Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Mithaiwala, Mustafa N.; Santana‐Coelho, Danielle; Porter, Grace A.; O’Connor, Jason C.

doi:10.3390/cells10061548

Cited by 74 publications

(64 citation statements)

References 322 publications

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“… 40 Meanwhile, KYNA counteracts the neurotoxic effects of tryptophan metabolites through antioxidant activity and a nonselective antagonistic effect at NMDA receptors, but such neuroprotective effects of KYNA are weakened in neuroinflammation. 46 The production of KYNA from kynurenine is inhibited by proinflammatory cytokines such as IL-1β, TNF-α, and IFN-γ. 46 A chronic imbalance in the kynurenine pathway—increases in neurotoxic metabolites (i.e., QUIN, 3-HK, and 3-HA) and decreases in the neuroprotective metabolite (i.e., KYNA)—exerts detrimental effects on the brain by disrupting the homeostasis of glutamatergic neurotransmission.…”

Section: How Peripheral and Central Inflammation Processes Affect The Brainmentioning

confidence: 99%

“… 46 The production of KYNA from kynurenine is inhibited by proinflammatory cytokines such as IL-1β, TNF-α, and IFN-γ. 46 A chronic imbalance in the kynurenine pathway—increases in neurotoxic metabolites (i.e., QUIN, 3-HK, and 3-HA) and decreases in the neuroprotective metabolite (i.e., KYNA)—exerts detrimental effects on the brain by disrupting the homeostasis of glutamatergic neurotransmission. 47 This results in greater activation of the NMDA receptors, which leads to increases in calcium and sodium influx and potentially causes increased excitotoxicity and apoptosis, decreased synaptic plasticity, and eventually neuron death.…”

Section: How Peripheral and Central Inflammation Processes Affect The Brainmentioning

confidence: 99%

“… 40 Thereafter, increased levels of proinflammatory cytokines may exert a direct neurotoxic effect or induce glutamate-mediated excitotoxicity by stimulating IDO enzyme activity in microglial cells. 46 This implies that microglial cells play a pivotal role in the link between neuroinflammation and brain damage, and furthermore that microglial cells may provide a clue to how neuroinflammation affects the neural circuits involved in depression. 15 Several studies have suggested that neuroinflammatory processes affect specific brain regions, particularly the anterior cingulate cortex (ACC), prefrontal cortex (PFC), hippocampus, and insula, which are closely involved in the pathophysiology of depression.…”

Section: Neuroinflammation and Dysfunction Of Neural Circuits Involved In Depressionmentioning

confidence: 99%

See 2 more Smart Citations

How Inflammation Affects the Brain in Depression: A Review of Functional and Structural MRI Studies

Han

Ham

2021

J Clin Neurol

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This narrative review discusses how peripheral and central inflammation processes affect brain function and structure in depression, and reports on recent peripheral inflammatory marker-based functional and structural magnetic resonance imaging (MRI) studies from the perspective of neural-circuit dysfunction in depression. Chronic stress stimulates the activity of microglial cells, which increases the production of pro-inflammatory cytokines in the brain. In addition, microglial activation promotes a shift from the synthesis of serotonin to the synthesis of neurotoxic metabolites of the kynurenine pathway, which induces glutamate-mediated excitotoxicity in neurons. Furthermore, the region specificity of microglial activation is hypothesized to contribute to the vulnerability of specific brain regions in the depression-related neural circuits to inflammation-mediated brain injury. MRI studies are increasingly investigating how the blood levels of inflammatory markers such as C-reactive protein, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α are associated with functional and structural neuroimaging markers in depression. Functional MRI studies have found that peripheral inflammatory markers are associated with aberrant activation patterns and altered functional connectivity in neural circuits involved in emotion regulation, reward processing, and cognitive control in depression. Structural MRI studies have suggested that peripheral inflammatory markers are related to reduced cortical gray matter and subcortical volumes, cortical thinning, and decreased integrity of white matter tracts within depression-related neural circuits. These neuroimaging findings may improve our understanding of the relationships between neuroinflammatory processes at the molecular level and macroscale in vivo neuralcircuit dysfunction in depression.

