Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications
Abstract
:Highlights
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- Disturbances in KP metabolism and its regulation affect CNS disease progression and associated pathology with notable changes in KP metabolite levels, enzyme function and gene induction.
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- KP of tryptophan metabolism is ubiquitous in eukaryotic cells and regulates several key biological systems including oxidative stress, energy metabolism, immune function, gut-microbiota functions and neurotransmitter functions.
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- Aging, genetic and environmental risk factors ensue a feedforward loop between neuroinflammation and KP metabolic imbalance during CNS disease.
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- Broadly targeting neuroinflammation in CNS disorders with currently available anti-inflammatory pharmacotherapy is inefficacious for a lack of specificity.
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- Therapeutic targeting of KP for CNS diseases requires a better understanding of KP metabolite functions, cellular and molecular events affected by KP and neuroinflammation in effector cells like microglia and astrocytes.
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- In this review, we describe and discuss evidence from the field that elaborates on KP metabolite production and function, alterations in KP metabolic imbalance arising during CNS diseases and potential targets tested in pre-clinical or clinical stages.
1. Introduction
2. Neuroinflammation
3. The Kynurenine Pathway
4. KP Metabolism, Immune Cell Trafficking and Neuroimmune Signaling
5. The Gut-Microbiota-Brain Axis and KP
6. Brain Regional Heterogeneity in KP Metabolism
7. KP Metabolites and Molecular Mechanisms
7.1. Kynurenine
7.2. 3-Hydroxykynurenine (3-HK)
7.3. 3-Hydroxyanthranillic Acid (3-HANA)
7.4. Quinolinic Acid (QA)
7.5. Kynurenic Acid (KA)
7.6. Xanthurenic Acid (XA)
7.7. Cinnabarinic Acid
7.8. Picolinic Acid (PA)
8. Translational and Therapeutic Considerations
9. Single Nucleotide Polymorphisms (SNP’s) in The Kynurenine Pathway of Tryptophan Metabolism
10. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
1-MT | 1-methyltryptophan |
3-HAAO | 3-hydoxyanthranillic acid dioxygenase |
3-HK | 3-Hydroxykynurenine |
α7nAChR | Alpha-7-nicotinic acetylcholine receptor |
AβPP/PS | double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) |
ACMSD | 2-Amino-3-carboxymuconic-6-semiladehyde decarboxylase |
AD | Alzheimer’s disease |
AhR | Aryl hydrocarbon receptor |
BBB | blood–brain barrier |
CA | Cinnabarinic acid |
CA1 | Cornu Ammonis 1 |
CNS | Central nervous system |
COX2 | Cyclooxygenase 2 |
CSF | Cerebrospinal fluid |
FCMTE | Familial cortical myoclonic tremor with epilepsy |
GlyB | Glycine B Site |
GPR35 | G-protein couples receptor 35 |
GWAS | Genome Wide Association Studies |
HD | Huntington’s disease |
HIV | Human immunodeficiency virus |
ICV | Intracerebroventricular |
IDO | Indoleamine-2,3-dioxygenase |
KAT | Kynurenine aminotransferase |
KA | Kynurenic acid |
KAT | Kynurenine aminotransferase |
Kyn | Kynurenine |
KMO | Kynurenine-3-monooxygenase |
KP | kynurenine Pathway |
LAT1 | Large amino acid transporter 1 |
LPS | Lipopolysaccharide |
LTP | Long term potentiation |
MDD | Major depressive disorder |
mGLUR | Metabotropic glutamate receptors |
MPTP | 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine |
NAD | Nicotinamide adenine dinucleotide |
NMDAR | N-methyl-D-aspartate receptor |
PD | Parkinson’s disease |
PA | Picolinic acid |
PDD | Postpartum depression |
