Mannitol promising for PD ?

Artificial Sweetener Promising for Parkinson's?

Pauline Anderson

Jun 25, 2013

NOTE FROM CLUB PD EDITOR: "This summary of a research study may be misleadingly titled. While mannitol is used as a sweetner in products like chewing gum, it is a naturally occuring sugar alchohol which is found in watermelon, pineapple, sweet potato, asparagus, mushrooms etc.. The study may be of profound significance in that mannitol may prevent further accumulations of alpha-synuclein in human brains by "chaperoning" the folding of this protein. So it is not inconceivable that something like a diet which is high in mannitol, could help explain why a very small percentage of PD patients (5%) have very low disease progression rates. More research is needed on mannitol and probably needs to include looking at whether mannitol also produces improvements in small motor control. Mannitol is poorly absorbed by the gut but can cross the blood brain barrier. Mannitol also acts as a diuretic, and is used in intravenous infusions with cancer radiation treatments."    

The original study was entitled A NOVEL DUAL MECHANISM OF MANNITOL FOR THE TREATMENT OF PD (Journal of Biological Chemistry, 1 May 2013)


Early evidence suggests that the artificial sweetener mannitol inhibits the aggregation of the protein α-synuclein in the brain, a finding that could have implications for movement disorders, such as Parkinson's disease (PD).


Mannitol's ability to interfere with protein clumping, together with its propensity to disrupt the blood-brain barrier (BBB), indicates that the administration of this sugar substitute in combination with other drugs could be a promising new approach for treating PD and other brain-related diseases, such as Alzheimer's disease, researchers conclude.


A new series of experiments on flies and mice show that mannitol is one of the most promising small sugars tested so far and have left researchers "very excited," said Daniel Segal, PhD, head, Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Israel, who carried out the experiments along with his colleagues.

Mannitol, a sugar alcohol produced by fungi, bacteria, and algae, is a common component of sugar-free gum and candy. It is also approved by the Food and Drug Administration (FDA) in the United States as a diuretic and for use during surgery to open the BBB to ease passage of drugs.


Their findings were published in the June 14 issue of Journal of Biological Chemistry.


Structural Characteristics

In a series of experiments, researchers first identified the structural characteristics that facilitate the development of clumps of α-synuclein. After testing several possible agents, they found that mannitol was the most effective in inhibiting this aggregation process in vitro.

In an experiment with fruit flies using a "locomotion climbing assay," the researchers found that only 38% of flies that were genetically engineered to carry α-synuclein were able to climb the walls of the test tube, indicating they had a severe motor dysfunction, compared with 72% of normal flies. But after being fed food containing mannitol for 27 days, 70% of the mutated flies could climb the test tube.The researchers also observed a 70% reduction in aggregates of α-synuclein in the mannitol-fed mutated flies compared with those that had not.

But Dr. Segal remains cautious. "We see an effect of mannitol on α-synuclein in the test tube; we see an effect on flies that express α-synuclein when we treat them with mannitol; but do we know for sure, or have we shown positively, that what mannitol does in the fly is exactly what it does in the test tube? No, but it is very compelling."

What was equally compelling was the next experiment, where the researchers injected mice engineered to produce human α-synuclein with mannitol. After 4 months, these mice also showed a dramatic reduction in α-synuclein in several brain regions.

The results suggest that mannitol promotes clearance of the protein in cell bodies and has a neuroprotective effect on the dopaminergic system.

An encouraging observation with this experiment was that the treated mice did not exhibit any adverse effects, he noted. "But the sample size was small, and one has to bear these limitations in mind before jumping to any conclusions," warned Dr. Segal.

The mouse experiments could not demonstrate what effect, if any, mannitol had on normal mice, he said. Further, the experiment did not include a behavioral analysis, which could be the next step, said Dr. Segal.


Crucial Questions

Although the work so far has been exciting, there is still a lot more to do to answer some crucial questions. For example, said Dr. Segal, it's important to show that mannitol actually enters the brain (perhaps using radioactive labels) and to determine the exact concentration needed to have the effect of inhibiting protein aggregation.

"A series of experiments need to be done before we can even think in terms of starting to really do some preclinical systematic work in human beings," said Dr. Segal.

In patients with PD, α-synuclein in the brain's substantia nigram is fold-and-form sheets that aggregate and then form gummy fibrils. To date, delivering therapeutic agents to the brain through the BBB to interrupt this process has been challenging.

Because mannitol is already FDA approved, and if all goes well, research in patients with PD could begin in 3 years, said Dr. Segal. Things might be speeded along if researchers develop and then patent a slightly different compound.

In the meantime, while the findings are hopeful, "I'd be very reluctant to suggest, or to imply even, that people should start taking mannitol on a daily basis," he added, because adverse effects of oral administration have not been tested in humans.

Medscape Medical News asked Michael S. Okun, MD, professor, Departments of Neurology, Neurosurgery, Neuroscience, and Psychiatry, University of Florida in Gainesville, and national medical director, National Parkinson Foundation, to comment on this new development.


Information from Industry

"The idea that mannitol, which is a common and readily available drug that may disrupt the blood-brain barrier and have a positive effect on the depositions known to cause Parkinson's disease in animal models (α-synuclein) is intriguing but will need much more supportive data to flesh out safety issues and to show a true disease-modifying effect in Parkinson's disease human patients," said Dr. Okun.

"We would not advise our patients to use mannitol for the symptomatic treatment of Parkinson's disease, but we do look forward to seeing more research in this area."

The research was funded by a grant from the Parkinson's Disease Foundation and was supported in part by the Lord Alliance Family Trust.

J Biol Chem. 2013;288:17579-17588. Abstract


The following observations, from the original paper issued by the researchers, are worthy of note:

"Mannitol also exhibited specific neuroprotective qualities in the dopaminergic system of the treated mice, where it was able to restore TH immunoreactivity in the mThy1-alpha-syn tg mice back to levels comparable with vehicle-treated non-tg mice in the BG. Importantly, mannitol had no general neuroprotective effect on the control non-tg mice. Mannitol seems to have a preventive ability to inhibit alpha-syn aggregation, but not a reversive ability. Mannitol was not able to dissolve preformed alpha-syn aggregates in vitro nor to dissolve alpha-syn aggregates when dripped on brain sections taken from alpha-syn tg mice. Abnormal protein misfolding and aggregation are key features in many neurodegenerative disorders. Interestingly, a decline in the intracellular level of molecular chaperones was shown to increase the levels of abnormally folded proteins inside the cell (39). Therefore, it was proposed that the cell toxicity in neurodegenerative disorders may result from an imbalance between normal chaperone capacity and the production of misfolded protein species (40). Hence, the addition of chemical and molecular chaperones, which are able to stabilize misfolded proteins, was suggested as a therapeutic approach in neurodegenerative disorders (22). In addition to its BBB-disrupting properties, mannitol was previously suggested to function as a chemical chaperone, demonstrating a very potent effect on the stabilization of protein structure (19–21). Here, we have demonstrated that mannitol interferes with alpha-syn aggregation in vitro and in vivo, whereas no adverse effects were observed in control-treated flies or mice. In addition to its osmotic diuretic effect, mannitol is known for its BBB-disrupting properties (41). To the best of our knowledge, mannitol has not been tested or used until now in the clinic for drug delivery into the brain. Therefore, we suggest that mannitol administration in combination with other drugs could be a promising new approach for treating PD and other brain-related diseases such as Alzheimer disease. This prediction is based on its chemical chaperone properties, its vast protective cellular capabilities, and its BBB-disrupting properties."