Yeah, you should check this out:

The authors started off by looking at the genes expressed in muscle biopsies from muscles undergoing atrophy, and they made note of which genes had high or low expression. Then, they screened 1300+ compounds for any that could (basically) decrease the high genes and increase the low genes, the idea being that any compound that could reverse the gene expression in muscle atrophy might be a good treatment. And they were right.

Ursolic acid

The screen identified ursolic acid, a compound found in large quantities in apple peels, as the only potential inhibitor of muscle atrophy. So the researchers injected ursolic acid into mice with atrophic muscles, which stopped muscle loss and increased muscle weight by 7%. Seven percent might not sound like a lot, but it is, considering that, again, this is the first compound shown to stop muscle loss at all. A 7% increase in muscle weight in a 180 lb man with typical muscle mass would mean a gain of over 5 pounds of muscle.

Ursolic acid diet shrinks fat cells

Things got even more interesting when normal mice were put on a diet with 0.27% ursolic acid: muscles got bigger and significantly stronger, blood levels of fat and cholesterol decreased, and fat cells shrank considerably, thus reducing fat weight significantly (see for yourself in a figure from the article, left). This is all in addition to the lowered blood sugar in fasting mice who received ursolic acid injections. To make things even better, the authors were able to identify genes that were increased or decreased by treatment, and that were probably responsible for these effects.

In my opinion, these scientists stumbled across something even greater than what they hoped to find. Their data on ursolic acid suggests its usefulness in treating everything from muscle atrophy to obesity to metabolic syndrome to type 2 diabetes. Not even mentioned in this paper is the work that has previously shown the ability of ursolic acid to inhibit cancer cells and Alzheimer’s proteins.

Okay, I’m impressed. What doesn’t ursolic acid do? Seems like it could be a future wonder drug! I’m very interested to see what scientists will try with this compound next…

Have a nerdy weekend!

Kunkel SD, Suneja M, Ebert SM, Bongers KS, Fox DK, Malmberg SE, Alipour F, Shields RK, & Adams CM (2011). mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell metabolism, 13 (6), 627-38 PMID: 21641545

Shishodia S, Majumdar S, Banerjee S, & Aggarwal BB (2003). Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer research, 63 (15), 4375-83 PMID: 12907607

Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, Kadara H, Guha S, Sethi G, & Aggarwal BB (2007). Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Molecular cancer research : MCR, 5 (9), 943-55 PMID: 17855663

Wilkinson K, Boyd JD, Glicksman M, Moore KJ, & El Khoury J (2011). A high-content drug screen identifies ursolic acid as an inhibitor of amyloid-{beta} interactions with its receptor CD36. The Journal of biological chemistry PMID: 21835916

Clearly inspired by her personal experiences, Genova‘s novel centers around Alice: Harvard psychology professor, wife, and mother. At 50 years of age she is highly respected amongst her colleagues as a world-renowned linguistics expert, and her problems seem no worse than would be expected – she wants to find more time to spend with her husband, and one of her three adult children wants to move to L.A. and take her chances on acting. However, when Alice starts forgetting little things here and there, like where she last had her Blackberry (and who doesn’t have this problem on occasion?), she tries to explain it away as menopause or maybe even a brain tumor. What she doesn’t expect is to be diagnosed with early onset Alzheimer’s Disease, which rapidly progresses and devastates her mental function.

Ultimately losing her professorship and the ability to recognize her family, Lisa Genova‘s Alice might bring you to tears, but in some ways that’s the point, and Genova has done her job - she makes you aware of the reality of this heartbreaking disease, and convinces you that it could happen to anyone at any level of society. For less than $5, it’s worth getting this novel for the appreciation it gives you towards neurodegeneration research. And maybe it will be as unforgettable an addition to your bookshelf as it was to mine.

These researchers exploit this tryptophan-neurodegeneration link to make headway in finding better treatments for neurodegenerative diseases.

Title: Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration

Authors: 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

Date of publication: June 6, 2011

Direct link: http://www.sciencedirect.com/science/article/pii/S0092867411005812

PMID: 21640374

Abstract: When the amino acid tryptophan is broken down by the body, a metabolite called kynurenine is produced, and this metabolite also goes on to be broken down into other products. One of the products of kynurenine breakdown is kynurenic acid, which is thought to have a protective effect on the brain and is decreased in those with neurodegenerative disease. The authors of this paper synthesized a drug called JM6 that inhibits the enzyme responsible for breaking down kynurenic acid – theoretically this drug would allow kynurenic acid levels to remain high and provide continued neuroprotection. In mouse models of Alzheimer’s and Huntington’s, administration of JM6 led to fewer memory deficits and longer lifespans, among other improvements in brain function.

Methods: These researchers first developed “slow release” versions of a drug already known to increase kynurenic acid levels by inhibiting the enzyme responsible for kynurenic acid breakdown. Slow-release drugs remain in blood circulation for an extended time and are thought to be more effective for that reason; the slow-release drug tested in this paper is called JM6. In mice known to have Alzheimer’s or Huntington’s like conditions, JM6 was given daily before the onset of disease symptoms. At 6-7 months of age, mice were behaviorally assessed (e.g. by time spent completing a maze) and some mice were sacrificed in order to study changes in brain tissue.

Results: In short, the drug JM6 works quite well in mouse models of both Alzheimer’s and Huntington’s Diseases, as evidenced by better spatial memory and longer lives in mice treated with the drug compared to mice that did not receive treatment. Alzheimer’s mice that were receiving JM6 were about 10% better at performing maze tasks than mice who did not receive the drug, which was a statistically significant difference. These mice also showed a more appropriate response to anxiety-inducing situations, which is important because in human Alzheimer’s cases, patients often display social and/or sexual “disinhibition” stemming from a loss of anxiety responses. Lastly, the mice modeling Huntington’s Disease lived significantly longer (on the order of a few weeks) with JM6 treatment than without. Both the Alzheimer’s and the Huntington’s mice treated with JM6 showed healthier brain tissue, e.g. an undiminished number of synapses, which are responsible for sending messages between cells in the brain.

Bottom line: In mice (not humans!) fated to develop Alzheimer’s and Huntington’s-like symptoms, the drug JM6 worked convincingly well to improve mental condition. Whether or not this drug could work in humans remains to be seen, but this research is powerful because the authors know that the drug JM6 works by increasing the amount of kynurenine in the blood (recall: kynurenine is a product of breaking down the amino acid tryptophan). This means that a potentially new approach to finding treatments for Alzheimer’s and/or Huntington’s could be to develop more drugs that act by increasing the body’s levels of kynurenine; and knowing what to target with a drug is often the first step to creating an effective treatment.

Zwilling D, Huang SY, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, Lee J, Truong J, Andrews-Zwilling Y, Hsieh EW, Louie JY, Wu T, Scearce-Levie K, Patrick C, Adame A, Giorgini F, Moussaoui S, Laue G, Rassoulpour A, Flik G, Huang Y, Muchowski JM, Masliah E, Schwarcz R, & Muchowski PJ (2011). Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell, 145 (6), 863-74 PMID: 21640374