Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury

Dejan Milatovic, Ramesh C. Gupta, Yingchun Yu, Snjezana Zaja-Milatovic, Michael Aschner

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Exposure to excessive manganese (Mn) levels leads to neurotoxicity, referred to as manganism, which resembles Parkinson's disease (PD). Manganism is caused by neuronal injury in both cortical and subcortical regions, particularly in the basal ganglia. The basis for the selective neurotoxicity of Mn is not yet fully understood. However, several studies suggest that oxidative damage and inflammatory processes play prominent roles in the degeneration of dopamine-containing neurons. In the present study, we assessed the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates and associated neuronal dysfunctions both in vitro and in vivo. Results from our in vitro study showed a significant (p<0.01) increase in biomarkers of oxidative damage, F 2-isoprostanes (F 2-IsoPs), as well as the depletion of ATP in primary rat cortical neurons following exposure to Mn (500μM) for 2h. These effects were protected when neurons were pretreated for 30min with 100 of an antioxidant, the hydrophilic vitamin E analog, trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), or an anti-inflammatory agent, indomethacin. Results from our in vivo study confirmed a significant increase in F 2-IsoPs levels in conjunction with the progressive spine degeneration and dendritic damage of the striatal medium spiny neurons (MSNs) of mice exposed to Mn (100mg/kg, s.c.) 24h. Additionally, pretreatment with vitamin E (100mg/kg, i.p.) or ibuprofen (140μg/ml in the drinking water for two weeks) attenuated the Mn-induced increase in cerebral F 2-IsoPs? and protected the MSNs from dendritic atrophy and dendritic spine loss. Our findings suggest that the mediation of oxidative stress/mitochondrial dysfunction and the control of alterations in biomarkers of oxidative injury, neuroinflammation and synaptodendritic degeneration may provide an effective, multi-pronged therapeutic strategy for protecting dysfunctional dopaminergic transmission and slowing of the progression of Mn-induced neurodegenerative processes.

Original languageEnglish (US)
Pages (from-to)219-226
Number of pages8
JournalToxicology and Applied Pharmacology
Volume256
Issue number3
DOIs
Publication statusPublished - Nov 1 2011
Externally publishedYes

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Keywords

  • Ibuprofen
  • Manganese
  • Medium spiny neurons
  • Neurodegeneration
  • Oxidative stress
  • Trolox
  • Vitamin E

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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