Oxidative damage and neurodegeneration in manganese-induced neurotoxicity.
Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson's disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterations in biomarkers of oxidative damage, F2-isoprostanes (F2-IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 microM Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E2 (PGE2). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F2-IsoPs and PGE2 in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration.
Milatovic
Dejan
D
Vanderbilt University Medical Center, Department of Pediatrics/Pediatric Toxicology, 2215-B Garland Avenue, 11415 MRB IV, Nashville, TN 37232-0414, USA. dejan.milatovic@vanderbilt.edu
Zaja-Milatovic
Snjezana
S
Gupta
Ramesh C
RC
Yu
Yingchun
Y
Aschner
Michael
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D002712:Chlorides; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D028441:F2-Isoprostanes / Q000378:metabolism; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D017895:Manganese Compounds; D020149:Manganese Poisoning / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D015415:Biomarkers; D002712:Chlorides; D028441:F2-Isoprostanes; D018836:Inflammation Mediators; D017895:Manganese Compounds; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D015232:Dinoprostone; C025340:manganese chloride