Cancer survivors often experience neuropsychological changes, including cognitive impairment, anxiety, and depression during and after treatment completion. Cancer-related cognitive impairment (CRCI, commonly referred to as “chemobrain” or “chemo fog”) affects a considerable portion of non-central nervous system (non-CNS) adult cancer survivors. Over 60% of patients report experiencing CRCI during treatment, and up to 35% of cancer survivors experience persistent neurological sequelae years after completing chemotherapy (Janelsins et al., 2014). These impairments reduce survivors' health-related quality of life (HRQoL), disrupt activities of daily living, and may reduce adherence to treatment plans (Horowitz et al., 2018). Although many advances have been made in the past 20 years within the fields of cancer neuroscience and cancer survivorship to understand the etiology and biological mechanisms underlying cancer and chemotherapy-related neurological complications, no FDA-approved treatments are available for CRCI (Horowitz et al., 2018; Winkler et al., 2023; Lomeli et al., 2021).

Critical gaps of knowledge in the field of CRCI stem from inequalities based on sex and age, as most pre-clinical studies have been conducted with younger male rodents, even though aging increases the risk of cancer (White et al., 2014). The incidence rates of many cancer types (including breast, ovarian, colon, prostate, and lung) rise during midlife. The majority of cancer patients are diagnosed at ages >60 years (Ahles and Root, 2018). CRCI and poor health-related quality of life (HRQoL) are especially prevalent among women treated for ovarian (Correa and Hess, 2012; Hess et al., 2015) and breast cancer (Whittaker et al., 2022; Wefel et al., 2004). Additionally, cancer-related stress, defined as stress related to cancer diagnosis and treatment, is common and can substantially affect long-term HRQoL. However, the impact of cancer-related stress and the contributions to CRCI in aged pre-clinical models remains understudied (Martins-Klein et al., 2021; Lutgendorf et al., 2013).

Brain-derived neurotrophic factor (BDNF) is a crucial mediator of functional and structural plasticity in the central nervous system (CNS); it plays a vital role in the growth and development of neuronal synapses and hippocampal adult neurogenesis. Reductions in neurogenesis and spine density can alter learning and memory and contribute to neurodegeneration (Colucci-D'Amato et al., 2020). Numerous studies have linked the downregulation of BDNF to the pathogenesis of various neurological disorders, including Alzheimer's disease, mild cognitive impairment (MCI), and depression (Phillips et al., 1991; Arosio et al., 2021; Miranda et al., 2019). In addition, elevated serum BDNF levels have been associated with better cognitive outcomes in healthy older adults. In contrast, lower BDNF levels may underlie age-related synaptic loss and cortical and hippocampal atrophy (Gunstad et al., 2008; Erickson et al., 2010). CRCI clinical studies have linked reductions in blood BDNF levels to elevated risks of cognitive impairment in cancer survivors (Ng et al., 2022; Yap et al., 2020; Jehn et al., 2015; Zimmer et al., 2015). Low BDNF levels have been associated with CRCI in female breast cancer survivors (Yap et al., 2020; Yap et al., 2021). Breast and ovarian cancer are commonly diagnosed in peri-menopausal to menopausal women aged 50–69 years. The median age at diagnosis for female breast and ovarian cancer is 62–63 years (Giaquinto et al., 2022) (Torre et al., 2018). Older patients are at a higher risk of experiencing chemotherapy toxicity than younger patients. Chemotherapy dose reductions, delays, and treatment plan modifications are common in the older cancer patient population to minimize toxicity risks (Hamid et al., 2022). Our current understanding of the mechanisms underlying CRCI using chemotherapy regimens for breast and gynecological malignancies has been based on pre-clinical studies conducted in young adult female rodents (aged 2–4 months). A better understanding of CRCI using sex and age-relevant models is essential for identifying biological pathways and developing clinically relevant therapeutic strategies to improve survivors' quality of life.

Our previous studies showed that cisplatin reduced BDNF expression in primary rat hippocampal neurons (Andres et al., 2014). Cisplatin-induced reductions in dendritic branching, spine density, and neural apoptosis were associated with cognitive impairments in rats (Lomeli et al., 2017; Andres et al., 2014). The reductions in dendritic branching in primary hippocampal neurons were irreversible, even after cisplatin's removal, suggesting that chemotherapy's effects may result in persistent neurological changes after treatment completion (Andres et al., 2014). Enhancement of BDNF has been shown to protect neuronal dendritic integrity and improve cognitive function in models of Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebral ischemic stroke, and chronic stress (Miranda et al., 2019; Blurton-Jones et al., 2009; Li et al., 2022). Ampakines, positive allosteric modulators of the AMPA family of postsynaptic ionotropic glutamate receptors, have been shown to reduce memory impairments and rescue synaptic plasticity in models of aging, Huntington's disease, and other neurological disorders (Seese et al., 2020; Simmons et al., 2011; Simmons et al., 2009; Lauterborn et al., 2016). Recently, BDNF enhancement via riluzole, an FDA-approved treatment for amyotrophic lateral sclerosis (ALS), has been shown to protect against loss of neurogenesis and reverse doxorubicin-induced cognitive dysfunction in adult female mice (Usmani et al., 2023). In this study, we examine the hypothesis that BDNF enhancement may be a pharmacologically plausible strategy to prevent CRCI. The first aim of this study is to describe an aged female rat model of cisplatin-induced CRCI and examine the influence of medical stress and cisplatin on serum BDNF levels and cognitive function. The second aim is to conduct an in vitro screening of the pharmacological agents, riluzole, and ampakines CX546 and CX1739 in primary rat hippocampal neurons to assess their neuroprotective effects against cisplatin-induced morphological damage. Lastly, the third aim is to screen the oncologic safety of these compounds in conjunction with chemotherapy as potential treatments by evaluating their impact on cisplatin's anti-cancer efficacy in human ovarian cancer cell lines.