Effects of expression level of DNA repair-related genes involved in the NHEJ pathway on radiation-induced cognitive impairment

Abstract

Cranial radiation therapy can induce cognitive decline. Impairments of hippocampal neurogenesis are thought to be a paramountly important mechanism underlying radiation-induced cognitive dysfunction. In the mature nervous system, DNA double-strand breaks (DSBs) are mainly repaired by non-homologous end-joining (NHEJ) pathways. It has been demonstrated that NHEJ deficiencies are associated with impaired neurogenesis. In our study, rats were randomly divided into five groups to be irradiated by single doses of 0 (control), 0 (anesthesia control), 2, 10, and 20 Gy, respectively. The cognitive function of the irradiated rats was measured by open field, Morris water maze and passive avoidance tests. Real-time PCR was also used to detect the expression level of DNA DSB repair-related genes involved in the NHEJ pathway, such as XRCC4, XRCC5and XRCC6, in the hippocampus. The influence of different radiation doses on cognitive function in rats was investigated. From the results of the behavior tests, we found that rats receiving 20 Gy irradiation revealed poorer learning and memory, while no significant loss of learning and memory existed in rats receiving irradiation from 0–10 Gy. The real-time PCR and Western blot results showed no significant difference in the expression level of DNA repair-related genes between the 10 and 20 Gy groups, which may help to explain the behavioral results, i.e. DNA damage caused by 0–10 Gy exposure was appropriately repaired, however, damage induced by 20 Gy exceeded the body's maximum DSB repair ability. Ionizing radiation-induced cognitive impairments depend on the radiation dose, and more directly on the body's own ability to repair DNA DSBs via the NHEJ pathway.

The Current Utilization of Cognitive Tests in the Research of Radiation-Induced Cognitive Dysfunction in Rodent Models

“…However, the effect of dose on associative memory has not always been negative. A dosage of 2 Gy/ 1 f was used in Ji's research and Zhang's research, and did not induce any impairment of associative memory [35,51]. In Caceres's research, whole brain irradiation of 5 Gy/1f in Wistar rats improved the associative memory by increasing the latency to enter the dark compartment [34].…”

“…However, the results of Roughton's research were the opposite by decreasing the total time in the center, which indicated that a dosage of 8 Gy/1 f increased the level of anxiety [16]. In addition, the research work undertaken by Zhang and Sun indicated that dosages of 2 Gy/1 f, 10 Gy/1 f, 20 Gy/1 f and 30 Gy/1 f had no effects on the level of anxiety by exerting no influence on the total time or distance spent in the center [35,52]. 33 Gy respectively) were used to induce impairment in cognition.…”

“…The irradiation doses utilized ranged from 2 Gy/1f [35,51] to 30 Gy/1f [51] (BED=3.33 Gy and 330Gy respectively), among which 5 Gy/1 f [34,59] and 10 Gy/1 f [35,51,63] (BED=13.33 Gy and 43.33Gy respectively) were the most frequently used. Decreased latency to enter the dark compartment and increased latency to enter the light compartment indicated impaired associative memory.…”

“…On the contrary, a dosage of 5 Gy/1 f in Oh's research impaired the associative memory of C57BL/6J mice 17 days post-irradiation by decreasing the latency to enter the dark compartment [59]. Larger doses, such as 10 Gy/5 f [63], 10 Gy/1 f [51], 36 Gy/ 8 f [50] and 30 Gy/1f [51] (BED=16.67 Gy, 43.33 Gy, 90 Gy and 330 Gy respectively), induced the impairment of associative memory by decreasing the latency to enter the dark compartment, except that 10 Gy/1 f and 20 Gy/1 f did not change the latency to enter the dark compartment after two months postirradiation [35]. Different fractionations may yield different results in the passive and active avoidance test.…”

“…In each cognitive test, different endpoints are applied to evaluate cognition. In the open field test, a decreased number of crossings and total distance moved represent less locomotor activity [34,35]. In some studies, the number of stops and rearings are used to evaluate locomotor activity [36,37].…”