ATM Kinase Small Molecule Inhibitors Prevent Radiation-Induced Apoptosis of Mouse Neurons In Vivo.

ATM kinase is becoming an important therapeutic target for tumor radiosensitization. Radiation is known to cause neuro-inflammation and neurodegeneration; however, the effects of small molecule ATM inhibitors (ATMi's) and radiation on normal tissue, including healthy brain, are largely unexplored. Therefore, we examined the mouse CNS after ATMi radiosensitization with a focus on the fate of neurons. We used several approaches to assess the effects on the DNA damage response (DDR) and apoptosis of neurons using immunostaining. In vivo, a significant decrease in viable neurons and increase in degenerating neurons and apoptosis was observed in mice treated with radiation alone. On the other hand, an ATMi alone had little to no effect on neuron viability and did not induce apoptosis. Importantly, the ATMi's did not further increase radiation toxicity. In fact, multiplex immunostaining showed that a clinical candidate ATMi (AZD1390) protected mouse neurons from apoptosis by 90% at 4 h after radiation. We speculate that the lack of toxicity to neurons is due to a normal ATM-p53 response that, if blocked transiently with an ATMi, is protective. Altogether, in line with previous work using ATM knockout mice, we provide evidence that ATM kinase inhibition using small molecules does not add to neuronal radiation toxicity, and might, in fact, protect them from radiation-induced apoptosis at least in the short term.