scholarly journals The Emerging Role of the Double-Edged Impact of Arachidonic Acid- Derived Eicosanoids in the Neuroinflammatory Background of Depression.

2020 ◽  
Vol 19 (2) ◽  
pp. 278-293 ◽  
Author(s):  
Magdalena Regulska ◽  
Magdalena Szuster-Głuszczak ◽  
Ewa Trojan ◽  
Monika Leśkiewicz ◽  
Agnieszka Basta-Kaim
Keyword(s):  
Arachidonic Acid ◽  
Depressive Disorders ◽  
Future Research ◽  
Chronic Neuroinflammation ◽  
Lipid Signalling ◽  
Therapeutic Benefits ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
Future Research Directions ◽  
Anti Inflammatory

: Eicosanoids are arachidonic acid (AA) derivatives belonging to a family of lipid signalling mediators that are engaged in both physiological and pathological processes in the brain. Recently, their implication in the prolonged inflammatory response has become a focus of particular interest because, in contrast to acute inflammation, chronic inflammatory processes within the central nervous system (CNS) are crucial for the development of brain pathologies including depression. The synthesis of eicosanoids is catalysed primarily by cyclooxygenases (COX), which are involved in the production of pro-inflammatory AA metabolites, including prostaglandins and thromboxanes. Moreover, eicosanoid synthesis is catalysed by lipoxygenases (LOXs), which generate both leukotrienes and anti-inflammatory derivatives such as lipoxins. Thus, AA metabolites have double- edged pro-inflammatory and anti-inflammatory, pro-resolving properties, and an imbalance between these metabolites has been proposed as a contributor or even the basis for chronic neuroinflammatory effects. This review focuses on important evidence regarding eicosanoid-related pathways (with special emphasis on prostaglandins and lipoxins) that has added a new layer of complexity to the idea of targeting the double-edged AA-derivative pathways for therapeutic benefits in depression. We also sought to explore future research directions that can support a pro-resolving response to control the balance between eicosanoids and thus to reduce the chronic neuroinflammation that underlies at least a portion of depressive disorders.

scholarly journals Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review

2021 ◽  
pp. 026988112110264
Author(s):  
Emma Kopra ◽  
Valeria Mondelli ◽  
Carmine Pariante ◽  
Naghmeh Nikkheslat
Keyword(s):  
Systematic Review ◽  
Animal Studies ◽  
Bipolar Depression ◽  
Strong Support ◽  
Kynurenine Pathway ◽  
Future Research ◽  
Downstream Effects ◽  
Tnf Α ◽  
The Central Nervous System ◽  
Anti Inflammatory

Background: Ketamine is a novel rapid-acting antidepressant with high efficacy in treatment-resistant patients. Its exact therapeutic mechanisms of action are unclear; however, in recent years its anti-inflammatory properties and subsequent downstream effects on tryptophan (TRP) metabolism have sparked research interest. Aim: This systematic review examined the effect of ketamine on inflammatory markers and TRP–kynurenine (KYN) pathway metabolites in patients with unipolar and bipolar depression and in animal models of depression. Methods: MEDLINE, Embase, and PsycINFO databases were searched on October 2020 (1806 to 2020). Results: Out of 807 initial results, nine human studies and 22 animal studies on rodents met the inclusion criteria. Rodent studies provided strong support for ketamine-induced decreases in pro-inflammatory cytokines, namely in interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α and indicated anti-inflammatory effects on TRP metabolism, including decreases in the enzyme indoleamine 2,3-dioxygenase (IDO). Clinical evidence was less robust with high heterogeneity between sample characteristics, but most experiments demonstrated decreases in peripheral inflammation including in IL-1β, IL-6, and TNF-α. Preliminary support was also found for reduced activation of the neurotoxic arm of the KYN pathway. Conclusion: Ketamine appears to induce anti-inflammatory effects in at least a proportion of depressed patients. Suggestions for future research include investigation of markers in the central nervous system and examination of clinical relevance of inflammatory changes.

