Alzheimer type II astrocytic changes following sub-acute exposure to manganese and its prevention by antioxidant treatment.
Exposure to manganese in an industrial or clinical setting can lead to manganism, a neurological disorder with similarities to Parkinson's disease. Although the pathogenetic basis of this disorder is unclear, studies indicate this metal is highly accumulated in astrocytes, suggesting an involvement of these glial cells. To investigate this issue, we have used a recently characterized, sub-acute model of manganese neurotoxicity. Treatment of rats with manganese (II) chloride (50 mg/kg body weight, i.p.) once daily for 1 or 4 days led to increases in manganese levels of up to 232, 523, and 427% in the cerebral cortex, globus pallidus, and cerebellum, respectively, by instrumental neutron activation analysis. These changes were accompanied by development of pathological changes in glial morphology identified as Alzheimer type II astrocytosis in both cortical and sub-cortical structures. Co-treatment with either the antioxidant N-acetylcysteine or the manganese chelator 1,2-cyclohexylenedinitrilotetraacetic acid completely blocked this pathology, indicating the cellular transformation may be mediated by oxidative stress associated with the presence of this metal. These findings represent, to our knowledge, the first report of early induction of this pathological hallmark of manganese neurotoxicity, an event previously considered a consequence of chronic exposure to manganese in primates and in human cases of manganism. Our results also indicate that use of this rodent model may provide a novel opportunity to examine the nature and role of the Alzheimer type II astrocyte in the pathophysiology of this disorder as well as in other disease processes in which cerebral accumulation of manganese occurs.
Hazell
Alan S
AS
Department of Medicine, University of Montreal, Montreal, Que., Canada. alan.stewart.hazell@umontreal.ca
Normandin
Louise
L
Norenberg
Michael D
MD
Kennedy
Gregory
G
Yi
Jae-Hyuk
JH
D000111:Acetylcysteine / Q000627:therapeutic use*; D000544:Alzheimer Disease / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D002614:Chelating Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D004347:Drug Interactions; D004492:Edetic Acid / Q000008:administration & dosage; D008297:Male; D008345:Manganese / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000975:Antioxidants; D002614:Chelating Agents; D008345:Manganese; D004492:Edetic Acid; D000111:Acetylcysteine