Wednesday, April 18, 2012

2 Father & Son Develop Drug Which Could Reduce Lyme Excitotoxin

While looking for articles and papers on neurodegeneration in Lyme disease, I came across this interesting article in the San Francisco Chronicle about a father and son team who are working on a drug to treat neurodegeneration in conditions such as Alzheimer's disease and Huntington's disease. The father, Joseph Muchowski, is a retired chemist from Swiss drug maker, Roche. The son, Paul Muchowski, is a full time investigator at the Gladstone Institute in San Francisco, California.

The article states that the drug - currently called JM6 - inhibits an enzyme, kynurenine 3-monooxygenase (KMO) that when left unchecked, allows a toxic chemical to build up in the brain. And that JM6's effect on the brain is indirect - it inhibits the KMO enzyme in the blood, setting off a chain of events that ultimately leads to a reduction in one harmful chemical in the brain and an increase in a second, preventive chemical.

I looked at this article and realized that the specific pathway mentioned - the kynurenine pathway - is said to be involved in Lyme disease. I wondered if JM6 could potentially help people suffering with Lyme disease - and in particular, suffering from neuroborreliosis. So I decided to do a little more digging on this drug and the KMO enzyme and see what I could find out.

First of all, the Gladstone Institute already has a research page for the Muchowski Lab which mentions research related to JM6 under "Project 4": http://www.gladstone.ucsf.edu/gladstone/files/muchowski/labsite/research.htm#Research

An excerpt about Project 4 states:
"Metabolites in the kynurenine pathway (KP), generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer’s and Huntington’s diseases. 
In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with increased levels of the toxic tryptophan metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN), and decreased levels of the neuroprotective metabolite kynurenic acid (KYNA). 
In 2005 our lab reported the results from a large-scale genetic screen in yeast that identified mutations in 28 genes that suppress toxicity of mutant huntingtin (Giorgini et al., Nature Genetics, 2005). Among the most potent mutations identified in our screen was one in a gene that encodes kynurenine 3-monooxygenase (KMO), an enzyme that plays a critical role in the KP."
From there, JM6 is said to inhibit KMO in the blood, increase KYNA levels, and reduce extracellular glutamate in the brain.

In a mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. In another mouse model for Huntington's disease, JM6 extends life span, prevents synaptic loss, and decreases microglial activation.

"How does all this relate to Lyme disease?" you might be wondering.

Hold on, I'll get to that in a moment, because the next thing I'd like to share is that I found a patent which appears to be related to JM6:

Source: http://www.google.com/patents/US20080070937

Patent title: SMALL MOLECULE INHIBITORS OF KYNURENINE-3-MONOOXYGENASE
Inventors: Paul J. Muchowski et al

In the patent, it states that a small molecule inhibitor (in this case, I would guess JM6) can work on a number of different conditions where the kynurenine pathway (KP) plays a role in its development.

Referring to page four of the patent, it lists all conditions which fall under this category:
[0054] Diseases mediated at least in part by kynurenine3-monooxygenase include those selected from the group consisting of Huntington's disease and other polyglutamine disorders such as spinocerebellar ataxias, Alzheimer's disease, Parkinson's disease, high-pressure neurological syndrome, dystonia, olivopontocerebellar atrophy, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consequences of stroke, cerebral ischemia, hypoxia, multi-infarct dementia, consequences of cerebral trauma or damage, damage to the spinal cord, AIDS-dementia complex, viral or bacterial meningitis, general central nervous system (CNS) infections such as viral, bacterial or parasites, for example, poliomyelitis, Lyme disease (Borrelia burgdorferi infection) and malaria, cancers with cerebral localization, Tourette's syndrome, hepatic encephalopathy, systemic lupus, analgesia and opiate withdrawal symptoms, feeding behaviour, schizophrenia, chronic anxiety, depressive disorders, disorders of the developing or aged brain, diseases of addiction, diabetes, and complications thereof. The compounds of this invention may also influence synaptogenesis after brain injury. The compounds also may influence memory.
And in this patent, I found information which may indicate that this new drug, JM6, may be able to reduce quinolinic acid which has been shown to build up in the nervous system during infection with Borrelia burgdorferi.

