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Urate Protects Dopaminergic Neurons in Mouse Model of Parkinsonís Disease

Boosting urate levels in the brain protects mice from the kind of damage that underlies Parkinson’s disease (PD), according to new research in the January 2 issue of the Proceedings of the National Academy of Sciences. In contrast, mice with lower-than-normal levels of urate suffered more damage. The study supports the idea that increasing the level of urate in the brain could protect against PD or slow its progression.

Urate is a natural antioxidant produced by the body. Previous research has shown that people with higher levels of urate in their blood have a reduced risk of PD. Also, among people living with PD, higher urate levels are associated with slower PD progression. Understanding the mechanism that links urate to lower PD risk could help scientists develop safe and effective therapies.

Researchers led by Xiqun Chen, M.D., Ph.D., at Massachusetts General Hospital studied the effects of raising or lowering urate levels in mice. All of the mice were genetically engineered to have either higher- or lower-than-normal amounts of urate in their brains. They were also treated with a toxin to experience a loss of dopamine neurons and symptoms similar to those of PD. The researchers studied the mice’s reactions to behavioral tests and studied the impact of urate levels on the brain.

Results

  • Compared to mice with normal urate levels, the mice with high levels showed significantly less brain damage. They retained twice as many dopaminergic neurons and about twice as much dopamine on the side of the brain treated with PD-causing agents. They also had fewer movement abnormalities.
  • The mice with abnormally low levels of urate showed more damage than mice with normal urate levels. These mice had fewer surviving dopaminergic neurons, less dopamine, and more movement abnormalities than their counterparts.

What Does It Mean?

This study strengthens the theory that urate may have protective effects against PD.

Its results showed that urate protects against toxins that damage the brain in a similar way to PD. The fact that mice with high levels of urate kept more neurons and experienced fewer movement problems, supports study into drugs that might raise urate levels for the treatment and prevention of PD.

However, researchers do not yet understand how urate is protective. For example, the toxin they studied causes cell death from oxidative stress. But the researchers were surprised to see signs of oxidative stress even in the brains of mice with high levels of urate. This suggests that urate may protect neurons in a different, yet unknown, way, not necessarily by preventing oxidative stress.

Observations about urate have prompted a clinical trial called SURE-PD (Safety of Urate Elevation in PD) that will evaluate the safety of a medication that boosts urate in people with early PD. It is important to caution that very high levels of urate can cause gout and kidney stones and may contribute to heart disease. In fact, the mice in the study with high levels of urate experienced severe kidney damage. Researchers will need to determine when developing drugs, whether there is an optimal amount of urate that will protect against PD, but not cause severe side effects.

Reference: Chen, X., Burdett, T. C., Desjardins, C. A., Logan, R., Cipriani, S., Xu, Y., & Schwarzschild, M. A. (2013). Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America, 110(1), 300–305. doi:10.1073/pnas.1217296110

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Source Date: Feb 20 2013