Common Sweetener May Offer Treatment Option for Parkinson’s Disease

The Tel Aviv University (Israel) investigators’ findings were presented April 9, 2013, at the Genetics Society of America’s 54th annual Drosophila Research Conference, held in Washington DC (USA). Mannitol is a sugar alcohol used as a component of sugar-free gum and candies and was first isolated from flowering ash. Algae, fungi, bacteria, and plants produce mannitol, but the human body cannot. For most commercial uses, it is extracted from seaweed although chemists can synthesize it, and it can be used for more than just a sweetener.

The US Food and Drug Administration (FDA) approved mannitol as an intravenous diuretic to flush out excess fluid. It also enables drugs to cross the blood-brain barrier (BBB), the tightly linked cells that form the walls of capillaries in the brain. The tight junctions holding together the cells of these miniscule blood vessels come slightly apart five minutes after an infusion of mannitol into the carotid artery, and they stay open for approximately 30 minutes.

Mannitol has another, less-studied advantage: it prevents a sticky protein called α-synuclein from adhering to the substantia nigra region of the brains of individuals with PD and Lewy body dementia (LBD), which has similar symptoms to PD. In the disease state, the proteins first misfold, then form sheets that aggregate and then extend, forming gummy fibrils.

Molecular chaperones, which are specific biochemical components that typically stabilize proteins and help them fold into their native three-dimensional forms, which are essential to their functions. Mannitol is a chemical chaperone. So like a delivery person who both opens the door and brings in the pizza, mannitol may be used to treat Parkinson's disease by getting into the brain and then restoring normal folding to α-synuclein.

Daniel Segal, PhD, and colleagues at Tel Aviv University studied the effects of mannitol on the brain by feeding it to fruit flies with a form of PD that has highly aggregated α-synuclein. The researchers used a locomotion-climbing assay to study fly movement. Normal flies scamper right up the wall of a test tube, but flies whose brains are encumbered with α-synuclein aggregates stay at the bottom, presumably because they cannot move normally. The percentage of flies that climb one centimeter in 18 seconds assesses the effect of mannitol.

An experimental run tested flies daily for 27 days. After that time, 72% of normal flies ascended up, in comparison to 38% of the PD flies. Their absence of climbing up the sides of the test tube indicated severe motor dysfunction. By contrast, flies bred to harbor the human mutant α-synuclein gene, who as larvae feasted on mannitol that sweetened the medium at the bottoms of their vials managed much better—70% of them could climb after 27 days. Furthermore, brain slices revealed a 70% decrease in accumulated misfolded protein compared to the brains of mutant flies raised on the regular medium lacking mannitol.

This research suggests a potential innovative therapeutic application. Dr. Segal, however, cautioned that people with PD or similar movement disorders should not consume a lot of mannitol-sweetened gum or sweets; that will not help their current condition. The next step for researchers is to demonstrate a rescue effect in mice, similar to enhanced climbing by flies, in which a rolling drum (rotarod) activity assesses mobility.

“Until and if mannitol is proven to be efficient for PD on its own, the more conservative and possibly more immediate use can be the conventional one, using it as a BBB disruptor to facilitate entrance of other approved drugs that have problems passing through the BBB,” Dr. Segal said. An early clinical trial of mannitol on a small number of volunteers might follow if mice study findings validate those seen in the flies, he added, but that is still is not yet ready for human trials.

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