Elucidating The Mechanisms Underlying Neurocognitive Dysfunction in Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder characterized by persistent airflow limitation and both lung and systemic inflammation. In Australia, 2021, an approximate $832 million was spent on COPD associated costs and the fast-growing disease accounted for approximately 4% of all deaths. The primary cause of COPD in developing countries is primarily due to air pollution, but in developed countries, cigarette smoking (CS) takes the lead. COPD is often accompanied by multiple comorbidities that can significantly impact disease progression, quality of life, and overall prognosis. These comorbidities may be arising due to shared risk factors, systemic inflammation, and oxidative stress. The chronic systemic inflammation seen in COPD is hypothesised to contribute to extrapulmonary conditions including osteoporosis, kidney failure, diabetes mellitus, metabolic disease, musculoskeletal dysfunction, cardiovascular dysfunction, endothelial dysfunction and atherosclerosis, increasing the risk of heart attacks and strokes.

Patients with COPD also frequently experience neurocognitive decline, affecting memory, attention, executive function, and processing speed. This impairment is theorised to result from chronic hypoxia, systemic inflammation, vascular damage, and/or oxidative stress, all of which contribute to structural and functional changes in the brain. While emerging evidence suggests a significant link between COPD and neurocognitive impairment, the molecular mechanisms underlying the comorbidity is unknown. Chronic inflammation and oxidative stress are hallmarks of COPD and may be contributing to neurocognitive decline by affecting neuroinflammation, neurogenesis, and synaptogenesis. Persistent low-grade inflammation, characterized by elevated levels of cytokines such as tumour necrosis factoralpha (TNF-α) and interleukin-6 (IL-6), has been linked to neuronal injury and neurocognitive decline. Inflammation contributes to vascular dysfunction, increasing the risk of cerebrovascular diseases such as small vessel disease and stroke, which further exacerbate neurocognitive deficits. Additionally, oxidative stress resulting from chronic inflammation and environmental exposures, such as smoking, accelerates neuronal damage and brain aging. Structural brain changes have also been observed in COPD patients using neuroimaging techniques. Studies have shown reductions in grey matter volume, particularly in areas related to neurocognition, such as the hippocampus, prefrontal cortex, and temporal lobes. These brain alterations correlate with poorer performance on neurocognitive tests assessing memory, problem-solving, and attention. White matter abnormalities, including lesions and decreased connectivity between brain regions, have also been reported, further contributing to neurocognitive dysfunction. The presence of these brain changes suggests that COPD-related neurocognitive impairment is not merely a transient phenomenon but may be part of a progressive neurodegenerative process.

The clinical implications of neurocognitive dysfunction in COPD are profound. Neurocognitive decline may contribute to social withdrawal, depression, and reduced quality of life, further compounding the burden of COPD. Patients with more severe neurocognitive impairment may also struggle with decision-making and self-care, increasing their dependence on caregivers and healthcare resources. Additionally, neurocognitive impairment can reduce a patient’s ability to adhere to complex treatment regimens, including medication management, inhaler techniques, and pulmonary rehabilitation programs. This can lead to worsening disease control, increased hospitalizations, and higher mortality rates.

Apocynin and ebselen are two compounds with significant antioxidant and antiinflammatory properties, making them promising candidates for various disease treatments, particularly those involving oxidative stress-related pathologies. Both compounds target different mechanisms of oxidative damage, with apocynin primarily acting as an NADPH oxidase (NOX) inhibitor and ebselen functioning as a glutathione peroxidase (GPx) mimetic. Due to their unique pharmacological properties, these compounds have been investigated for potential therapeutic applications in conditions such as COPD, neurodegenerative disorders, cardiovascular diseases, and cancer. The therapeutic applications of both apocynin and ebselen continue to be a subject of extensive research. In COPD, apocynin’s ability to reduce airway inflammation and oxidative damage offers a potential strategy to alleviate disease progression. Similarly, ebselen’s neuroprotective properties have gained attention in treating neurological disorders linked to oxidative stress and inflammation. However, despite their promising pharmacological profiles, challenges remain regarding bioavailability, long-term safety, and clinical efficacy in humans. Future studies focusing on optimizing their formulations, delivery methods, and understanding their precise mechanisms of action could pave the way for their inclusion in mainstream medical therapies.

In summary, this thesis explored the mechanisms underlying COPD-related neurocognitive dysfunction, with a focus on inflammation and oxidative stress. CS induced- COPD in mice exhibited a phenotype closely resembling clinical quantitative traits following 8 weeks and 24 weeks of full body CS exposure. This phenotype included pulmonary and systemic inflammation, along with inflammatory gene expression. This model also presented with translatable neurocognitive dysfunction in the form of spatial, recognition, and social memory deficits. Impacts of CS were also seen on neuroinflammation, neurogenesis, and synaptogenesis in specific brain regions. Apocynin was administered prophylactically to determine molecular mechanisms underlying COPD associated neurocognitive dysfunction and to understand its preventative potential. Ebselen was administered therapeutically once disease was established to determine its curative potential. Both treatments revealed insights into the mechanisms at play and suggest promise in targeting the oxidative stress pathway to alleviate the neurocognitive health burden associated with COPD.