Child and Adolescent Depression

Depression ◽  
2019 ◽  
pp. 399-417
Author(s):  
Andrew Diederich ◽  
Jessica M. Jones ◽  
Graham J. Emslie
Keyword(s):  
Children And Adolescents ◽  
Early Onset ◽  
Adolescent Depression ◽  
Depressive Disorders ◽  
Future Research ◽  
Evidence Based ◽  
Research Directions ◽  
Psychosocial Impairment ◽  
Future Research Directions ◽  
Irritable Mood

Early onset depression is prevalent and causes significant morbidity, mortality, and psychosocial impairment. Evidence-based psychosocial and psychopharmacological treatments are available for depressed youth, but many children and adolescents do not receive sufficient treatment. Pediatric and adult depressive disorders involve essentially the same symptoms, with the exception of irritability, as depressed youth may present with irritable mood in the absence of explicit sadness. This chapter examines aspects of depression that are unique to children and adolescents. It focuses on diagnosis and symptomatology, epidemiology, and pharmacological, psychotherapeutic, and other treatments. The chapter also addresses barriers to treatment of early onset depression and future research directions.

scholarly journals Neuroprotective Mechanisms of PPARδ: Modulation of Oxidative Stress and Inflammatory Processes

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Caroline I. Schnegg ◽  
Mike E. Robbins
Keyword(s):  
Energy Homeostasis ◽  
Peroxisome Proliferator ◽  
Cellular Processes ◽  
Wide Range ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
Chronic Injuries ◽  
Neuroprotective Efficacy ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARα,δ, andγ) are ligand-activated transcription factors that regulate a wide range of cellular processes, including inflammation, proliferation, differentiation, metabolism, and energy homeostasis. All three PPAR subtypes have been identified in the central nervous system (CNS) of rodents. While PPARαand PPARγare expressed in more restricted areas of the CNS, PPARδis ubiquitously expressed and is the predominant subtype. Although data regarding PPARδare limited, studies have demonstrated that administration of PPARδagonists confers neuroprotection following various acute and chronic injuries to the CNS, such as stroke, multiple sclerosis, and Alzheimer's disease. The antioxidant and anti-inflammatory properties of PPARδagonists are thought to underly their neuroprotective efficacy. This review will focus on the putative neuroprotective benefits of therapeutically targeting PPARδin the CNS, and specifically, highlight the antioxidant and anti-inflammatory functions of PPARδagonists.

scholarly journals Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 918 ◽  
Author(s):  
Kinga Tóth ◽  
Dorottya Ádám ◽  
Tamás Bíró ◽  
Attila Oláh
Keyword(s):  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
The Body ◽  
Future Research ◽  
Research Directions ◽  
Physiological Processes ◽  
Barrier Formation ◽  
The Central Nervous System ◽  
Future Research Directions ◽  
Pigmentation Disorders

The endocannabinoid system (ECS) has lately been proven to be an important, multifaceted homeostatic regulator, which influences a wide-variety of physiological processes all over the body. Its members, the endocannabinoids (eCBs; e.g., anandamide), the eCB-responsive receptors (e.g., CB1, CB2), as well as the complex enzyme and transporter apparatus involved in the metabolism of the ligands were shown to be expressed in several tissues, including the skin. Although the best studied functions over the ECS are related to the central nervous system and to immune processes, experimental efforts over the last two decades have unambiguously confirmed that cutaneous cannabinoid (“c[ut]annabinoid”) signaling is deeply involved in the maintenance of skin homeostasis, barrier formation and regeneration, and its dysregulation was implicated to contribute to several highly prevalent diseases and disorders, e.g., atopic dermatitis, psoriasis, scleroderma, acne, hair growth and pigmentation disorders, keratin diseases, various tumors, and itch. The current review aims to give an overview of the available skin-relevant endo- and phytocannabinoid literature with a special emphasis on the putative translational potential, and to highlight promising future research directions as well as existing challenges.

scholarly journals Effects of a Novel GPR55 Antagonist on the Arachidonic Acid Cascade in LPS-Activated Primary Microglial Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2503
Author(s):  
Soraya Wilke Saliba ◽  
Franziska Gläser ◽  
Anke Deckers ◽  
Albrecht Keil ◽  
Thomas Hurrle ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Therapeutic Option ◽  
The Novel ◽  
Cns Disorders ◽  
Chronic Neuroinflammation ◽  
The Central Nervous System ◽  
Cox 2 ◽  
G Protein Coupled ◽  
Cox 1

