Manganese toxicity is associated with mitochondrial dysfunction and DNA fragmentation in rat primary striatal neurons

Manganese (Mn) in excess is toxic to neurons of the globus pallidus, leading to a Parkinsonian-like syndrome. We used rat primary neuron cultures to examine the cellular events following manganese exposure. Following exposure to Mn2+ for 48 h, striatal neurons showed dose-dependent losses of mitochondrial membrane potential and complex II activity. The Mn exposure effect on mitochondrial membrane potential was significant at every concentration measured (5, 50, and 500 muM), and the manganese exposure effect on complex II activity was significant at 50 and 500 muM. Exposure of striatal neurons to both Mn2+ and the complex II inhibitor 3-nitropropionic acid resulted in additive toxicity. Striatal neurons exposed to 5 muM Mn2+ for 48 h exhibited DNA fragmentation and decreases in the immunohistochemically detectable microtubule-associated protein MAP-2. These results indicate that manganese may trigger apoptotic-like neuronal death secondary to mitochondrial dysfunction. Rescue of neurons by apoptosis inhibitors may be helpful in treating manganese toxicity and similar neurodegenerative processes. (C) 2001 Elsevier Science Inc.