QA | Quinolinic acid |
SBI | Surgical brain injury |
SNI | Spared nerve injury |
SNP | Single nucleotide polymorphism |
SNRI | Selective norepinephrine reuptake inhibitor |
SSRI | Selective serotonin reuptake inhibitor |
TCA | Tricyclic antidepressants |
TDO | Tryptophan-2,3-dioxygnease |
TRD | Treatment resistant depression |
TRP | Tryptophan |
VGLUT | Vesicle glutamate transporter |
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Metabolite | Metabolite-Receptor Target | Neurotransmitter Activity | Biological Functions | Ref |
---|---|---|---|---|
3-Hydroxyanthranilic Acid | Unknown | Unknown | Anti-Inflammatory, Oxidative stress regulation | [114,115,116,117] |
3-Hydroxykynurenine | Unknown | Unknown | Oxidative Stress Regulation | [118,119,120] |
Cinnabarinic Acid | mGLUR4, AhR | Glutamate | Immunomodulation | [65,121,122] |
Kynurenine | AhR | Unknown | Transcription factor, Immunomodulation, Anti-Cancer, Oxidative stress regulation | [103,111,112,113] |
Kynurenic Acid | α7nAChR, AhR, NMDAR, GPR35 | Glutamate, GABA and Nicotinic | Anti-Oxidant, Immunomodulation, Anti-convulsant | [123,124,125,126,127] |
Picolinic Acid | Unknown | Glutamate | Anti-convulsant, Anti-viral, Anti-microbial, Immunomodulation | [125,128,129,130] |
Quinolinic Acid | NMDAR | Glutamate | Pro-convulsant, Pro-oxidant | [46,56,131] |
Xanthurenic Acid | mGLUR 2/3 * | Glutamate | Anti-convulsant, Anti-oxidant | [63,132,133,134] |
Drug | Target | Disease Model | Pre/Clinical | Effect | Study |
---|---|---|---|---|---|
Gemst | Anti-inflammatory Poly-l-lysine compound | Stroke | Rat model of ischemia | Treatment down-regulates IDO pathway, reduction of microglia activation and gliosis in late phase of stroke | [224] |
1-MT | IDO inhibitor | epilepsy-induced depression | Pilocarpine induced Chronic temporal lobe epilepsy in rats | Prevented depressive-like behavior but did not influence spontaneous seizures | [225] |
1-MT | IDO inhibitor | Inflammation-induced depression | Mice treated with LPS (ICV) | Treatment prevented depressive-like behavior | [226] |
Coptisine | IDO inhibitor | Alzheimer’s Disease | Alzheimer’s transgenic AβPP/PS mice | Prevented neuronal cell loss and cognitive impairment, reduced amyloid plague development; decreased activation of microglia and astrocytes | [227] |
N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride-SZR-72 | KA analogue | Huntington’s Disease | HD N171-82Q transgenic mouse model | Treatment increased survival, restored locomotor activity, increased body weight and prevented striatum neuronal loss | [228] |
2-(2-N,N-dimethylaminoethylamine-1carbonyl)-1H-quinolin-4-one hydrochloride | KA analogue | Stroke | Rat model of global forebrain ischemia | Treatment prevents neuronal cell loss in CA1 region; preserves induction of LTP | [229] |
SZR104 | KA analogue | Epilepsy | Pentylenetetrazole induced epileptiform seizures in rats | Treatment decreased population spike activity and epileptiform seizures | [230] |
Ro-61-8048 | KMO inhibitor | Parkinson’s | MPTP cynomolgus monkey | Chronic treatment with Ro-61-8048 reduced levodopa-induced dyskinesia’s | [228] |
Ro-61-8048 | KMO inhibitor | Paroxysmal dystonia | dtsz mutant Syrian golden hamsters | Anti-dystonic; reduced severity of dystonic attacks | [231] |
Ro-61-8048 | KMO inhibitor | Brain injury/Neurotrauma | Surgical brain injury in rats | Treatment reduced brain edema and improved long-term neurological function after SBI | [232] |
Ro 61-8048 | KMO inhibitor | Spared nerve injury model | Neuropathic pain and depression like behavior in SNI mice | Anti-depressant effect following treatment but no effect on improving mechanical allodynia | [233] |
