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

Area of Science:

• Neuroscience
• Oncology
• Radiotherapy

Background:

• ATM kinase is a therapeutic target for tumor radiosensitization.
• Radiation can cause neuro-inflammation and neurodegeneration.
• Effects of ATM inhibitors (ATMi) on healthy brain tissue are largely unknown.

Purpose of the Study:

• To investigate the impact of ATMi combined with radiation on the central nervous system (CNS), specifically focusing on neuronal fate.
• To assess DNA damage response (DDR) and apoptosis in neurons following ATMi and radiation treatment.

Main Methods:

• In vivo studies using mice.
• Immunostaining techniques to assess neuronal viability, degeneration, and apoptosis.
• Multiplex immunostaining to evaluate the effect of a clinical candidate ATMi (AZD1390).

Main Results:

• Radiation alone significantly decreased viable neurons and increased neuronal degeneration and apoptosis.
• ATMi alone had minimal impact on neuron viability or apoptosis.
• ATMi did not exacerbate radiation-induced toxicity.
• AZD1390 protected mouse neurons from apoptosis by 90% at 4 hours post-radiation.

Conclusions:

• ATM kinase inhibition with small molecules does not increase neuronal radiation toxicity.
• ATM inhibition may offer short-term protection against radiation-induced neuronal apoptosis.
• Transient ATM blockade might be protective due to a normal ATM-p53 response.