key: cord-0751289-ahce25c1 authors: Mahalakshmi, Arehally M; Paneyala, Shasthara; Ray, Bipul; Essa, Musthafa Mohamed; Dehhaghi, Mona; Heng, Benjamin; Guillemin, Gilles J; Babu Chidambaram, Saravana title: Alterations in Tryptophan Metabolism Affect Vascular Functions: Connected to Ageing Population Vulnerability to COVID-19 Infection? date: 2022-03-14 journal: Int J Tryptophan Res DOI: 10.1177/11786469221083946 sha: 498a57f510a282a4e681abe5dcf867e9b739647e doc_id: 751289 cord_uid: ahce25c1 nan The essential amino acid tryptophan is the unique substrate for the biosynthesis of neurotransmitter serotonin, sleep hormone melatonin and co-factor nicotinamide adenine dinucleotide (NAD + ) through its metabolic pathways. 1 The catabolism of tryptophan by indoleamine 2,3-dioxygenases (IDO1/2) through the kynurenine pathway (KP) leads to the generation of multiple bioactive metabolites referred as kynurenines. 2, 3 Within the central nervous system (CNS), brain cells including glia and neurons produce different kynurenines. 4 During ageing a shift from the serotonergic to kynurenine pathway progressively occurs in the tryptophan catabolism resulting in an increased activity of the enzyme IDO-1 in turn increases the production of neuroactive KP metabolites. 5 The progressive alterations of the innate immune system linked to ageing trigger the development of chronic inflammatory cascades referred as 'inflammaging' which include astrogliosis, microgliosis and increased production of cytokines like IL-6, IL-1β, IFN-γ, TNF-α etc. . .. 2,6 IFN-γ and TNF-α are both know to trigger a strong induction of IDO1 through positive feedback mechanism in older population. 7 This increased IDO1 activity with age not only results in higher production of kynurenines, but also stimulates inducible nitric oxide synthase (iNOS) activity and increases nitric oxide (NO) production. iNOS is mainly expressed by activated microglia, astrocytes, endothelial cells and infiltrating lymphocytesa. [8] [9] [10] Could IDO-1 Activation be Associated With Vascular Dementia? The activation of IDO-1 and KP could possibly elicit vascular dementia directly through vasoactive metabolites and/or indirectly by stimulating iNOS through multiple pathways. (1) Several KP metabolites can have a direct effect on blood vessel by eliciting vascular inflammation mediated arterial stiffness and atherosclerosis by binding to aryl hydrocarbon receptors. KYN is an endothelium-derived relaxing factor produced during inflammation. [11] [12] [13] [14] [15] [16] The basolateral increase of kynurenines especially quinolinic acid at BBB endothelial cells and pericytes also results in local neurotoxicity thus leading to BBB disruption. 17 The excess of quinolinic acid also contribute to the production of β-amyloid and neurofibrillary tangles, 4, 18, 19 while amyloid precursor protein and β-amyloid are involved in eliciting endothelium dependent vasoconstriction, reduced cerebral blood flow thus abnormal vascular autoregulation 20 leading to neurodegeneration and cognitive impairment. 4 Alterations in tryptophan metabolism in aged population contribute to the occurrence of vascular impairments, progressive neurodegeneration and in turn cognitive impairment. (2) As IDO-1 activation leads to iNOS induction, the generated NO reacts with reactive oxygen species (ROS) to produce peroxynitrite (ONOO − ) which causes oxidative damage to biomacromolecules like lipids, proteins and deoxyribonucleic International Journal of Tryptophan Research acid (DNA) leading to deposition of toxic substances. All those compounds disrupt mitochondrial functions resulting in the failure to meet the biological energy needs for the neuronal homoeostasis. The overall effects lead to neuronal apoptosis and blood brain barrier (BBB) disruption contributing to neurovascular dysfunctions. 21 Additionally, increased levels of NO inhibit long-term potentiation (LTP) formation by decreasing production of Brain derived neurotrophic factor (BDNF), shifting the neuronal stem cells to differentiate into astrocytes thus hindering neurorepair and neurovascular impairment. 22 (3) The excessive formation of NO triggers intracellular accumulation of p53 (pro-apoptotic factor), leading to necrosis of cerebrovascular endothelial cells and vascular smooth muscle cells (VSMCs) and ultimately to neurovascular dysfunctions. 23 (4) iNOS also inhibits proliferation of T cells (Th-17), and increases circulating levels of IL-17, which then activates the Rho A/RHO kinase pathway. The latter inhibits endothelial nitric oxide synthase (eNOS) activity leading to cerebrovascular endothelial cells dysfunction. 