Ro-61-8048, mNBA | KMO inhibitor | Stroke | Rat and gerbil models of ischemia | Treatment prevented neuronal loss and decreased infarct volume | [234] |
JM6 | KMO inhibitor | Alzheimer’s and Huntington’s | AD (APPtg) and HD (R6/2) transgenic mouse models | Prevents AD and HD behavioral deficits and synaptic loss; increased life span of HD mice | [235] |
CHDI-340246 | KMO inhibitor | Huntington’s Disease | Multiple HD transgenic mouse models | Treatment ameliorates electrophysiological alterations in striatum, no improvement in behavioral phenotype | [236] |
PNU 156561A | KMO inhibitor | Huntington’s Disease | Chemical model of HD in rat; QA induced neurodegeneration and seizures | Anti-convulsant and neuroprotective | [237] |
Leucine | LAT1 competitor | Inflammation-induced depression | LPS induced depressive like behavior | Anti-depressant effect due to blockade of kynurenine entry to the brain. | [238] |
Electroconvulsive therapy | NA | Depression | Humans with MDD | Treatment improved depressive symptoms; reduced kyn and QA levels in plasma, significantly reduced the QA/KA ratio | [239] |
Electroconvulsive therapy | NA | Depression | Humans with MDD | Treatment improved depressive symptoms, increased serum KA levels, increased the KYN/TRP, KA/KYN, and KA/3-HK ratios | [240] |
Ketamine | NMDAR antagonist | Inflammation-induced depression; Treatment Resistant Depression | Mice treated with LPS; humans with TRD | Reduces QA and elevates KA in mice treated with LPS, reduced depressive behaviors | [34] |
Ketamine | NMDAR antagonist | Treatment Resistant Depression | Humans with TRD | Treatment reduced depressive symptoms; elevated KYNA and KA/KYN ratio in responders | [241] |
Ketamine | NMDAR antagonist | Treatment Resistant Depression | Humans with TRD | Treatment reduced depressive symptoms; statistical non-significant trend of elevating KA and KA/KYN | [242] |
AV-101 (4-Chloro-kynurenine) | selective GlyB-NMDA receptor antagonist | Epilepsy | Kainate induced seizures and lesion | Anti-convulsant and neuroprotective effects, prevents seizures and lesion in rats | [243] |
AV-101 (4-Chloro-kynurenine) | selective GlyB-NMDA receptor antagonist | Depression | Healthy C57BL/6J mice | Anti-depressant like effects on behavioral paradigms used in mice | [244] |
AV-101 (4-Chloro-kynurenine) | selective GlyB-NMDA receptor antagonist | Pain | Capsaicin induced experimental pain in humans | Treatment trends to decrease in algesic response, feeling of wellbeing in small cohort of patients | [245] |
Escitalopram | SSRI | Depression | Humans with MDD | Treatment improved depressive symptoms, reduced QA and 3-HK, increased KA/QA ratio | [246] |
Escitalopram + celecoxib | SSRI, COX-2 inhibitor | Bipolar disorder | Treatment resistant Bipolar depression | Combination of drugs improved treatment response, statistically non-significant trend of reduced peripheral QA | [247] |
amitriptyline, imipramine, fluoxetine, citalopram | SSRI, TCAs | Depression | Humans with MDD | All antidepressants increase KA level in hippocampus and increased KAT1 and KAT2 expression in hippocampus | [248] |
D-1MT, allopurinol, Ro 61-8048 | IDO inhibitor, TDO inhibitor, KMO inhibitor | Schizophrenia | Ketamine-induced increased locomotor activity in rats | All inhibitors reverse the increased locomotor activity in response to ketamine | [249] |
Allopurinol | TDO inhibitor | Depression | Rat model of chronic restraint stress | Reduced immobility time in forced swim test, prevented increase in kynurenine levels induced by stress | [250] |
Gene Allele | SNP | Disease Model | Nature of Association with SNP | Study |
---|---|---|---|---|
