Inhibiting Myeloperoxidase May be Useful in Treating Parkinson’s Disease

Jay W. Heinecke, MD
University of Washington
NIEHS Grant P30ES007033

Background: Parkinson’s disease is characterized by progressive and severe motor impairment caused by the loss of dopamine producing neurons in the substantia nigra region of the brain. There has been a great deal of research that suggests that oxidative stress, damage to cells, tissues, and organs resulting from exposure to reactive oxygen molecules such as hydroxyl radical, superoxide, hydrogen peroxide, and peroxynitrite, is responsible for the gradual decline of dopaminergic neurons.

Mistakes in the production of the illicit drug 1­methyl­4­phenyl­4­propionoxypiperidine (MPPP) can result in its contamination with 1­methyl­4­phenyl­1,2,3,6­tetrahydropyridine (MPTP). As MPPP became more popular in the 1970s and 80s, hospitals began admitting patients as young as 19 with severe end­stage Parkinsonian symptoms. The source was tracked down to MPTP and its effect was found to be permanent damage to the neurons of the substantia nigra. Since then a mouse model utilizing MPTP­induced Parkinson’s disease has been developed to study the illness.

Advance: An NIEHS­supported researcher at the University of Washington, along with colleagues at Columbia University and Konkuk University in Korea, has determined that production of a key oxidant producing enzyme, myeloperoxidase, is increased in the brains of Parkinson’s disease patients and mice with MPTP­induced symptoms. The research also shows that mutant mice lacking the ability to make myeloperoxidase are more resistant to MPTP­induced cellular toxicity than their wild­type littermates. Additional evidence supporting the oxidative damaging role of myeloperoxidase is the increase of two markers of the enzyme’s activity in the brains of MPTP­treated mice.

Implications: Although myeloperoxidase produces oxidants during inflammation, it was not previously considered to be a contributor to cell damage in Parkinson’s disease. This study shows that myeloperoxidase is a component of the MPTP neurotoxic process and suggests that substances that inhibit myeloperoxidase may be useful in treating Parkinson’s disease.

Citation: Choi DK, Pennathur S, Perier C, Tieu K, Teismann P, Wu DC, Jackson­Lewis V, Vila M, Vonsattel JP, Heinecke JW, Przedborski S. Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson’s disease in mice. J Neurosci. 2005 Jul 13;25(28):6594-600.