Abstract 5218: Leveraging a PARP inhibitor as neuroprotection against chemotherapy induced cognitive impairments

Abstract Platinum-based (Pt) chemotherapies are lifesaving for many cancers, yet they induce persistent DNA damage and neuroinflammation that can profoundly alter cognitive function, collectively known as chemotherapy-induced cognitive impairments (CICI). The molecular drivers of these long-lasting effects remain mostly unknown, but symptoms include impaired concentration, memory deficits, and declines in speech and motor function this suggesting significant hippocampal vulnerability. Cisplatin, a widely used Pt agent causes extensive DNA crosslinking and robust proinflammatory signaling. Emerging evidence implicates poly (ADP-ribose) polymerase 1 (PARP1) in this process; when persistently activated by cisplatin-induced DNA damage- PARP1 drives metabolic dysfunction, inflammatory amplification, and impaired neuronal repair. PARP1 inhibitors have shown neuroprotective effects in other neurodegenerative disorders, reducing neuroinflammation and delaying functional decline. We hypothesized that excessive PARP1 activation contributes significantly to cisplatin-induced hippocampal dysfunction, and that targeted PARP inhibition could mitigate these neurotoxic cascades and preserve neuronal health. To determine whether the PARP inhibitor niraparib acts as a neuroprotective or rescue agent, we evaluated multiple treatment windows in vitro using mouse neural stem cells (MNSCs) from C57BL/6 mice. Cells were exposed to cisplatin (IC50: 0.4 µM) with niraparib (1 µM) administered pre-, post-, or concurrently. Niraparib significantly improved viability across all time points compared to cisplatin alone (p<0.0001). In primary hippocampal neurons (cisplatin IC50: 0.6 µM), combination treatment markedly increased PSD95 puncta and dendritic branching (p<0.0001), indicating preserved synaptic structure. To ensure that niraparib’s neuroprotection did not dimmish cisplatin’s anticancer efficacy, we tested the same low-dose combination in ID8/MOSEC and SKOV3.ip1 (IC50: 34.11 µM and IC50: 13.5 µM) ovarian cancer cell lines. No increase in viability was observed relative to cisplatin alone, confirming that niraparib did not interfere with cisplatin cytotoxicity. Together, these findings suggest that niraparib mitigates cisplatin-induced neurotoxicity while maintaining anti-cancer activity. Our next phase will evaluate niraparib alongside clinically relevant cisplatin dosing in C57BL/6 mice to assess cognitive outcomes in vivo. This works aims to clarify the mechanisms underlying CICI and identify strategies to improve quality of life and survivorship patients undergoing treatment. Citation Format: Dahlia A. Ordaz, Shashi Jain, Daniela A. Bota. Leveraging a PARP inhibitor as neuroprotection against chemotherapy induced cognitive impairments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5218.