Abstract 4766: Androgen deprivation in mice is linked with cognitive impairment
Authors: Verma Shiv Shankar , Swain Diya , Singh Vaibhav , Shankar Eswar , Lee Zhenghong , Gupta Sanjay 
Published: March 2024

Androgens play a neuroprotective role in maintaining the normal physiological functions of the brain. It also plays a pivotal role in prostate cancer development and progression. Advance-stage prostate cancer treatment is primarily based on androgen deprivation therapy (ADT) that blocks the male hormone testosterone. Moreover, prostate cancer patients who undergo ADT develop cognition impairment such as loss of memory, learning, reasoning, and decision-making. Several studies have shown a positive association between ADT and the risk of cognitive impairment. Currently, there are no clinical markers to identify patients at-risk to ADT-mediated cognition. This demands a need for biomarkers that can help distinguish the vulnerability of patients toward cognitive impairment undergoing ADT. We utilized a in-vivo model to identify biomarkers and the impact of ADT in different regions of the brain. Sixteen-week-old BALB/c mice were gavage 50 mg/kg/day of enzalutamide (mimicking ADT) for 5 days per week (0.2 ml of vehicle consisting of 0.5% methylcellulose and 0.025% Tween 20) for a total of 8 weeks. Control animals received 0.2 ml vehicle per day for the same time period. Mice were observed for behavioral changes post-enzalutamide treatment and brain PET scans were generated. The experiment was terminated, the brain was excised for cortex, cerebellum, and hippocampus, and subjected to mass spectroscopic (MS) analysis. Differentially expressed proteins were identified and validated using qRT-PCR in the mice blood. Enzalutamide treatment for 8 weeks resulted in a modest weight gain and lack of attention and letharginess in these mice. Examination of PET scan and H&E sections of mice brain from control group by light microscopy showed a normal morphology of neurons in the cortex. Enzalutamide treatment showed lower neuron density and signs of neuron injury, as well as cytoplasmic swelling of the astrocytes. MS analysis identified a number of differentially expressed proteins that were validated in the blood. These include ABCB10, CAB, DAZAP1, DCU, DERL1, FBXO, MBNL, PUM2, SERL1, SLC8A3, SLC9A, TCF20, VIM, and ZYXIN. Among them, the expression of SLC8A3, PUM2, and SERL1, were significantly higher than others in the enzalutamide-treated group. Taken together, our findings suggest that enzalutamide treatment in mice leads to cognitive impairment like that observed in men on ADT protocol. Our study highlights that blood-based markers can be developed for ADT-mediated cognition which can lead to the identification of new strategies for prevention and early intervention to improve the quality-of-life of patients suffering with advance-stage prostate cancer.

Citation Format: Shiv Shankar Verma, Diya Swain, Vaibhav Singh, Eswar Shankar, Zhenghong Lee, Sanjay Gupta. Androgen deprivation in mice is linked with cognitive impairment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4766.