Countermeasures to the impact of cosmic radiation exposure on myocardial mitochondrial function.

Abstract

Space travel increases solar particle radiation exposure to astronauts and this is significantly elevated once travel moves beyond low Earth orbit. This includes γ radiation, as well as a combinations of high energy protons and heavy ions such as 56Fe, 28Si, and 16O.There are distinct differences in the biological response to low‐energy transfer (x‐rays) or high‐energy transfer (High‐LET) (56Fe) events. Airline flight crews are chronically exposed to High‐LET and higher incidents of cancer are reported for these individuals. Much of what we know about the consequences of high‐LET exposure comes from studies of nuclear workers and atom bomb survivors. For flight crews (astronauts), most estimates of galactic radiation exposure have a low fluence rate that is much lower that patients undergoing radiotherapy or the acute exposure of those that survived the A‐bomb. However, the cumulative radiation dose is likely to have long‐term deleterious effects on the health of astronauts. And this risk increases as flight duration is increased.The underlying mechanisms for these elevated risks are unknown, although direct DNA damage and elevated oxidant stress are highly suspected. Given the relatively low fluence rate of exposure it might be possible to manage these deleterious effects using small molecules currently available. To that end we have utilized the FDA approved drug library from MedChem Express (723 drugs) to perform a high throughput screen of cultured cells following exposure to cosmic radiation. The H9c2 cell and RBL‐2H3 mast cell lines were exposed to a total of 75 cGy using a simplified 5‐ion GCR protocol developed by NASA at the NSRL facility at the Brookhaven National Laboratory. Following GCR exposure cells were split onto 96 well test plates and treated for 7 days with vehicle or 10 μM drug. Media and drugs were changed on alternate days. At harvest cells were tested for viability (MTT), oxidant stress (DHE), cellular senescence (ONPG) and mitochondrial function (ATP). Using the non‐drug treated cells as controls, Z‐scores were calculated and a composite score was developed for each drug. The top 160 composite scores were retested following a similar protocol using1 μM of each drug. Within the 160 drugs, 33 are considered to have an anti‐inflammatory capacity. 5 of the eight 5‐HT antagonists considered useful were 5‐HT3 specific. 12 of 25 angiotensin converting enzyme inhibitors or AT1 antagonists were observed to be effective while no AT2 antagonists appeared useful. 10 of 46 drugs indentified as interacting with histamine receptors were deemed effective. 7 of 54 COX inhibitors deemed effective were COX2 but not COX1 inhibitors. Collectively these findings suggest that drugs interacting with GPCR/G coupled proteins that modulate inflammation and anti‐oxidant pathways may be useful in the management of cosmic radiation exposure of long duration flight crews.Support or Funding InformationSupported in part by NASA 80NSSC19K0436