Basal Ganglia Accumulation and Motor Assessment Following Manganese Chloride Exposure in the C57BL/6 Mouse

Abstract

Equivocal clinical evidence for involvement of manganese in development of Parkinson's disease necessitates experimental studies on this issue. The aged, 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine-treated C57BL/6 mouse is one of the most common models for Parkinson's disease. However, there is little information on brain bioaccumulation of manganese, and little or no information on clinical/behavioral manifestations of manganese neurotoxicity, in this strain. Male C57BL/6 retired breeder mice were given a single subcutaneous injection of either 0, 50, or 100 mg/kg of MnCl(2) (single-dose regimen) or three injections of either of these doses over 7 days (multiple-dose regimen). Behavioral assessment was performed 24 h after final injection, followed by sacrifice, and body weight was recorded each day. There was a 105% increase in striatal manganese concentration 1 day after a single 100 mg/kg injection, and 421% and 647% increases, respectively, 1 day after multiple doses of 50 or 100 mg/kg of MnCl(2). One day after a single injection, there were respective 30.9% and 38.9% decreases in horizontal movement (grid crossing) for the 50 and 100 mg/kg doses and a 43.2% decrease for the multiple dose of 100 mg/kg. There was no significant main effect of dose level on rearing, swimming, grip strength, or grip fatigue. Unlike previous work with the C57BL/6 strain using smaller intraperitoneal doses, this study established dosing regimens that produced significant increases in basal ganglia manganese concentration reminiscent of brain increases in the CD-1 mouse following subcutaneous doses close to our lowest. A decrease in locomotor behavior, significant but not severe in this study, has been reported following manganese exposure in other mouse strains. These data, particularly the significant increase in basal ganglia manganese concentration, provide guidance for designing studies of the potential role of manganese in Parkinson's disease using the most common animal model for the disorder.

Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model

“…Mn exposure followed the previously published sub-chronic, 7-day paradigm[14, 15]. Briefly, 12-week-old male animals [at an age prior to neurodegeneration and neurogliosis[16]] or 42-week-old female animals were injected subcutaneously with a 1% solution of MnCl 2 × 4H 2 O in filtered MilliQ water at 50 mg/kg body weight, or with vehicle (filtered water), on experimental days 0, 3 and 6.…”

“…To test this hypothesis we exposed wild type (WT) and YAC128Q (HD) mice (12 weeks of age, preceding neuroinflammation and neurodegeneration) to subcutaneous injections of vehicle or MnCl 2 [14]. …”

Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies

“…Various symptoms of manganese toxicity are routinely tested in animals (Burton and Guilarte, 2009;Calabresi et al, 2001;Gwiazda et al, 2007;Newland, 1999;Olanow et al, 1996;Shukakidze et al, 2003). In particular, the effect of manganese on motor function has been reliably reproduced in different animals and experimental paradigms; this effect is apparent across a wide range of doses, different routes of administration and chemical species of manganese (Calabresi et al, 2001;Dodd et al, 2005;Mohammad and Faris, 2006;Nam and Kim, 2008;Newland and Weiss, 1992;Normandin et al, 2004). Manganese treatment typically results in decreased motor activity or disturbances in motor coordination, although a manganese-induced hyperactivity has also been reported (Calabresi et al, 2001;Eriksson et al, 1987).…”

Fractionated manganese injections: effects on MRI contrast enhancement and physiological measures in C57BL/6 mice

“…After systemic application, acute stress to heart and liver can be observed (22). In humans, overexposure to Mn 2þ may lead to so-called manganism, a form of parkinsonism (23), apparently related to the accumulation and slow clearance of Mn 2þ in the basal ganglia (6,24,25). Therefore, to ensure minimal toxic side effects in animals while obtaining optimal MRI contrast enhancement, it is necessary to optimize the Mn 2þ application scheme.…”