TDO2 | rs3755910 | Autism | Polymorphism in TDO2 promoter region; CC genotype associated with autism | [286] |
KMO | rs1053230 | Bipolar disorder | Associated with elevated CSF KA in bipolar patients and common in bipolar patients with psychotic features during manic episode | [274] |
KMO | rs1053230, rs2275163 | Depression | No association between rs2275163 and depression. Association trend for rs 1053230 G/G genotype and depression | [276] |
IDO2 | rs2929115, rs2929116 | Depression | Nature of association unclear, SNP may alter SSRI citalopram response | [279] |
KATII, KMO | KATII-rs1480544, KMO-rs1053230 | Depression in HIV patients | C-allele in KATII-rs1480544 appears to be protective, KATII-TT-carriers at risk | [277] |
IDO1 | rs9657182 | Inflammation-induced depression | Associated with depressive symptoms development post immune therapy; CC genotype more at risk that TT genotype | [287] |
KAT III, KMO | KAT III-rs12729558, KMO-rs1053230 | Major Depressive Disorder and Bipolar Disorder | Associated with bipolar disorder and trend for association with MDD | [278] |
ACMSD | p.Trp26Stop codon | Familial cortical myoclonic tremor and epilepsy | ACMSD p.Trp26Stop mutation associated with family history of FCMTE | [283] |
ACMSD | rs775129424 | Parkinson’s Disease | Risk associated mutation found in patient with PD; affects response to treatment | [284] |
ACMSD | rs6710823 | Parkinson’s Disease | Meta-analysis of GWAS reveals ACMSD SNP predicts PD risk | [285] |
KMO | rs1053230 | Post-partum depression | Associated with elevated levels of 3-HK and higher 3-HK/KYN ratio in serum of women in post-partum depression. Significantly associated with post-partum depression | [280] |
IDO1 | rs10108662 | Post-partum depression | Associated with post-partum depression | [281] |
KATI, KATII, KATIII | NA | Post-partum depression | No association between eight KAT I–III SNPs and PPD | [282] |
KMO | rs1053230 | Schizophrenia | SNP associated with Increased KA in the CSF of schizophrenia patient | [288] |
KMO | rs1053230, rs2275163 | Schizophrenia | Increased risk were the GG genotype (rs1053230) and the T*GG diplotype (rs2275163 and rs1053230) | [289] |
KMO | rs2275163 | Schizophrenia | Associated with oculomotor measures of predictive pursuit and visuospatial working memory deficits in schizophrenic patients | [272] |
KMO | rs2275163, rs1053230 | Schizophrenia | rs2275163C>T allele is associated with poor performance on battery of cognitive tests in schizophrenia with decrease cognitive scores associated but rs1053230 is not | [273] |
KMO | rs2275163 | Schizophrenia | Associated with schizophrenia in one cohort, but effect was not replicated in second larger cohort | [275] |
ACMSD | rs2121337 | Suicide | SNP associated with higher QA in suicidal patients and reduced PA production | [154] |
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Mithaiwala, M.N.; Santana-Coelho, D.; Porter, G.A.; O’Connor, J.C. Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications. Cells 2021, 10, 1548. https://doi.org/10.3390/cells10061548
Mithaiwala MN, Santana-Coelho D, Porter GA, O’Connor JC. Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications. Cells. 2021; 10(6):1548. https://doi.org/10.3390/cells10061548
Chicago/Turabian StyleMithaiwala, Mustafa N., Danielle Santana-Coelho, Grace A. Porter, and Jason C. O’Connor. 2021. "Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications" Cells 10, no. 6: 1548. https://doi.org/10.3390/cells10061548
APA StyleMithaiwala, M. N., Santana-Coelho, D., Porter, G. A., & O’Connor, J. C. (2021). Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications. Cells, 10(6), 1548. https://doi.org/10.3390/cells10061548