Inhibiting the kynurenine pathway in spinal cord injury: multiple therapeutic potentials?

Chronic induction of the kynurenine pathway（KP） contributes to neuroinflammation by producing the excitotoxin quinolinic acid（QUIN）. This has led to significant interest in the development of inhibitors of this pathway, particularly in the context of neurodegenerative disease. However, acute spinal cord injury（SCI） also results in deleterious increases in QUIN, as secondary inflammatory processes mediated largely by infiltrating macrophages, become predominant. QUIN mediates significant neurotoxicity primarily by excitotoxic stimulation of the N-methyl-D-aspartate receptor, but other mechanisms of QUIN toxicity are known. More recent focus has assessed the contribution that neuroinflammation and modulations in the KP make in mood and psychiatric disorders with recent studies linking inflammation and modulations in the KP, to impaired cognitive performance and depressed mood in SCI patients. We hypothesize that these findings suggest that in SCI, inhibition of QUIN production and other metabolites, may have multiple therapeutic modalities and further studies investigating this are warranted. However, for central nervous system-based conditions, achieving good blood-brain-barrier permeability continues to be a limitation of current KP inhibitors.

Kynurenine pathway metabolism and neuroinflammatory disease

Immune-mediated activation of tryptophan（TRYP） catabolism via the kynurenine pathway（KP） is a consistent finding in all inflammatory disorders.Several studies by our group and others have examined the neurotoxic potential of neuroreactive TRYP metabolites,including quinolinic acid（QUIN） in neuroinflammatory neurological disorders,including Alzheimer＇s disease（AD）,multiple sclerosis,amylotropic lateral sclerosis（ALS）,and AIDS related dementia complex（ADC）.Our current work aims to determine whether there is any benefit to the affected individuals in enhancing the catabolism of TRYP via the KP during an immune response.Under physiological conditions,QUIN is metabolized to the essential pyridine nucleotide,nicotinamide adenine dinucleotide（NAD＋）,which represents an important metabolic cofactor and electron transporter.NAD＋ also serves as a substrate for the DNA ‘nick sensor＇ and putative nuclear repair enzyme,poly（ADP-ribose） polymerase（PARP）.Free radical initiated DNA damage,PARP activation and NAD＋ depletion may contribute to brain dysfunction and cell death in neuroinflammatory disease.

Research progress of kynurenine pathway in Alzheimer's disease

The kynurenine pathway(KP)has been shown to be involved in the pathophysiology of dementia diseases.Among the dementia diseases,the neurodegenerative diseases Alzheimer's disease and cerebrovascular diseases are vascular.The highest incidence of dementia.KP activation results in the production of neuroactive metabolites,which may interfere with normal neuronal function,leading to the appearance of symptoms of cognitive impairment.This review investigated KP's involvement in the neurological diseases Alzheimer's disease and vascular dementia,suggesting that KP is a potential therapeutic target for both diseases.

Metabolic pathways as possible therapeutic targets for progressive multiple sclerosis

Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth： insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc. Furthermore, repair processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g., oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g., ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.

抑郁症伴自杀的犬尿氨酸通路机制研究进展

抑郁症是全球重大的慢性、致残性精神疾病之一,预计到2030年其将位居所有疾病负担的首位。抑郁症是一种高患病率、高复发率、高致残率、高自杀率的精神疾病,自杀死亡是该疾病最为严重的后果。在抑郁症患者中,其中枢神经系统及外周血中的炎症因子水平均较高;而对于伴自杀意念或行为的抑郁症患者,其炎症因子水平的升高更为显著。相关研究显示,炎症因子水平的升高与犬尿氨酸代谢通路的失调相关,如神经毒性产物喹啉酸过量、保护性神经产物吡啶甲酸减少等。该文通过综述对犬尿氨酸代谢途径的研究,以期为探索抑郁症伴自杀的生物学标记物提供参考。

Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage

Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan(Trp)àkynurenine(KYN)àkynurenic acid(KA) axis metabolism. Mechanistically,chemotherapy-induced intestinal damage triggered the formation of an interleukin-6(IL-6)àindoleamine2,3-dioxygenase 1(IDO1)àaryl hydrocarbon receptor(AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35(GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic.This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.

Yixin Ningshen Tablet Alleviates Comorbidity of Myocardial Infarction and Depression by Enhancing Myocardial Energy Metabolism and Increasing Availability of Monoamine Neurotransmitter

Objective: To investigate the therapeutic effect of Yixin Ningshen Tablet(YXNS) on comorbidity of myocardial infarction(MI) and depression in rats and explore the underlying mechanism. Methods: The Sprague-Dawley rats were randomly divided into 5 groups with 7 rats in each group according to their weights,including control, model, fluoxetine(FLXT, 10 mg/kg), low-dose YXNS(LYXNS, 100 mg/kg), and high-dose YXNS(HYXNS, 300 mg/kg) groups. All rats were pretreated with corresponding drugs for 12 weeks. The rat model of MI and depression was constructed by ligation of left anterior descending coronary artery and chronic mild stress stimulation. The echocardiography, sucrose preference test, open field test, and forced swim test were performed. Myocardial infarction(MI) area and myocardial apoptosis was also detected. Serum levels of interleukin(IL)-6, IL-1β, tumor necrosis factor-α(TNF-α), 5-hydroxytryptamine(5-HT), adrenocorticotrophic hormone(ACTH), corticosterone(CORT), and norepinephrine(NE) were determined by enzyme linked immunosorbent assay. The proteins of adenosine 5’-monophosphate-activated protein kinase(AMPK), p-AMPK,peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α), and nuclear respiratory factor 1(NRF1) in heart were detected by Western blot analysis. The expression levels of TNF-α, IL-6, indoleamine 2,3-dioxygenase(IDO1), kynurenine 3-monooxygenase(KMO), and kynureninase(KYNU) in hippocampus were detected by real-time quantitative polymerase chain reaction. Results: Compared with the model group,the cardiac function of rats treated with YXNS significantly improved(P<0.01). Meanwhile, YXNS effectively reduced MI size and cardiomyocytes apoptosis of rats(P<0.01 or P<0.05), promoted AMPK phosphorylation,and increased PGC-1α protein expression(P<0.01 or P<0.05). HYXNS significantly increased locomotor activity of rats, decreased the levels of TNF-α, IL-6 and IL-1β, and increased the serum levels of 5-HT, NE, ACTH,and CORT(all P<0.05). Moreover, HYXNS decreased the m RNA expressions of IDO1, KMO and KYNU(P<0.05).Conclusions: YXNS can relieve MI by enhancing myocardial energy metabolism. Meanwhile, YXNS can alleviate depression by resisting inflammation and increasing availability of monoamine neurotransmitters. It may be used as a potential drug to treat comorbidity of MI and depression.