Neuroinflammation is a crucial process to maintain homeostasis in the central nervous system (CNS). However, chronic neuroinflammation is detrimental, and it is described in the pathogenesis of CNS disorders, including Alzheimer’s disease (AD) and depression. This process is characterized by the activation of immune cells, mainly microglia. The role of the orphan G-protein-coupled receptor 55 (GPR55) in inflammation has been reported in different models. However, its role in neuroinflammation in respect to the arachidonic acid (AA) cascade in activated microglia is still lacking of comprehension. Therefore, we synthesized a novel GPR55 antagonist (KIT 10, 0.1–25 µM) and tested its effects on the AA cascade in lipopolysaccharide (LPS, 10 ng / mL)-treated primary rat microglia using Western blot and EIAs. We show here that KIT 10 potently prevented the release of prostaglandin E2 (PGE2), reduced microsomal PGE2 synthase (mPGES-1) and cyclooxygenase-2 (COX-2) synthesis, and inhibited the phosphorylation of Ikappa B-alpha (IκB-α), a crucial upstream step of the inflammation-related nuclear factor-kappaB (NF-κB) signaling pathway. However, no effects were observed on COX-1 and -2 activities and mitogen-activated kinases (MAPK). In summary, the novel GPR55 receptor antagonist KIT 10 reduces neuroinflammatory parameters in microglia by inhibiting the COX-2/PGE2 pathway. Further experiments are necessary to better elucidate its effects and mechanisms. Nevertheless, the modulation of inflammation by GPR55 might be a new therapeutic option to treat CNS disorders with a neuroinflammatory background such as AD or depression.

scholarly journals Flavonoids: modulators of brain function?

2008 ◽  
Vol 99 (E-S1) ◽  
pp. ES60-ES77 ◽  
Author(s):  
Jeremy P. E. Spencer
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Future Research ◽  
Lipid Kinase ◽  
Beneficial Effects ◽  
Sequence Of Events ◽  
Mitogen Activated Protein ◽  
The Central Nervous System ◽  
Future Research Directions ◽  
Neurological Effects

Emerging evidence suggests that dietary phytochemicals, in particular flavonoids, may exert beneficial effects on the central nervous system by protecting neurons against stress-induced injury, by suppressing neuroinflammation and by improving cognitive function. It is likely that flavonoids exert such effects, through selective actions on different components of a number of protein kinase and lipid kinase signalling cascades, such as the phosphatidylinositol-3 kinase (PI3K)/Akt, protein kinase C and mitogen-activated protein kinase (MAPK) pathways. This review explores the potential inhibitory or stimulatory actions of flavonoids within these pathways, and describes how such interactions are likely to underlie neurological effects through their ability to affect the activation state of target molecules and/or by modulating gene expression. Future research directions are outlined in relation to the precise site(s) of action of flavonoids within signalling pathways and the sequence of events that allow them to regulate neuronal function.

Phototherapy for Depressive Disorders: A Review

1989 ◽  
Vol 34 (2) ◽  
pp. 140-147 ◽  
Author(s):  
Raymond W. Lam ◽  
Daniel F. Kripke ◽  
J. Christian Gillin
Keyword(s):  
Effective Treatment ◽  
Empirical Evidence ◽  
Mechanism Of Action ◽  
Depressive Disorders ◽  
Bright Light ◽  
Future Research ◽  
Research Directions ◽  
Seasonal Depression ◽  
Future Research Directions ◽  
Promising Treatment

The use of bright light (phototherapy) for psychiatric disorders has recently generated much interest among researchers and the lay population. The authors review the treatment studies of phototherapy for seasonal and non-seasonal depressive disorders, and the empirical evidence for theories of the psychophysiology of phototherapy. Although its mechanism of action remains to be explained, phototherapy appears to be a safe and effective treatment for seasonal depression and a promising treatment for non-seasonal depression. Further questions and future research directions are presented.

