α-Synuclein has long been known to accumulate in the brains of people with Parkinson’s and cause cognitive changes. Finding treatment to prevent clumping of α-synuclein has been very complex and challenging. But a substance used by surgeons during surgery to open the blood-brain barrier and allow necessary drugs to pass may hold the key. Mannitol is also Federal Drug Administration (FDA) approved as a diuretic, to flush out excess fluids. And it is a popular artificial sweetener in sugar free gum.
Researchers Ehud Gazit and Daniel Segal identified the structures of α-synuclein that cause it to form clumps and bind together. Understanding how those structures worked lead them to look for various substances that might prevent the clumps from forming. It was in that process that they identified Mannitol as being one of the most effective at preventing aggregation of α-synuclein in test tubes. Making it an even more attractive candidate was the fact that it was already FDA approved for other medical uses.
They began by testing Mannitol in the brains of very simple creatures: fruit flies that were genetically engineered to express human α-synuclein and ordinary fruit flies without any genetic changes. Next, they measured the fruit flies ability to climb up the walls of a test tube, a so called “climbing assay”. In the first trial, 72 percent of the “normal” fruit flies were able to complete the climb up the test tube, but only 38 per cent of the genetically modified fruit flies were able to successfully climb the test tube.
For 27 days they added Mannitol to the food of the genetically altered fruit flies, but not to the food of the control flies. When the “climbing assay” was again administered, 70 per cent of the genetically altered fruit flies were able to climb the test tube walls. On examining the brains of these flies, they found a 70 per cent reduction in α-synuclein.
Dr. Eliezer Masliah of the University of San Diego repeated the experiment, this time using genetically modified mice. The results showed a dramatic reduction in the aggregates of α-synuclein after four months of injections of Mannitol.
Fruit flies and mice are still a long way from human people with Parkinson’s disease! The proven reduction of α-synuclein in the brain is exciting, but more studies of behavior in other animal models of Parkinson’s are needed. The researchers are presently searching for ways to modify the Mannitol compound in order to optimize its effectiveness and insure its safety. Much more animal research will need to be performed before trials for humans can begin.
Dr. Segal does not advise people with Parkinson’s to begin chewing quantities of sugar free gum! But he does hold hope that because Mannitol is useful in crossing the blood-brain barrier, it may prove useful as a transporter for other medications for Parkinson’s that are now very difficult to get into certain regions of the brain.
This research was done at Tel Aviv University, Depoartment of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience. Collegue Ronit Shaltiel-Karyo and Ph.D. candidate Moran Frenkel-Pinter were also participants in this study. The results were presented at the Drosophilia Conference in Washington, D.C. in April.
A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor: A NOVEL DUAL MECHANISM OF MANNITOL FOR THE TREATMENT OF PARKINSON DISEASE (PD)J. Biol. Chem. 2013 288: 17579-17588. First Published on May 1, 2013,doi:10.1074/jbc.M112.434787