23 Severe acute respiratory syndrome coronavirus-2 (SARS Cov-2) infection initially begins with peripheral inflammation and causes activation of endothelial cells leading to BBB disruption associated with astrogliosis and microgliosis. 24 At later stage, this latter events triggers neuroinflammation with increased cytokine/chemokine production, oxidative stress, and the altered immune cells trafficking contribute to further damage of the BBB, generating a strong neuroinflammatory and neurotoxic loop. [25] [26] [27] The dysregulated tryptophan metabolism, especially the high levels of quinolinic acid, in elderly population will amplify the COVID-19 associated risk factors by elevating neuroinflammation, 28 compromised the BBB, neurovascular impairments through cerebrovascular endothelial cells and VSMCs dysfunctions. 17 This chain of complex and multifactorial of detrimental events highlights the important effects resulting of the alteration of the tryptophan metabolism in older patients with Covid-19. The viral infection by itself triggers CNS pathologies including strong inflammatory responses, formation of amyloid plaques both leading to increased risk of intracerebral haemorrhage and ischaemic brain damage. 29, 30 The dysregulation of the KP in elderly population could be linked with an higher incidence of cerebrovascular diseases like acute stroke and increased fatality rate in COVID-19 affected elderly population. 29, 31, 32 We hypothesise that it is likely that the activation of the kynurenine pathway in elderly COVID-19 patients and survivors ('long-term COVID') could be a major contributor for cerebrovascular damages and a likely therapeutic target (Figure 1 ). Abbreviations: BDNF, brain derived neurotrophic factor; IDO-1, indoleamine 2,3-dioxygenases; IFN-γ, interferon-gamma; iNOS, inducible nitric oxide synthase; LTP, long term potentiation; NO, Nitric oxide; TNF-α, tumour necrosis factor-alpha. Effects of sleep deprivation on the tryptophan metabolism Tryptophan metabolism in inflammaging: from biomarker to therapeutic target An empirical review on oxidative stress markers and their relevance in obsessive-compulsive disorder Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation Sleep, brain vascular health and ageing Interferon-gamma-induced tryptophan degradation: neuropsychiatric and immunological consequences Central kynurenine pathway shift with age in women Age-and disease-specific changes of the kynurenine pathway in Parkinson's and Alzheimer's disease Quinolinic acid: an endogenous neurotoxin with multiple targets Evidence that a deviation in the kynurenine pathway aggravates atherosclerotic disease in humans Aortic stiffness-is kynurenic acid a novel marker? Cross-sectional study in patients with persistent atrial fibrillation Metabolic phenotyping in venous disease: the need for standardization The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall Impairment of kynurenine metabolism in cardiovascular disease Kynurenine is an endothelium-derived relaxing factor produced during inf lammation Kynurenine pathway metabolism in human blood-brain-barrier cells: implications for immune tolerance and neurotoxicity Expression of tryptophan 2,3-dioxygenase and production of kynurenine pathway metabolites in triple transgenic mice and human Alzheimer's disease brain Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease β-amyloid, blood vessels, and brain function Oxidative stress-mediated blood-brain barrier (BBB) disruption in neurological diseases Nitric oxide downregulates brain-derived neurotrophic factor secretion in cultured hippocampal neurons The roles of nitric oxide synthase/nitric oxide pathway in the pathology of vascular dementia and related therapeutic approaches Neuropathobiology of COVID-19: the role for Glia Brain dysfunction in COVID-19 and CAR-T therapy: cytokine storm-associated encephalopathy The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19 Why severe COVID-19 patients are at greater risk of developing depression: a molecular perspective Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes Influence of COVID-19 on cerebrovascular disease and its possible mechanism Does COVID-19 contribute to development of neurological disease? Potential mechanisms of cerebrovascular diseases in COVID-19 patients AhR and IDO1 in pathogenesis of covid-19 and the "Systemic AhR Activation Syndrome" translational review and therapeutic perspectives