MPP+ Analogs Acting on Mitochondria and Inducing Neuro-Degeneration

Y.      Kotake; S.      Ohta

Abstract

This review focuses on the mechanisms of action and the injurious effect of complex I inhibitors, of which 1-methyl-4-phenylpyridinium ion (MPP+) is a well studied example. These compounds can be divided into two groups, i.e. competitive inhibitors with respect to ubiquinone, such as piericidine A, and noncompetitive inhibitors such as rotenone. Complex I inhibitors such as MPP+ have been reported to induce anatomical, behavioral, and biochemical changes similar to those seen in Parkinsons disease, which is characterized by nigrostriatal dopaminergic neuro-degeneration. Spectroscopic analyses and structure-activity relationship studies have indicated that the V-shaped structure of the rotenone molecule is critical for binding to the rotenone binding site on complex I. Many isoquinoline derivatives, some of them endogenous, are also complex I inhibitors. Many lines of evidence show that complex I inhibitors elicit neuronal cell death. Recently, it was reported that chronic and systemic exposure to low-dose rotenone reproduces the features of Parkinsons disease. This work further focused attention on compounds acting on mitochondria, such as MPP+. In Guadeloupe, the French West Indies, patients with atypical parkinsonism or progressive supranuclear palsy are frequently encountered. These diseases seem to be associated with ingestion of tropical herbal teas or tropical fruits of the Annonaceae family, which contain complex I inhibitors such as benzylisoquinoline derivatives and acetogenins. Complex I inhibitors may not simply result in reactive oxygen species generation or ATP exhaustion, but may influence complex downstream signal transduction processes. An understanding of these changes would throw light on the ways in which complex I inhibitors induce a wide range of abnormalities.

Keywords: complex I inhibitor, parkinson's disease, rotenone, apoptosis, tetrahydroisoquinoline, benzylisoquinoline alkaloid, acetogenin

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