Mustafa Mithaiwala, a student in the Neuroscience discipline of the Integrated Biomedical Sciences Ph.D. program and laboratory of Dr. Jason O’Connor, recently had a first author review article published in the peer reviewed journal Cells.

Cells is an international, peer-reviewed, open access, journal of cell biology, molecular biology, and biophysics published monthly online by Multidisciplinary Digital Publishing Institute (MDPI) (5-year impact factor: 5.2). The article is titled “Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications” and was published under the special issue of Cells, ‘Studies around Neuroinflammation – series 2’ in June 2021. The paper describes and discusses evidence from the field that elaborates on kynurenine pathway (KP) metabolite production and function, alterations in KP metabolic imbalance arising during central nervous system diseases and potential KP targets tested in pre-clinical or clinical stages.

According to the Global, regional, and national burden of neurological disorders during 1990–2015: A systematic analysis for the Global Burden of Disease Study 2015 which is cited in the review article, “Central nervous system disorders are the second-leading cause of death globally (~17%), and they pose a major healthcare problem affecting over 250 million people worldwide when accounting for disability adjusted life years.”

“Diseases of the central nervous system remain a significant health, social and economic problem around the globe,” Mithaiwala said. “The development of therapeutic strategies for central nervous conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Moreover, the antiquated idea that the brain is an immuno-privileged organ devoid of active inflammatory processes has been replaced by new understanding that the CNS has dynamic and robust, albeit unique and very tightly regulated, immune activity. Broadly targeting neuroinflammation in CNS disorders with currently available anti-inflammatory pharmacotherapy has been inefficacious for a lack of specificity.”

Mithaiwala explained that the review paper provides mechanistic insights between different central nervous system disorders, neuroinflammation and the KP. “KP of tryptophan metabolism is ubiquitous in eukaryotic cells and regulates several key biological systems including oxidative stress, energy metabolism, immune function, gut-microbiota functions and neurotransmitter functions. Therapeutic targeting of KP for central nervous system diseases requires a better understanding of KP metabolite functions, cellular and molecular events affected by KP and neuroinflammation in effector cells like microglia and astrocytes,” he said. A major takeaway from this review paper, he emphasizes is that “Under CNS disease conditions, neuroinflammatory stimuli, including systemic and local insults, disrupt physical, genetic and metabolic checkpoints. The cascade of chronic inflammation ensues allowing an enhanced flux of toxic KP metabolites in the CNS system in addition to gliosis mediated release of cytokine, chemokines and KP metabolites that fuels the fire to this vicious loop.”

He added that the development of rapidly available and brain penetrant drugs continues to remain the cornerstone need of current pharmacotherapy for central nervous system disease. He also believes that large scale omics studies and additional research on the basic biology of kynurenine pathway metabolites will further the quest in the discovery of targets for central nervous system drug development.

This work was supported by a Translational Sciences Training Award TL1 TR002647 from the NIH National Center for Advancing Translational Sciences (to G.A.P.), National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR002645 (to J.C.O.), and Merit Review Award I01BX003195 from the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Service (to J.C.O.).