Alkylating agents are commonly used to treat
cancer. Although base excision repair (BER) is a major pathway for repairing
DNA alkylation damage, under certain conditions, the initiation of BER produces toxic repair intermediates that damage healthy tissues. The initiation of BER by the
alkyladenine DNA glycosylase (AAG, a.k.a. MPG) can mediate alkylation-induced cytotoxicity in specific cells in the retina and cerebellum of male mice. Cytotoxicity in both wild-type and Aag-transgenic (AagTg) mice is abrogated in the absence of
Poly(ADP-ribose) polymerase-1 (PARP1). Here, we tested whether
PARP inhibitors can also prevent alkylation-induced
retinal and cerebellar degeneration in male and female WT and AagTg mice. Importantly, we found that WT mice display sex-dependent alkylation-induced
retinal damage (but not cerebellar damage), with WT males being more sensitive than females. Accordingly,
estradiol treatment protects males against alkylation-induced
retinal degeneration. In AagTg male and female mice, the alkylation-induced tissue damage in both the retina and cerebellum is exacerbated and the sex difference in the retina is abolished.
PARP inhibitors, much like Parp1 gene deletion, protect against alkylation-induced AAG-dependent neuronal degeneration in WT and AagTg mice, regardless of the gender, but their efficacy in preventing alkylation-induced neuronal degeneration depends on
PARP inhibitor characteristics and doses. The recent surge in the use of
PARP inhibitors in combination with
cancer chemotherapeutic
alkylating agents might represent a powerful tool for obtaining increased therapeutic efficacy while avoiding the collateral effects of
alkylating agents in healthy tissues.