Date of Award

2024

Document Type

Thesis

Degree Name

Master of Science in Pharmacology and Toxicology

Department

Pharmacology and Toxicology

First Advisor

Avinash Kumar

Committee Chair and Members

Avinash Kumar, Chari

Eun-Jung Park, Co-Chair

Sasmita Das

Keywords

Cellular damage, Chemobrain, Doxorubicin, Neurite length outgrowth, Neuroinflammatory, SH-SY5Y

Abstract

Chemotherapy-induced cognitive impairment (CICI), commonly referred to as "Chemobrain", represents a significant challenge for cancer survivors, affecting their quality of life by impairing memory, attention, and executive function. This study aims to elucidate the mechanisms behind CICI and evaluate the efficacy of potential neuroprotective agents in mitigating its effects. By focusing and developing in-vitro models, including differentiated SH-SY5Y neuron-like cells, undifferentiated SH- SY5Y neuroblastoma cells and co-culture systems with astrocytoma CCF-STTG1 and human microglia HMC3 cells, this study provides insights into the cellular and molecular alterations induced by chemotherapy and explores the protective capacities of selected compounds.

Chemotherapy drugs such as 5-Fluorouracil (5-FU), Methotrexate (MTX), and Doxorubicin (DOX) were used in this study, they are known for their cytotoxic effects not only on cancer cells but also on healthy neuronal cells, contributing to the development of CICI. To investigates the response of both differentiated and undifferentiated SH-SY5Y cells to these drugs, highlighting the impact of chemotherapy on cell viability, apoptosis, and neurite outgrowth. The differentiation of SH-SY5Y cells into a more mature neuron-like phenotype induced by retinoic acid (RA) is examined for its potential to confer resistance against chemotherapy-induced cytotoxicity.

Four compounds with the potential neuroprotective effects were evaluated: LM22A-4, ibudilast, ebselen, and resveratrol. Through a series of assays measuring cell viability, inflammation markers, and neurite outgrowth, the research assesses the ability of these agents to counteract the detrimental effects of chemotherapy drugs. Among these, ibudilast emerges as a particularly promising candidate, demonstrating significant protective effects against DOX-induced cytotoxicity and the ability to promote neuronal health and functionality.

Using co-culture systems can reveal the complex interactions between neuronal and glial cells in the presence of chemotherapy and neuroprotective compounds. This approach shows the differential sensitivities and adaptive responses of cells to treatment, underscoring the importance of the cellular microenvironment in mediating the effects of chemotherapy and the potential benefits of neuroprotection.

In addition to cytotoxicity assays, this study explores the production of inflammatory cytokines such as TNF-α and IL-1β, investigating the role of ibudilast in modulating the inflammatory response to chemotherapy. The findings suggest that ibudilast not only protects neuronal cells from direct cytotoxic effects but also reduces inflammation, potentially alleviating one of the pathways through which CICI develops.

Furthermore, this research highlights the capacity of ibudilast to encourage neurite outgrowth in SH-SY5Y cells exposed to DOX, indicating its potential to support neuronal differentiation and network formation. The ibudilast's action in neuroprotection and the promotion of neurite outgrowth, offering a promising avenue for addressing the symptoms of Chemobrain.

In conclusion, this thesis contributes critical insights into the pathophysiology of CICI and the search for effective neuroprotective strategies. The findings make known the potential of ibudilast as a multifaceted agent capable of combating the neurological side effects of chemotherapy, offering hope for improved interventions to enhance the cognitive well-being of cancer survivors. Future research should focus on validating these in-vitro results through in-vivo studies and maybe clinical trials, exploring the drug's pharmacokinetics, dosing, safety profile, and impact on cognitive functions in cancer patients, thereby paving the way for the development of comprehensive treatment to address both cancer and its cognitive sequelae.

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