So what is quinolinic acid? And what role does it play in Lyme disease?

Quinolinic acid (QA) is a dicarboxylic acid which has a powerful neurotoxic effect.



(Hard to believe something so simple could cause so many problems?)

Quinolinic acid is a metabolite of tryptophan which is produced by activated microglia and macrophages in the brain and binds to N-methyl-d-aspartate (NMDA) receptors in the central nervous system. (In other words, QA can be activated by the immune response.)

Some quinolinic acid is necessary for the production of NAD+ - but too much quinolinic acid and it leads to excitotoxicity. If NDMA receptors are overstimulated by too much quinolinic acid, too much calcium enters the neurons and prevents the uptake of glutamate into the synaptic vesicle. Too much glutamate leads to the death of neurons harboring these receptors.

Clinical studies have established that sustained elevations of quinolinic acid, l-kynurenine and kynurenic acid within the cerebrospinal fluid occur in patients with a broad spectrum of inflammatory diseases and correlate with markers of immune activation and interferon-gamma (IFN-γ) activity.[1]

Increased production of quinolinic acid has been demonstrated in the CSF of patients with neurologic Lyme disease (Halperin and Heyes, 1992).[2] The level of quinolinic acid, an excitotoxin and N-methyl-D aspartate (NMDA) agonist, correlated strongly with CSF leukocytosis and was noted to be greater in patients with CNS inflammation and less in Lyme encephalopathy.[3] The presence of quinolinic acid may contribute to the neurologic and cognitive deficits such as memory loss which is seen in many Lyme disease patients.

Now that you have a basic idea of what quinolinic acid is and that it may play a role in neurologic and cognitive deficits in Lyme disease, I can move on to what JM6 is supposed to do, in theory:

In mammals, tryptophan is a precursor for serontonin - but it is also metabolized via the kynurenine pathway to generate three neuroactive substances:
  1. hydroxykynurenine  (3-hydroxykrynurenine = neurotoxic)
  2. kynurenic acid  (neuroprotective)
  3. quinolinic acid  (neurotoxic)
Kynurenic acid has neuroprotective activities in vivo while 3-hydroxykynurenine and quinolinic acid are neurotoxic.

Simplified kynurenine pathway of tryptophan metabolism. IDO,
indolamine-2,3-dioxygenase; KAT, kynurenine aminotransferase; KMO,
kynurenine 3-monooxygenase or kynurenine 3-hydroxylase;
 KYNU, kynureninase; TDO, tryptophan-2,3-dioxygenase; TPH, tryptophan hydroxylase.
Image from: 
Neuropsychopharmacology 37, 939-949 (March 2012)
Studies have shown that 3-hydroxykynurenine and quinolinic acid are causative or can contribute to delayed neurological damage and both are associated with neurodegenerative disorders and psychiatric diseases.

Drugs which block 3-hydroxykynurenine and quinolinic acid synthesis and/or increase kynurenic acid formation have been created before, such as in treatment of neurological diseases and their peripheral indications (e.g. diabetes).

Kynurenine-3-monooxygenase (KMO) is an enzyme in the tryptophan degradation pathway that catalyzes the conversion of kynurenine into 3-hydroxykynurenine (which is a precursor of the neurotoxin quinolinic acid).

Drugs which act as inhibitors of KMO are of value since they block the metabolism toward quinolinic acid and at the same time, increase the formation of neuroprotective metabolite kynurenic acid.

JM6 is one of these drugs.

The Muchowski Lab writes about what JM6 might do in vivo:
"We hypothesize that the biotransformation of JM6 to Ro 61-8048 in the gut results in KMO inhibition in peripheral monocytes, causing the accumulation of both kynurenine (KYN) and KYNA in blood. Unlike KYNA, KYN is then actively transported into the brain, where it is rapidly converted by astrocytes to KYNA. KYNA released from astrocytes mediates neuroprotection, at least in part, by decreasing glutamate levels via antagonism of presynaptic α7 nicotinic acetylcholine receptors. However, at high local concentrations, KYNA might also directly block glutamate receptors to reduce excitotoxicity. Neuroprotection by JM6 might also involve a decrease in inflammation and modulation of mitochondrial function."
So there you have it - JM6 blocks KMO in monocytes. 3-hydroxykynurenine and quinolinic acid are not converted from kynurenine - so your two neurotoxins aren't there. The available kynurenine is supposed to reduce glutamate levels and also block glutamate receptors to reduce excitotoxicity. And by extension, inflammation may be decreased and mitochondrial function improved.

