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.

Maternal Chronic Ultrasound Stress Provokes Immune Activation and Behavioral Deficits in the Offspring: A Mouse Model of Neurodevelopmental Pathology

“…The present study demonstrated that chronic exposure to unpredictably alternating ultrasound frequencies, that are naturally emitted by rodents to communicate with conspecifics, is capable of inducing depressive syndrome in female mice, associated with systemic pro-inflammatory changes, and eliciting behavioral deficits in offspring. The present data are in accordance with earlier demonstrated findings in males that 21 days of exposure of BALB/c mice to unpredictably alternating frequencies of ultrasound between the ranges of 20-25 and 25-45 Hz led to decreased sucrose intake, a sign of anhedonia in rodents and increased anxiety-like behavior, as shown by decreased time spent in the center of the open field and open arms in the elevated plus maze [29,37]. Notably, here we demonstrated that ultrasound exposure causes pro-inflammatory changes locally in the hippocampus of dams and systemically in the blood, suggesting a profound pro-inflammatory effect of ultrasound stress.…”

“…Additionally, the overexpression of GSK-3β in the hippocampus, that we revealed in pregnant dams, is known to be a marker of distress and depressive syndrome [42]. In this paper, we report an over-expression of GSK-3β, IL-1β, and IL-6 mRNA in the hippocampus of ultrasound-exposed females, which is similar to the changes found in males [29,30,37].…”

“…The ultrasound exposure in male mice was associated with upregulated corticosterone level [30], activated hippocampal microglia, upregulated IL-1β and IL-6 locally in the hippocampus and in systemic circulation [30], and increased content of a marker of oxidative stress protein carbonyl in limbic structures [29]. Notably, ultrasound-exposed male mice developed prominent depressive-like and anxietylike behavioral changes [29][30][31]37,38] that were counteracted by chronic dosing with the classic antidepressant fluoxetine [39].…”

Association between triglyceride glucose index and depression in hypertensive population

“…Brain tissue is extremely high in oxygen consumption and has weak antioxidant capacity. Brain cell membranes are abundant in lipid components, contain a large number of metal ions, and are important sites for oxidative stress 44,45 . An elevated TyG index significantly exacerbates oxidative stress, which produces large amounts of free radicals that can damage brain tissue, eventually leading to depression 46–48 .…”

“…Brain cell membranes are abundant in lipid components, contain a large number of metal ions, and are important sites for oxidative stress. 44,45 An elevated TyG index significantly exacerbates oxidative stress, which produces large amounts of free radicals that can damage brain tissue, eventually leading to depression. [46][47][48] In addition, oxidative stress can damage the structure and function of mitochondria, which subsequently leads to impairment of the mitochondrial respiratory chain, reduction of ATP synthesis, and disruption of cellular energy metabolism.…”