Neuroscience Letters 396 (2006) 167–171 Alzheimer type II astrocytic changes following sub-acute exposure to manganese and its prevention by antioxidant treatment Alan S. Hazell a,∗ , Louise Normandin a , Michael D. Norenberg c , Gregory Kennedy b , Jae-Hyuk Yi a a Department of Medicine, University of Montreal, Montreal, Que., Canada b Department of Engineering Physics, ´ Ecole Polytechnique, Montreal, Que., Canada c Departments of Pathology and Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL, USA Received 15 September 2005; received in revised form 15 November 2005; accepted 15 November 2005 Abstract 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. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Manganism; Astrocyte; Globus pallidus; Alzheimer type II astrocytosis; Manganese neurotoxicity; Oxidative stress Since the initial finding that manganese exposure can lead to an unsteady gait and muscular weakness [7], many cases of manganese neurotoxicity (manganism), a neurological disease similar to Parkinson’s disease, have been reported, particularly in miners, smelters and workers involved in the battery and alloy industry [8,22]. Such cases typically exhibit extrapyramidal anomalies that include hypokinesia, rigidity, and tremor associ- ated with accumulation of manganese in the basal ganglia, and highlight the potential health hazard associated with exposure to relatively high levels of manganese-containing compounds in and around the workplace. In addition, the use of methylcy- ∗ Corresponding author at: NeuroRescue Laboratory, Hˆ opital Saint-Luc (CHUM), 1058 Saint-Denis, Montreal, Que., Canada H2X 3J4. Tel.: +1 514 890 8310x35740; fax: +1 514 412 7314. E-mail address: alan.stewart.hazell@umontreal.ca (A.S. Hazell). clopentadienyl manganese tricarbonyl, a manganese-containing antiknock agent which improves octane rating in unleaded gaso- line [12], and which leads to increased manganese emissions in the atmosphere, has attracted considerable environmental atten- tion. Studies have revealed that astrocytes accumulate manganese by a high affinity, high capacity, specific transport system, with a major consequence of exposure to this metal being the development of Alzheimer type II astrocytosis in humans and primates, an important pathological hallmark of this disorder [4,16]. Alzheimer type II astrocytes have enlarged, pale nuclei with margination of chromatin and prominent nucleoli and can also be found in several hyperammonemic disorders [3,6]. At the ultrastructural level, the major abnormal features can be visualized, consisting of an enlargement of the cytosolic com- partment, containing increased numbers of mitochondria and rough endoplasmic reticulum [13]. Although such features are 0304-3940/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2005.11.064