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.