ABSTRACT
Introduction: Alzheimer’s disease (AD) is associated with cerebral cognitive deficits exhibiting two cardinal hallmarks: accruement of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The currently accessible therapeutic armamentarium merely provides symptomatic relief. Therefore, the cry for prospective neuroprotective strategies seems to be the need of the hour.
Areas covered: This review comprehensively establishes correlation between kynurenine pathway (KP) metabolites and AD with major emphasis on its two functionally contrasting neuroactive metabolites i.e. kynurenic acid (KYNA) and quinolinic acid (QUIN) and enlists various clinical studies which hold a potential for future therapeutics in AD. Also, major hypotheses of AD and mechanisms underlying them have been scrutinized with the aim to brush up the readers with basic pathology of AD.
Expert opinion: KP is unique in itself as it holds two completely different domains i.e. neurotoxic QUIN and neuroprotective KYNA and disrupted equilibrium between the two has a hand in neurodegeneration. KYNA has long been demonstrated to be neuroprotective but lately being disparaged for cognitive side effects. But we blaze a trail by amalgamating the pharmacological mechanistic studies of KYNA in kinship with α7nAChRs, NMDARs and GABA which lends aid in favour of KA.
Article Highlights
AD is the major cause of dementia worldwide which affects a persons’ lifestyle and social behaviour dramatically.
KP is the main route for tryptophan degradation and its metabolite QUIN is the main perpetrator behind the pathophysiological changes in AD
KYNA has hailed as neuroprotective metabolite by antagonizing the effects of quinolinic acid
Selective inhibition of various enzymes in the pathway can be of therapeutic importance with major emphasis on KMO inhibitors.
4-Cl-kynurenine (AV-101) has successfully completed phase-1 clinical trial
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Declaration of interests
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.