Chapter 6 - Neurooxidative and neuronitrosative mechanisms in bipolar disorder: Evidence and implications
Abstract
Bipolar disorder (BD) is a chronic and severe illness, causing serious disability. It presents with neurocognitive impairment both in acute and euthymic phases of illness. Increasing evidence shows brain structural changes involving white matter microstructure and cortical abnormalities in BD, both pointing at alterations at the microstructural and molecular levels as molecular activity and brain structure are known to influence each other. Inflammation and immunological abnormalities may well represent a significant component of the pathophysiology of BD. Emerging evidence indicate that BD may predispose individuals, even at an early age and at a rate of nearly 95% to inflammatory medical comorbidities, encompassing endocrine, autoimmune, cardiovascular, respiratory and metabolic systems, and chronic infections. A line of data points is at a bidirectional relationship between BD, inflammation, and immune dysfunction where all three may be feeding each other in an interactive way. During peripheral inflammatory conditions, binding of cytokines to cerebral vascular endothelium leads to neuroinflammation and results in simultaneous release of secondary messengers (e.g., nitric oxide (NO)) in large amounts. NO is known to appear in inflammation related damage sites in neurodegenerative processes associated with neuroinflammatory diseases such as Alzheimer’s disease, multiple sclerosis. Converging evidence lists neuroinflammatory/neuroimmune processes, oxidative stress, and formation of reactive oxygen species (ROS), among potential common pathogenic mechanisms underlying various neurodegenerative disorders. Increased oxidative and nitrosative stress and DNA damage have repeatedly been suggested as one of the key mechanisms underlying the high medical comorbidity including several degenerative diseases, vulnerability to various cancers, neurocognitive impairment, and early aging in BD.
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A comparative meta-analysis of peripheral 8-hydroxy-2′-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) levels across mood episodes in bipolar disorder
2023, PsychoneuroendocrinologyOxidative DNA damage has been associated with the pathophysiology of bipolar disorder (BD) as one of the common pathways between increased medical comorbidity and premature aging in BD. Previous evidence shows increased levels of oxidatively induced DNA damage markers, 8-hydroxy-2′-deoxyguanosine (8-OHdG) or its tautomer 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG), in patients with BD in comparison to healthy individuals. With the current research, we aim to analyze data on peripheral (blood or urine) 8-OHdG/8-oxo-dG levels across mood states of BD using a meta-analytical approach.
A literature search was conducted using the databases PubMed, Scopus, and Web of Science to identify eligible studies (January 1989 to July 2022). Relevant studies were systematically reviewed; a random-effects meta-analysis and a meta-regression analysis were conducted.
The current meta-analysis included 12 studies consisting of 808 BD patients (390 in euthymia, 156 in mania, 137 in depression, 16 in mixed episode, 109 not specified) and 563 healthy controls. BD patients that were currently depressed had significantly higher levels of 8-OHdG/8-oxo-dG than healthy controls, while euthymic or manic patients did not differ from healthy controls. A meta-regression analysis showed sex distribution (being female) and older age to be significantly related to increased 8-OHdG/8-oxo-dG levels.
Our findings suggest that 8-OHdG/8-oxo-dG may be a state-related marker of depression in BD and may be affected by older age and female gender.
DNA damage and repair mechanisms in bipolar disorder
2022, Biomarkers in Bipolar DisordersBipolar disorder (BD) is a chronic, severe, and disabling brain disorder, which has been associated with early aging and increased mortality and morbidity. Oxidative stress and related DNA damage are suggested as potential mechanisms underlying the pathophysiology of BD and as contributory mechanisms to the increased medical comorbidity and early aging in BD. More recent data highlight involvement of the DNA repair mechanisms in BD across different states of illness and in response to treatment introducing new potential biomarkers for illness progress and perhaps treatment opportunities.
In this chapter, data on oxidative stress and its relevance to DNA damage within the context of BD are presented. DNA damage and its measurement methods are given to provide the reader the context for variability in findings from different studies; various DNA repair mechanisms are introduced and the base excision repair (BER) mechanism is highlighted as the main mechanism to repair the oxidatively induced DNA damage. Data on BER and BD are presented as a source of new potential markers and finally the future directions for new horizons for the underlying mechanisms and future treatment options of BD are outlined.