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Section: How Peripheral and Central Inflammation Processes Affect The Brainmentioning

confidence: 99%

Section: How Peripheral and Central Inflammation Processes Affect The Brainmentioning

confidence: 99%

Section: Neuroinflammation and Dysfunction Of Neural Circuits Involved In Depressionmentioning

confidence: 99%

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How Inflammation Affects the Brain in Depression: A Review of Functional and Structural MRI Studies

Han

Ham

2021

J Clin Neurol

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“…An increased K/T ratio is a prominent feature of inflammation and mental disorders in AD studies [ 107 – 109 ]. Further, IDO activity can be monitored by circulating K/T [ 110 ].…”

Section: Metabolites and Molecular Mechanisms In The Kynurenine Pathwaymentioning

confidence: 99%

Kynurenine Pathway Metabolites as Biomarkers in Alzheimer’s Disease

Liang

Xie

et al. 2022

Disease Markers

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that deteriorates cognitive function. Patients with AD generally exhibit neuroinflammation, elevated beta-amyloid (Aβ), tau phosphorylation (p-tau), and other pathological changes in the brain. The kynurenine pathway (KP) and several of its metabolites, especially quinolinic acid (QA), are considered to be involved in the neuropathogenesis of AD. The important metabolites and key enzymes show significant importance in neuroinflammation and AD. Meanwhile, the discovery of changed levels of KP metabolites in patients with AD suggests that KP metabolites may have a prominent role in the pathogenesis of AD. Further, some KP metabolites exhibit other effects on the brain, such as oxidative stress regulation and neurotoxicity. Both analogs of the neuroprotective and antineuroinflammation metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic and neuroinflammation compounds may have potential therapeutic significance. This review focused on the KP metabolites through the relationship of neuroinflammation in AD, significant KP metabolites, and associated molecular mechanisms as well as the utility of these metabolites as biomarkers and therapeutic targets for AD. The objective is to provide references to find biomarkers and therapeutic targets for patients with AD.

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“…KMO expression levels are upregulated by proinflammatory cytokines, and an increased KMO metabolism results in the creation of compounds that activate glutamate receptors and elevate oxidative stress, which has fundamental consequences for CNS functioning. KMO plays a significant role in the regulation of peripheral inflammation [104] and central nervous system diseases [105]. In innate physiology, the KP participates in the regulation of early brain development [106].…”

Section: Kynurenine-3-monooxygenasementioning

confidence: 99%

The Kynurenine Pathway as a Potential Target for Neuropathic Pain Therapy Design: From Basic Research to Clinical Perspectives

Ciapała

Mika

Rojewska

2021

IJMS

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Accumulating evidence suggests the key role of the kynurenine pathway (KP) of the tryptophan metabolism in the pathogenesis of several diseases. Despite extensive research aimed at clarifying the mechanisms underlying the development and maintenance of neuropathic pain, the roles of KP metabolites in this process are still not fully known. Although the function of the peripheral KP has been known for several years, it has only recently been acknowledged that its metabolites within the central nervous system have remarkable consequences related to physiology and behavior. Both the products and metabolites of the KP are involved in the pathogenesis of pain conditions. Apart from the neuroactive properties of kynurenines, the KP regulates several neurotransmitter systems in direct or indirect ways. Some neuroactive metabolites are known to have neuroprotective properties (kynurenic acid, nicotinamide adenine dinucleotide cofactor), while others are toxic (3-hydroxykynurenine, quinolinic acid). Numerous animal models show that modulation of the KP may turn out to be a viable target for the treatment of diseases. Importantly, some compounds that affect KP enzymes are currently described to possess analgesic properties. Additionally, kynurenine metabolites may be useful for assessing response to therapy or as biomarkers in therapeutic monitoring. The following review describes the molecular site of action and changes in the levels of metabolites of the kynurenine pathway in the pathogenesis of various conditions, with a particular emphasis on their involvement in neuropathy. Moreover, the potential clinical implications of KP modulation in chronic pain therapy as well as the directions of new research initiatives are discussed.

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Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cited by 74 publications

References 322 publications

How Inflammation Affects the Brain in Depression: A Review of Functional and Structural MRI Studies

How Inflammation Affects the Brain in Depression: A Review of Functional and Structural MRI Studies

Kynurenine Pathway Metabolites as Biomarkers in Alzheimer’s Disease

The Kynurenine Pathway as a Potential Target for Neuropathic Pain Therapy Design: From Basic Research to Clinical Perspectives

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