Rollercoaster ride of kynurenines: steering the wheel towards neuroprotection in Alzheimer’s disease

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.

KEYWORDS:

• Alzheimer’s disease
• kynurenic pathway
• quinolinic acid
• kynurenic acid

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

This box summarizes key points contained in the article.

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.

Additional information

Funding

R Sharma is funded by a research scholarship from the All India Council of Technical Education. A Kuhad is funded by SERB, Department of Science & Technology (DST) and the University Grants Commission, New Delhi.