Increased Iron in the Substantia Nigra Compacta of the MPTP‐Lesioned Hemiparkinsonian African Green Monkey: Evidence from Proton Microprobe Elemental Microanalysis

Abstract: The association of free radicals and particularly free iron in the pathogenesis of idiopathic Parkinson's disease and MPTP‐induced parkinsonism remains controversial. Whereas the actual cause of dopamine cell death in the substantia nigra compacta (SNc) remains unknown, disturbances in lipid peroxidation and subsequent mitochondrial and cell membrane disruption has been demonstrated. In a genetically susceptible host, abnormal elimination of oxygen and trace metal free radicals may further damage dopamine cells. Using a unilaterally MPTP‐treated African Green monkey, which showed obvious contralateral hemiparkinsonism, the total free iron concentration was measured. Iron, Fe 2+ and Fe 3+ , but not other trace elements, was significantly elevated in the SNc compared with the opposite unlesioned side, which was similar to separate control animals. Iron content in the SNc, periaqueductal gray area, and crus cerebri was 228–270 ppm. Normal control SNc was 285 (±59) ppm, whereas iron levels of 532 (±151) ppm were found in the MPTP‐lesioned SNc. These animals were drug naive and not on long‐term levodopa maintenance. Proton microprobe elemental analysis was matched against adjacent immunocytochemically stained tissue slices to ensure the cells studied were in the SNc. Iron was found not only in the degenerating dopamine cells themselves but also in the surrounding matrix and glial cells. Whether free iron that is not bound to neuromelanin is responsible for dopamine cell death as suggested by these experiments remains to be proved.