Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies

Abstract

Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions.

Keywords: aggression; insulin receptor; major depressive disorder (MDD); myelination; neuroinflammation; oxidative stress.

Figure 1

Pathological molecular pathways of neuroinflammation, myelination and insulin receptor signalling resulting in impaired cognitive control and excessive aggression in patients with depression. Major depression disorder and elevated stress response can be accompanied by neuroinflammation and oxidative stress, which affect brain insulin receptor (IR) signalling and myelination. The autophosphorylation of IR was shown to be highly sensitive to H₂O₂ signalling enhanced by oxidative stress [187]. It may alter IGF-1 signalling, where IGF-1 has neuroprotective and anti-inflammatory effects [299]. IGF-1 also promotes myelination via IRs on oligodendrocytes [214,216]. Impaired myelination might further trigger neuroinflammation as myelin debris, products of neuron elimination, and dysregulation of activity-dependent astrocytes are known to activate microglia and macrophages [300]. In turn, pro-inflammatory cytokines and dysregulation of glia by inflammation negatively affect myelination [301]. Aberrant signal propagation, axon degradation and neuronal death due to a lack of metabolic support from myelin sheaths can impair t brain connectivity, resulting in deficient cognitive control, e.g., disruption of cortical-subcortical connections, and thus contributing to excessive aggression.