Efeito neuroprotetor da cafeína nos transtornos comportamentais e na resposta inflamatória em camundongos expostos à radiação ionizante no cérebro

Abstract

Introduction: Radiation therapy is one of the main interventions in the control of brain tumors and metastases. Although the benefits of treatment outweigh the risks associated with this practice, radiation can interact with adjacent healthy tissue and compromise the quality of life of the patient after treatment. One of the consequences of this interaction is the induction of chronic inflammatory process that impairs nervous tissue homeostasis contributing to behavioral and cognitive changes. In contrast, caffeine, in several studies related to neurodegenerative diseases, has shown anti-inflammatory potential and the ability to slow the progression of these diseases. Purpose: To evaluate whether continuously administered caffeine is able to mitigate neuroinflammation and behavioral changes in mice with irradiated brains. Methodology: Male C57BL/6 mice were divided into four groups (C- control, I- irradiated, Ca - caffeine, ICa - irradiated + caffeine). Groups I and ICa were irradiated in the brain with a single dose of 10 Gy, using X-ray photons, in the SARRP irradiator (DCR/ UERJ). The Ca and ICa groups received caffeine, administered ad libitum (0.25 g/L) and daily for the entire experimental period. The behavior of the animals was evaluated through the Open Field and Object Recognition tests that were performed from the 15th to the 18th and from the 90th to the 93rd days after irradiation and the beginning of caffeine consumption. After the behavioral tests in the last period, the brains were perfused for immunofluorescence analysis of Iba-1 and TNF-α in the hippocampus region, and plasma was obtained for ELISA analysis of plasma TNF-α. Results: From day 15 to day 17, the locomotor activity in the periphery of the open field of groups I and Ca were lower than that of group C, with the differences being more pronounced in the sessions on days 16 and 17. On day 15, the activity of group ICa was significantly higher than that of the other groups in the first session and showed a marked reduction in the consecutive days. From day 90 to 92, group I showed less activity and no significant differences were observed between the activity of groups C, Ca, ICa. In the object recognition test performed both on day 18 and 93, irradiation promoted a reduction in the exploration of the object whose position was modified. Caffeine treatment mitigated this effect, and the ICa group did not differ from the C and Ca groups, which showed an increase in the percentage of exploration of the object whose position was modified. In the presence of caffeine it was possible to observe a reduction in TNF-α immunolabeling and an increase in Iba-1 immunolabeling, which suggests its capacity to interrupt or mitigate neuroinflammation. Conclusion: Oral and daily caffeine consumption after whole-brain irradiation indicated a significant improvement of neuroinflammation and radioinduced behavioral changes. Behavioral and molecular disturbances were visibly ameliorated in the group that consumed caffeine for 3 months after irradiation. Despite the need for further studies, a possibility of a new pharmacological therapeutic method for the treatment of the side effects caused by ionizing radiation has been opened.