Glymphatic Dysfunction Induced Oxidative Stress and Neuro-Inflammation in Major Depression Disorders

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Abstract

Major Depression disorder (MDD) is a potentially life-threatening mental illness, however, many patients have a poor response to current treatments. Recent studies have suggested that stress- or trauma-induced oxidative stress and inflammation could be important factors involved in the development of MDD, but the mechanisms remain unclear. We showed that the glymphatic system is a recently discovered structure in the brain that may be involved in the clearance of large molecular and cell debris in extracellular space. In addition, the glymphatic system can help with the removal of reactive oxygen species (ROS) and cytokines such as IL-1β and HIF-1α. Glymphatic impairment can lead to ROS accumulation in the microenvironment, inducing cellular injury signaling and activating NLRP3 in microglia to induce inflammation and, thus, many brain diseases, including psychiatric disorders. Therefore, trauma-induced glymphatic impairment could induce oxidative stress and inflammation, and thus MDD. This paper will review recent advances with regard to stress-induced glymphatic system impairment and ROS-mediated inflammation in MDD.

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Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal

Antonio Ayala, Mario F Muñoz, Sandro Argüelles (2014)

Lipid peroxidation can be described generally as a process under which oxidants such as free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid peroxidation has shown its important role in cell biology and human health. Since the early 1970s, the total published research articles on the topic of lipid peroxidation was 98 (1970–1974) and has been increasing at almost 135-fold, by up to 13165 in last 4 years (2010–2013). New discoveries about the involvement in cellular physiology and pathology, as well as the control of lipid peroxidation, continue to emerge every day. Given the enormity of this field, this review focuses on biochemical concepts of lipid peroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting gene expression and promoting cell death. Finally, overviews of in vivo mammalian model systems used to study the lipid peroxidation process, and common pathological processes linked to MDA and 4-HNE are shown.

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Structural and functional features of central nervous system lymphatics

Antoine Louveau, Igor Smirnov, Timothy Keyes … (2015)

One of the characteristics of the CNS is the lack of a classical lymphatic drainage system. Although it is now accepted that the CNS undergoes constant immune surveillance that takes place within the meningeal compartment 1–3 , the mechanisms governing the entrance and exit of immune cells from the CNS remain poorly understood 4–6 . In searching for T cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the CSF, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the CNS. The discovery of the CNS lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.