Itaconate: A promising precursor for treatment of neuroinflammation associated depression

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Abstract

Neuroinflammation triggers the production of inflammatory factors, influences neuron generation and synaptic plasticity, thus playing an important role in the pathogenesis of depression and becoming an important direction of depression prevention and treatment. Itaconate is a metabolite secreted by macrophages in immunomodulatory responses, that has potent immunomodulatory effects and has been proven to exert anti-inflammatory effects in a variety of diseases. Microglia are mononuclear macrophages that reside in the central nervous system (CNS), and may be the source of endogenous itaconate in the brain. Itaconate can directly inhibit succinate dehydrogenase (SDH), reduce the production of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), activate nuclear factor erythroid-2 related factor 2 (Nrf2), and block glycolysis, and thereby improving the depressive symptoms associated with the above mechanisms. Notably, itaconate also indirectly ameliorates the depressive symptoms associated with some inflammatory diseases. With the optimization of the structure and the development of new delivery systems, the application value and therapeutic potential of itaconate have been significantly improved. Dimethyl itaconate (DI) and 4-octyl itaconate (4-OI), cell-permeable derivatives of itaconate, are more suitable for crossing the blood-brain barrier (BBB), exhibiting therapeutic effects in the research of multiple diseases. This article provides an overview of the immunomodulatory effects of itaconate and its potential therapeutic efficacy in inflammatory depression, focusing on the promising application of itaconate as a precursor of antidepressants.

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How mitochondria produce reactive oxygen species

Michael P. Murphy (2008)

The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2 •−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2 •− production within the matrix of mammalian mitochondria. The flux of O2 •− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2 •− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2 •− production is far lower. The generation of O2 •− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2 •− generation by mitochondria in vivo from O2 •−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2 •− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.

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Gout-associated uric acid crystals activate the NALP3 inflammasome.

Fabio Martinon, Virginie Pétrilli, Annick Mayor … (2006)

Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a 'danger signal' released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1beta activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1beta receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.

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Microglia and macrophages in brain homeostasis and disease

Qingyun Li, Ben A. Barres (2017)

Microglia and non-parenchymal macrophages in the brain are mononuclear phagocytes that are increasingly recognized to be essential players in the development, homeostasis and diseases of the central nervous system. With the availability of new genetic, molecular and pharmacological tools, considerable advances have been made towards our understanding of the embryonic origins, developmental programmes and functions of these cells. These exciting discoveries, some of which are still controversial, also raise many new questions, which makes brain macrophage biology a fast-growing field at the intersection of neuroscience and immunology. Here, we review the current knowledge of how and where brain macrophages are generated, with a focus on parenchymal microglia. We also discuss their normal functions during development and homeostasis, the disturbance of which may lead to various neurodegenerative and neuropsychiatric diseases.