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Can This Revelation Help Reverse Parkinson’s Symptoms?

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In this Parkinson’s Awareness Month, we came across interesting revelations about the potential reversal of the symptoms of neurodegenerative diseases like Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s (HD).

An international team of researchers in University of Leicester, UK carried out experiments on fruit fly models of the diseases. They indicated that by genetic and pharmacological inhibition of enzymes responsible for the generation of toxic neurodegeneration-causing metabolites, can lead to the decrease in the symptoms of neurodegenerative diseases.

The study was conducted in collaboration with Prof Robert Schwarcz and his team Korrapati V. Sathyasaikumar, Francesca M. Notarangelo of University of Maryland School of Medicine, Baltimore.

The kynurenine pathway (KP), which is the major catabolic route of tryptophan degradation (TRP) in mammals, forms several neuroactive metabolites- 3-Hydroxykynurenine (3-HK), quinolinic acid (QUIN), kynurenic acid (KYNA). The normal regulation of the KP depends on two critical regulatory enzymes- kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO).

A detailed analysis of the role of the genetic inhibition of the two KP enzymes and the effect of alterations in the level of the neuroactive KP metabolites were done. Additionally, it was noted that inhibition of TDO by a drug-like compound reverses various neurodegenerative disease symptoms.

Kynurenine pathway manipulation in Parkinson’s Disease

Figure 1. Effects of Kynurenine pathway manipulation in Parkinson’s Disease. (Photo Credit: Carlo Breda et al. PNAS doi:10.1073/pnas.1604453113)

The common laboratory fruit fly Drosophila melanogaster was employed in the research which demonstrated the improved locomotor performance and reduced neurodegeneration in these model flies by inhibition of TDO and KMO.

Professor Giorgini of the internationally acclaimed Department of Genetics at Leicester, said: “There is a fine balance between levels of “good” and “bad” metabolites that occurs in the kynurenine pathway. In disease, it shifts towards the “bad”, and by inhibiting TDO or KMO, we shift it back to “good”. For example, we find that if we inhibit either TDO or KMO in Huntington’s flies we reduce loss of neurons. In Alzheimer’s or Parkinson’s flies we see extension of the shortened lifespan exhibited by these flies, and we also reverse the defects they have in movement. We have even used a drug-like chemical to inhibit TDO and found that this also alleviates ‘symptoms’.”

Professor Giorgini added, “We are excited by these results, as they suggest that TDO and KMO inhibition could be a general strategy employed to improve symptoms in a myriad of neurodegenerative disorders, not just Parkinson’s and Alzheimer’s. Indeed, five years ago we first showed that these manipulations could improve “symptoms” in Huntington’s disease model flies, so our next step is to validate our work in mammalian models and ultimately to see if such drugs could be helpful to patients in clinical trials”

Professor Giorgini further added, “The two most common neurodegenerative disorders worldwide are Alzheimer’s and Parkinson’s disease. The treatment options for these diseases are limited, and to date no cures exist. Our hope is that by improving our knowledge of how these nerve cells become sick and die in the brain, we can help devise ways to interfere with these processes, and thereby either delay disease onset or prevent disease altogether.”

The work carried out by Giorgini and team emphasized on the potential therapeutic approaches for the treatment of various neurodegenerative diseases by the deep understanding of the KP and alterations in the levels of neuroactive KP metabolites.

Featured image credit: Close-up Of The Doctor Hand Pointing To The Brain Ct © sudok1 (Stock Photo ID: 89949719)

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