scholarly journals Comparative Review of Microglia and Monocytes in CNS Phagocytosis

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2555
Author(s):  
Megumi Andoh ◽  
Ryuta Koyama
Keyword(s):  
Neural Circuit ◽  
Future Research ◽  
Phagocytic Cells ◽  
Research Directions ◽  
Microglial Phagocytosis ◽  
Neuronal Synapses ◽  
Comparative Review ◽  
The Central Nervous System ◽  
Future Research Directions ◽  
Circuit Function

Macrophages maintain tissue homeostasis by phagocytosing and removing unwanted materials such as dead cells and cell debris. Microglia, the resident macrophages of the central nervous system (CNS), are no exception. In addition, a series of recent studies have shown that microglia phagocytose the neuronal synapses that form the basis of neural circuit function. This discovery has spurred many neuroscientists to study microglia. Importantly, in the CNS parenchyma, not only microglia but also blood-derived monocytes, which essentially differentiate into macrophages after infiltration, exert phagocytic ability, making the study of phagocytosis in the CNS even more interesting and complex. In particular, in the diseased brain, the phagocytosis of tissue-damaging substances, such as myelin debris in multiple sclerosis (MS), has been shown to be carried out by both microglia and blood-derived monocytes. However, it remains largely unclear why blood-derived monocytes need to invade the parenchyma, where microglia are already abundant, to assist in phagocytosis. We will also discuss whether this phagocytosis can affect the fate of the phagocytosing cell itself as well as the substance being phagocytosed and the surrounding environment in addition to future research directions. In this review, we will introduce recent studies to answer a question that often arises when studying microglial phagocytosis: under what circumstances and to what extent blood-derived monocytes infiltrate the CNS and contribute to phagocytosis. In addition, the readers will learn how recent studies have experimentally distinguished between microglia and infiltrating monocytes. Finally, we aim to contribute to the progress of phagocytosis research by discussing the effects of phagocytosis on phagocytic cells.

scholarly journals Immunological aspects of the treatment of depression and schizophrenia

2017 ◽  
Vol 19 (1) ◽  
pp. 55-63 ◽  
Keyword(s):  
Immune System ◽  
Therapeutic Benefit ◽  
Immune Reactivity ◽  
Altered Level ◽  
Immune System Dysfunction ◽  
Treatment Of Depression ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
Anti Inflammatory ◽  
Meta Analyses

Schizophrenia and major depression (MD) have been associated with immune system dysfunction. One example of this is the altered level of cytokines—important inflammatory mediators—in blood, and a proinflammatory immune state has been described in some subgroups of patients. A knock to the immune system in early life might trigger a life-long increased immune reactivity, and infections and autoimmune disorders are now known to be risk factors for development of schizophrenia and MD. Pro- and anti-inflammatory cytokines mediate indoleamine 2,3-dioxygenase activity; this enzyme drives metabolism of tryptophan and kynurenin in the central nervous system and degrades serotonin. Alterations of serotonergic, noradrenergic, and glutamatergic neurotransmission have been associated with low-level neuroinflammation, and anti-inflammatory compounds have a therapeutic benefit in MD and schizophrenia, as shown in meta-analyses. Moreover, antidepressants and antipsychotics have intrinsic immunomodulatory effects. With evidence pointing to the role inflammatory processes play in the pathogenesis of major psychiatric disorders, this review will look at various immunological aspects of treatment of such disorders.

scholarly journals Omega-3 fatty acids and inflammatory processes: from molecules to man

2017 ◽  
Vol 45 (5) ◽  
pp. 1105-1115 ◽  
Author(s):  
Philip C. Calder
Keyword(s):  
Fatty Acids ◽  
Transcription Factor ◽  
Arachidonic Acid ◽  
Fatty Acid ◽  
Phospholipid Fatty Acid ◽  
Phospholipid Fatty Acid Composition ◽  
Omega 3 ◽  
Epa And Dha ◽  
Inflammatory Processes ◽  
Anti Inflammatory

Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte–endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor κB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti-inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance.

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