Abstract
Worldwide, 50 million people suffer from dementia, a group of symptoms affecting cognitive and social functions, progressing severely enough to interfere with daily life. Alzheimer’s disease (AD) accounts for most of the dementia cases. Pathological and clinical findings have led to proposing several hypotheses of AD pathogenesis, finding a presence of positive feedback loops and additionally observing the disturbance of a branch of tryptophan metabolism, the kynurenine (KYN) pathway. Either causative or resultant of dementia, elevated levels of neurotoxic KYN metabolites are observed, potentially upregulating multiple feedback loops of AD pathogenesis. Memantine is an N-methyl-D-aspartate glutamatergic receptor (NMDAR) antagonist, which belongs to one of only two classes of medications approved for clinical use, but other NMDAR modulators have been explored so far in vain. An endogenous KYN pathway metabolite, kynurenic acid (KYNA), likewise inhibits the excitotoxic NMDAR. Besides its anti-excitotoxicity, KYNA is a multitarget compound that triggers anti-inflammatory and antioxidant activities. Modifying the KYNA level is a potential multitarget strategy to normalize the disturbed KYN pathway and thus to alleviate juxtaposing AD pathogeneses. In this review, the maintenance of KYN metabolism by modifying the level of KYNA is proposed and discussed in search for a novel lead compound against the progression of dementia.
Highlights
Dementia, currently known as major neurocognitive disorder (NCD) in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5), is an acquired cognitive decline of six discrete cognitive domains including complex attention, executive function, learning and memory, language, perceptual-motor function, and/or social cognition
A literature search was employed in PubMed/MEDLINE and Google Scholar, using appropriate search terms and filters according to a theme of each section, and a systematic review was conducted to synthesize studies of human samples regarding the status of KYNs in neurodegenerative diseases and psychiatric disorders that affect cognitive domains, as described in detail in Appendix A
3-HK and anthranilic acid (AA) are converted by 3-hydroxyanthranilate oxidase to highly redox-active 3-HAA, which may play a role in the regulation of oxidative stress. 3-HAA suppresses cytokine and chemokine production and neurotoxicity induced by IL-1 or IFN-γ [47]. 3-HAA is converted by 3-hydroxyanthranilate dioxygenase to 2-amino-3-carboxymuconate semialdehyde, which is further transformed into picolinic acid (PIC) and an excitotoxic and free-radical metabolite, quinolinic acid (QUIN)
Summary
Currently known as major neurocognitive disorder (NCD) in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5), is an acquired cognitive decline of six discrete cognitive domains including complex attention, executive function, learning and memory, language, perceptual-motor function, and/or social cognition. The neurodegenerative lesions of postmortem brain samples of AD patients correlate well with imaging studies. Regional patterns of the brain shrinkage may help identify affected cognitive domains and diagnose other causes of dementia. A literature search was employed in PubMed/MEDLINE and Google Scholar, using appropriate search terms and filters according to a theme of each section, and a systematic review was conducted to synthesize studies of human samples regarding the status of KYNs in neurodegenerative diseases and psychiatric disorders that affect cognitive domains, as described in detail in Appendix A
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