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Radiation-induced myelosuppression remains a rate-limiting factor of radiotherapy and chemotherapy. Therefore, hematological targets of radiation damage are of great significance for radiation oncology and normal tissue injury and protection. Protection of hematopoietic stem and progenitor cells is pivotal. In order to develop therapeutic targets, it is necessary to understand the mechanisms of stem cell renewal and differentiation. Recent advances in the molecular pathology of hematopoietic stem cells indicate a fine balance between various extrinsic and intrinsic signaling pathways in preserving the self-renewal and proliferative capacity of stem cells. Extrinsic signaling involves a microenvironment niche factors such as neighboring stromal cells, osteoblasts, and adipocytes secreting cytokines, chemokines, and metalloproteinases; intrinsic regulation involves Wnt/hedgehog/Notch signaling, DNA damage-induced epigenetic alterations, telomere shortening, and early senescence. Various drugs including synthetic cytokine mimetics, cytokine stimulators, and DNA repair modulators are being tested as radioprotectants. Colony-stimulating factors are routinely used in clinics to treat neutropenia induced by chemotherapy and radiotherapy as well as to mobilize and expand progenitors used in autologous transplantation. However, toxicity has limited their use. The vitamin E isoforms gamma tocotrienol, a potent free radical scavenger that has displayed promising anticarcinogenic properties, was recently shown to protect bone marrow (BM) from radiation injury and to stimulate hematopoiesis in a murine model. This chapter focuses on the potential targets of radiation damage in BM and speculates on the mechanisms of protection by γ-tocotrienol and how these mechanisms can contribute to radioprotection in general and to protection of BM during chemotherapy and radiotherapy in particular.

Novel pharmacological strategies are urgently needed to prevent or reduce radiation-induced tissue injury. Microvascular injury is a prominent feature of both early and delayed radiation injury. Radiation-induced endothelial dysfunction is believed to play a key role in the pathogenesis of post-irradiation tissue injury. Hence, strategies that could prevent or improve endothelial malfunction are expected to ameliorate the severity of radiation injury. This review focuses on the therapeutic potential of the nitric oxide synthase (NOS) cofactor 5,6,7,8-tetrahydrobiopterin (BH4) as an agent to reduce radiation toxicity. BH4 is an essential cofactor for all NOS enzymes and a critical determinant of NOS function. Inadequate availability of BH4 leads to uncoupling of the NOS enzyme. In an uncoupled state, NOS produces the highly oxidative radicals superoxide and peroxynitrite at the cost of NO. Under conditions of oxidative stress, such as after radiation exposure, BH4 availability might be reduced due to the rapid oxidation of BH4 to 7,8-dihydrobiopterin (7,8-BH2). As a result, free radical-induced BH4 insufficiency may increase the oxidative burden and hamper NO-dependent endothelial function. Given the growing evidence that BH4 depletion and subsequent endothelial NOS uncoupling play a major role in the pathogenesis of endothelial dysfunction in various diseases, there is substantial reason to believe that improving post-irradiation BH4 availability, by either supplementation with it or modulation of its metabolism, might be a novel strategy to reduce radiation-induced endothelial dysfunction and subsequent tissue injury.

The present study aimed at identifying early damage index in the cerebellum following total body irradiation (TBI). Adult male CD2F1 mice (n=18) with or without TBI challenge (8.5 Gy irradiation) were assessed for histology and expression of selected immunohistochemical markers including malondiadehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), protein 53 (p53), vascular endothelial growth factor receptor 2 (VEGF-R2), CD45, calbindin D-28k (CB- 28) and vesicular glutamate transport-2 (VGLUT2) in cerebellar folia II to IV. Compared to sham-controls, TBI significantly increased vacuolization of the molecular layer. At high magnification, deformed fiber-like structures were found along with the empty matrix space. Necrotic Purkinje cells were identified on 3.5 days after TBI, but not on 1 day. Purkinje cell count was reduced significantly 3.5 days after TBI. Compared with sham control, overall intensities of MDA and 8-OHdG immunoreactivities were increased dramatically on 1 and 3.5 days after TBI. Expression of VEGF-R2 was identified to be co-localized with 8-OHdG after TBI. This validates microvessel endothelial damage. The p53 immunoreactivities mainly deposited in the granular layer and microvessels after TBI and co-localization of the p53 with the CD45, both which were found within the microvessels. After TBI, CB28 expression decreased whereas the VGLUT2 expression increased significantly; Purkinje cells exhibited a reduced body size and deformity of dendritic arbor, delineated by CB28 immunoreactivity. Substantial damage to the cerebellum can be detectable as early as 1- 3.5 days in adult animals following sublethal TBI. Oxidative stress, inflammatory response and calcium neurotoxicity-associated mechanisms are involved in radiation-induced neuronal damage.