Corujo-Ramirez, Ana

Advances in cancer treatment by chemotherapy, radiation, and personalized targeted therapy have significantly improved cancer survivorship. Life extension from chemotherapy is arguably the most accessible non-surgical treatment strategy, but it is accompanied by neurotoxic sequelae that are detrimental to cognitive function in survivors. Using the platinum-based drug cisplatin to model chemotherapy induced cognitive impairments (CICI; also called chemobrain) in mice, we recently identified that elevated hippocampal adenosine A 2A receptor (A 2A R) levels are causally associated with CICI. Although neuroinflammation is a major pathological mechanism underlying CICI, it remains unclear whether A 2A R mediates cisplatin-induced neuroinflammation. To address this knowledge gap, we demonstrate for the first time that cisplatin increases microglial process extension and branching complexity, consistent with a primed, hyper-surveillant morphological phenotype. Remarkably, caffeine, a non-specific A 2A R antagonist and known cognitive enhancer, attenuated the primed microglial morphology caused by cisplatin. Furthermore, we show that caffeine mitigates cisplatin-induced body-weight loss, accelerates physical recovery, and protects against motor dysfunction. We also show that caffeine confers protection against cisplatin potentiated impairments in hippocampal dendritic spine density, neurogenesis, and confers modest memory benefits. Collectively, these results suggest that A 2A R-mediated microglial priming is associated with cognitive dysfunction in chemobrain and A 2A R inhibition by caffeine may represent a strategy to ameliorate the physical and cognitive impairments caused by cisplatin.

Abstract Chemotherapy-induced cognitive impairment (CICI, also termed “chemobrain”) is a major neurotoxic side effect exhibited by a wide range of chemotherapeutic agents. These side effects affect approximately 14 million cancer survivors. More importantly, CICI persists well after cessation of therapy, severely interfering with quality of life. Unfortunately, there is no treatment and novel therapies are urgently needed. Utilizing cisplatin, a platinum-based chemotherapy, to model chemobrain mice in vivo, we have established that cisplatin accelerates the brain aging process thus leading to long-term memory impairment in mice similar to what is clinically reported. We further show that cisplatin causes oxidative DNA damage, mitochondrial defects, impaired neurogenesis, synaptic defects, and increased gliosis in the adult hippocampus, a brain region critical for learning and memory. Mechanistically, our RNA-sequencing and qRT-PCR analysis revealed that cisplatin dramatically increases COX-2 (Ptgs2) expression and its major product, prostaglandin E2 (PGE2) in adult mouse brain and human cortical neurons derived from induced pluripotent stem cells (iPSCs). Similar as cisplatin treatment, the levels of COX-2 expression began to increase at 0.1 µM methotrexate treatment, which significantly increased at 1 µM in human cortical neurons, indicating that COX-2 induction is a common pathogenic mechanism mediating cognitive impairment associated with cisplatin and methotrexate in spite of the fact that these compounds have different mechanisms of action for cancer eradication. Most importantly, NS-398, a selective COX-2 inhibitor, effectively prevents cognitive deficits in mice and reduction in cell viability of human neurons associated with these chemotherapies, without promoting tumor growth or interfering with cisplatin’s anti-tumor activity. Taken together, our findings strongly suggest that COX-2 induction is a main cause of CICI, making COX-2 inhibition a therapeutic target for CICI. Given that COX-2 inhibitors are currently being tested in cancer prevention as well as age-related memory loss in clinical trials, inhibiting COX-2 may have far-reaching therapeutic effects on CICI and cancer treatment, which can be applied quickly, safely, and effectively to clinical trials, in the effort to improve cancer survivor quality of life. Citation Format: Mohammad Abdur Rashid, Jason J. Tang, Ki-Hyun Yoo, Ana Corujo-Ramirez, Sang Hoon Kim, Alfredo Oliveros, Peter Cole, John R. Hawse, Mi-Hyeon Jang. Blockade of the cyclooxygenase-2 prevents chemotherapy-induced cognitive impairments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2694.

Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A 2A receptor (A 2A R) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A 2A R inhibition by the Food and Drug Administration–approved A 2A R antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin’s antitumor activity. Collectively, our study identifies A 2A R signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.

Abstract Cisplatin chemotherapy, although efficacious in resolution of cancer, potentiates cognitive impairments (known as chemobrain) affecting approximately 14 million cancer survivors in the United States. Cisplatin is a frontline chemotherapy used to treat ovarian, testicular, breast and brain cancers. Despite the high prevalence of clinical reports of cognitive impairments during and following chemotherapy, there is little information on how learning/memory are detrimentally affected and no known cure. To elucidate the mechanisms by which chemobrain impairs cognition, we implemented a mouse model resembling intermittent cisplatin chemotherapy in humans. Our preliminary studies revealed that repeated intermittent cisplatin treatment detrimentally affects the structure of neuronal brain cells in the hippocampus, a brain region known for its ability to control learning/memory, emotional behaviors and motor function. Although the molecular pathways vulnerable to cisplatin in the brain remain elusive, gene sequencing from the hippocampus of mice administered cisplatin identified the adenosine A2A receptor (Adora2a) protein was concentrated in elevated quantities in this brain region. Importantly, the Adora2a receptor protein is known for its critical role in learning/memory and has been found to play a role in neurodegenerative conditions. To investigate Adora2a functionality in cisplatin-induced chemobrain, we assessed the efficacy of the non-selective Adora2a antagonist caffeine, in preventing cisplatin-induced cognitive dysfunction. Caffeine was selected as a therapeutic due to its safe pharmacological profile, its universal availability, and low cost. Our translational approach employing the non-selective Adora2a antagonist caffeine, protected against cisplatin-induced body weight deficits and motor dysfunction, both of which are common clinical symptoms of chemotherapy. Interestingly, relative to cisplatin alone, mice treated with caffeine in combination with cisplatin exhibited improved dendritic spine densities in the hippocampus, suggesting improved neuronal morphology by caffeine. Given that Adora2a antagonists are known to enhance anti-tumor activity while also showing neuroprotective promise in neurodegenerative conditions, inhibiting Adora2a during cancer treatment may have far-reaching synergistic effects on quality of life improvement for cancer survivors. Citation Format: Alfredo Oliveros, Ana M. Corujo-Ramirez, Ki-Hyun Yoo, Jason Tang, Danielle Brogren, Mohammad A. Rashid, Yuanhang Liu, Mi-Hyeon Jang. Adora2a inhibition via caffeine as a novel therapeutic target for cisplatin-induced chemobrain [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3115.

Abstract Chemotherapy-induced cognitive impairment (CICI) is often reported as a neurotoxic side effect of chemotherapy. Although CICI has emerged as a significant medical problem, meaningful treatments are not currently available due to a lack of mechanistic understanding underlying CICI pathophysiology. Using the platinum-based chemotherapy cisplatin as a model for CICI, we show here that cisplatin suppresses nicotinamide adenine dinucleotide (NAD+) levels in the adult female mouse brain in vivo and in human cortical neurons derived from induced pluripotent stem cells in vitro. Increasing NAD+ levels through nicotinamide mononucleotide (NMN) administration prevented cisplatin-induced abnormalities in neural progenitor proliferation, neuronal morphogenesis, and cognitive function without affecting tumor growth and antitumor efficacy of cisplatin. Mechanistically, cisplatin inhibited expression of the NAD+ biosynthesis rate-limiting enzyme nicotinamide phosphoribosyl transferase (Nampt). Selective restoration of Nampt expression in adult-born neurons was sufficient to prevent cisplatin-induced defects in dendrite morphogenesis and memory function. Taken together, our findings suggest that aberrant Nampt-mediated NAD+ metabolic pathways may be a key contributor in cisplatin-induced neurogenic impairments, thus causally leading to memory dysfunction. Therefore, increasing NAD+ levels could represent a promising and safe therapeutic strategy for cisplatin-related neurotoxicity. Significance: Increasing NAD+ through NMN supplementation offers a potential therapeutic strategy to safely prevent cisplatin-induced cognitive impairments, thus providing hope for improved quality of life in cancer survivors.