Mechanisms And Therapeutic Interventions Of Heavy Ion Induced Brain Injury

Heavy ion,in nuclear physics,any particle with one or more units of electric charge and a mass exceeding that of the helium-4 nucleus(alpha particle).Heavy ion is majorly applied on radiotherapy of cancer and used for mimicking space radiation for ground-based research.As the development of manned space flight continues,the duration and distance of shuttle missions extend from those in past years.However,it has also increased the risks of central nervous system(CNS)damage which is attributed to exposure to solar particles and cosmic rays.In general,these solar particles and cosmic rays mainly consist of high linear energy transfer(LET)ions such as photons and high(H)atomic number(Z)and high-energy(E)ions.In space,Fe ions are likely the most important component of cosmic rays as they provide the largest contribution to the equivalent dose in the radiation spectrum.For these reasons,Fe ions are ideal for ground-based research into space radiation.On the other hand,there's another important application of heavy ion beam as it can be used for radiotherapy.Owing to a focused dose distribution in addition to highLET and subsequently high relative biological effect,carbon ion radiotherapy in cancer treatment is growing rapidly.However,compared to low-LET ionizing irradiation,high-LET carbon ions,also produce more cytotoxic and genotoxic to normal cells.The brain with highly peroxidizable fatty acids and supraproportional oxygen consumption makes neuronal tissues easily damaged by ionizing radiation.Although modern radiation therapy techniques have eliminated acute and early delayed brain injury as well as most late demyelination and white matter necrosis.However,emerging role of late radiation-induced cognitive impairment affects patient's quality of life.Hence,it is imperative for us to find a resolution for those issues.In first chapter,we demonstrated radiation induced increased expression of 8-OHd G in the hippocampus with immunofluorescence after one-month exposure and also demonstrated that 56 Fe ions have a long-term effect on impairment of spatial learning and memory.These cognitive deficits were shown clearly to correlate with radiation-induced changes in pathology,an increase of oxidative stress and oxidative DNA damage,which were detected in the brain tissue and the hippocampus of mice.In addition,we also found that lipid peroxidation induced by low dose exposure can be eliminated in the brain tissue,but DNA damage and behavioral deficits induced by changes of oxidative stress are still existent and the underlying mechanisms need to be further studied.In this part,findings revealed a linkage between Fe ion radiationinduced oxidative stress and behavioral deficits and this may provide an experimental basis and ideas for further research on CNS protection and risk assessment.In second chapter,our study illustrated that carbon ion irradiation at 4?Gy induced the obvious spatial cognitive impairments,and disrupted the mitochondrial homeostasis and redox balanced,which closely associated with inactivation of NRF2 and PINK1 signaling.However,administration of melatonin upregulated the NRF2-PINK1 signaling and enhanced the crosstalk between NRF2 and PINK1.Moreover,in NRF2+/+ and PINK1+/+ hippocampal neuronal cells,the carbon ion-induced reductions in cell proliferation and survival were stirringly ameliorated.As a result,a carbon ion-caused cognitive deficit was effectively reversed through restoring the mitochondrial functions as well as eradicating the oxidative insults.