To learn more about JM6, check out the Gladstone Institute's published paper in Cell:

Daniel Zwilling, Shao-Yi Huang, Korrapati V. Sathyasaikumar, Francesca M. Notarangelo, Paolo Guidetti, Hui-Qiu Wu, Jason Lee, Jennifer Truong, Yaisa Andrews-Zwilling, Eric W. Hsieh, Jamie Y. Louie, Tiffany Wu, Kimberly Scearce-Levie, Christina Patrick, Anthony Adame, Flaviano Giorgini, Saliha Moussaoui, Grit Laue, Arash Rassoulpour, Gunnar Flik, Yadong Huang, Joseph M. Muchowski, Eliezer Masliah, Robert Schwarcz, and Paul J. Muchowski. Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration. Cell 145, 863–874, June 10, 2011

Full text: http://www.gladstone.ucsf.edu/gladstone/files/muchowski/labsite/PDFfiles_and_figures/Zwilling_et_al_Cell2011.pdf

References: 

1) K. Saito, S.P. Markey, M.P. Heyes. Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Neuroscience. Volume 51, Issue 1, November 1992, Pages 25–39 http://www.sciencedirect.com/science/article/pii/030645229290467G
2) Halperin, J.J., Heyes, M.P. Neuroactive kynurenines in Lyme borreliosis. Neurology 42 (1), 43–50.
3) Fallon, B.A., et al. Inflammation and central nervous system Lyme disease. Neurobiol. Dis. (2009), doi:10.1016/j.nbd.2009.11.016

Additional Resources:

  • Fuchs, D., Dotevall, L., Hagberg, L, Werner, E., Wachter, H. Kynurenine in cerebrospinal fluid of patients with Lyme neuroborreliosis. Immunology & Infectious Diseases. 1991 Vol. 1 271-74.
  • Dotevall,  L., Fuchs, D., Reibnegger, G, Wachter, H., Hagberg, G. Cerebrospinal Fluid and Serum Neopterin Levels in Patients with Lyme Neuroborreliosis. Infection 18 (1990) No. 4.
  • Gasse, T., Murr, C. Meyersbach, P., Schmutzhard, E., Wachter, H., Fuchs, D. Neopterin production and tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme encephalopathy. Eur J. Clin. Chem. Clin. Biochem. 1994 Sept 32(9):685-9.
[Edited April 19, 2012: to include KP image and mention NAD+/NADH generation using quinolinic acid.]

Addendum December 2012:

Ivan Oransky of Retraction Watch has reported that Dr. Paul Muchowski has been under investigation for submitting fraudulent data to the NIH and was found to have engaged in scientific misconduct. Muchowski is now conducting research under supervision for two years, and cannot serve on any NIH committee during this time period.

See this link for more information: http://retractionwatch.wordpress.com/2012/12/28/neuroscientist-made-up-data-in-nih-grant-applications-says-ori/

How this affects the research completed on JM6 and the related patent mentioned above remains to be seen.



2 comments:

  1. Quote: "Father and Son Developed Drug Which Might Reduce Lyme Excitotoxin "

    "Lyme" (B.b) produces a toxin??? That's new to me, don't believe it.

    That's on your "front page": if incorrect I would suggest correction.

    ReplyDelete
  2. Anonymous,

    Please reread the title of the article, the article itself, and the references. Nowhere did I state Lyme Borrelia produces a toxin. What is stated is that the brain produces an excitotoxin in response to the presence of Borrelia burgdorferi.

    No toxin has been found. The most one can claim so far is that an outer surface protein of Borrelia seems "endotoxin-like" - but that's different from stating it actually IS an endotoxin.

    The production of an excitotoxin in the host's own brain is well documented. Refer to all that I've written above and sources for more information.

    CO

    ReplyDelete

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