Microglia enhance manganese chloride-induced dopaminergic neurodegeneration: role of free radical generation.
Exposure to elevated levels of manganese has been shown to cause neuronal damage in the midbrain and the development of Parkinsonian symptoms. Activation of microglia and release of neurotoxic factors in particular free radicals are known to contribute to neurodegeneration. We have recently reported that manganese chloride (MnCl(2)) stimulates microglia to produce reactive oxygen species (ROS). The aim of this study is to determine the role of microglia in the MnCl(2)-induced degeneration of dopaminergic (DA) neurons that are particularly vulnerable to oxidative insult. MnCl(2) (10-300 microM; 7 days) was markedly more effective in damaging DA neurons in the rat mesencephalic neuron-glia cultures than the neuron-enriched (microglia-depleted) cultures. In addition, the microglia-enhanced MnCl(2) toxicity was found to be preferential to DA neurons. The microglial enhancement of DA neurotoxicity was further supported by the observation that replenishment of microglia to the neuron-enriched cultures significantly increased the susceptibility of DA neurons to the MnCl(2)-induced damage. Analysis of the temporal relationship between microglial activation and DA neurodegeneration revealed that MnCl(2)-stimulated microglial activation preceded DA neurodegeneration. Mechanistically, MnCl(2) (10-300 microM) stimulated a concentration- and time-dependent robust production of ROS and moderate production of nitric oxide but no detectable release of tumor necrosis factor-alpha and interleukin-1beta. Application of free radical scavengers including superoxide dismutase/catalase, glutathione, N-acetyl cysteine and an inhibitor of nitric oxide biosynthesis significantly protected DA neurons against the MnCl(2)-induced degeneration. These results demonstrate that microglial activation and the production of reactive nitrogen and oxygen free radicals promote the MnCl(2)-induced DA neurodegeneration.
Zhang
Ping
P
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
Wong
Tamika A
TA
Lokuta
Kyle M
KM
Turner
Deanne E
DE
Vujisic
Kristina
K
Liu
Bin
B
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D039481:CD11b Antigen / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002712:Chlorides; D018920:Coculture Techniques; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism; D017895:Manganese Compounds; D008636:Mesencephalon / Q000166:cytology; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014316:Tritium / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D039481:CD11b Antigen; D002712:Chlorides; D053583:Interleukin-1beta; D017895:Manganese Compounds; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014316:Tritium; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase; C025340:manganese chloride; D004298:Dopamine