- and tissue-specific control of extracellular superoxide dismutase. Genesis 47:142-54
Fishman, Kelly; Baure, Jennifer; Zou, Yani et al. (2009) Radiation-induced reductions in neurogenesis are ameliorated in mice deficient in CuZnSOD or MnSOD. Free Radic Biol Med 47:1459-67
Fike, John R; Rosi, Susanna; Limoli, Charles L (2009) Neural precursor cells and central nervous system radiation sensitivity. Semin Radiat Oncol 19:122-32
Rosi, Susanna; Andres-Mach, Marta; Fishman, Kelly M et al. (2008) Cranial irradiation alters the behaviorally induced immediate-early gene arc (activity-regulated cytoskeleton-associated protein). Cancer Res 68:9763-70
Rola, Radoslaw; Fishman, Kelly; Baure, Jennifer et al. (2008) Hippocampal neurogenesis and neuroinflammation after cranial irradiation with (56)Fe particles. Radiat Res 169:626-32
Andres-Mach, Marta; Rola, Radoslaw; Fike, John R (2008) Radiation effects on neural precursor cells in the dentate gyrus. Cell Tissue Res 331:251-62

Showing the most recent 10 out of 16 publications