Common cancer treatments targeting DNA double strand breaks affect long-term memory and relate to immediate early gene expression in a sex-dependent manner
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Sydney Weber Boutros1, Destine Krenik1, Sarah Holden1, Vivek K. Unni2,3,4 and Jacob Raber1,2,5,6,7
1 Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239, USA
2 Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA
3 Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR 97239, USA
4 OHSU Parkinson Center, Oregon Health and Science University, Portland, OR 97239, USA
5 Department of Psychiatry, Oregon Health and Science University, Portland, OR 97239, USA
6 Department of Radiation Medicine, Oregon Health and Science University, Portland, OR 97239, USA
7 Division of Neuroscience, The Oregon National Primate Research Center, Oregon Health and Science University, Portland, OR 97239, USA
Keywords: amifostine; etoposide; double strand breaks; memory; sex
Abbreviations: DSBs: Double strand breaks; IEGs: immediate early genes;
Received: September 06, 2021 Accepted: January 10, 2022 Published: January 24, 2022
DNA double strand breaks (DSBs) have been highly studied in the context of cancers, as DSBs can lead to apoptosis or tumorigenesis. Several pharmaceuticals are widely used to target DSBs during cancer therapy. Amifostine (WR-2721) and etoposide are two commonly used drugs: amifostine reduces DSBs, whereas etoposide increases DSBs. Recently, a novel role for DSBs in immediate early gene expression, learning, and memory has been suggested. Neither amifostine nor etoposide have been assessed for their effects on learning and memory without confounding factors. Moreover, sex-dependent effects of these drugs have not been reported. We administered amifostine or etoposide to 3–4-month-old male and female C57Bl/6J mice before or after training in fear conditioning and assessed learning, memory, and immediate early genes. We observed sex-dependent baseline and drug-induced differences, with females expressing higher cFos and FosB levels than males. These were affected by both amifostine and etoposide. Post-training injections of amifostine affected long-term contextual fear memory; etoposide affected contextual and cued fear memory. These data support the hypothesis that DSBs contribute to learning and memory, and that these could play a part in cognitive side effects during common treatment regimens. The sex-dependent effects also highlight an important factor when considering treatment plans.
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