title: Regional specificity of manganese accumulation and clearance in the mouse brain: implications for manganese-enhanced MRI.
abstract: Manganese-enhanced MRI has recently become a valuable tool for the assessment of in vivo functional cerebral activity in animal models. As a result of the toxicity of manganese at higher dosages, fractionated application schemes have been proposed to reduce the toxic side effects by using lower concentrations per injection. Here, we present data on regional-specific manganese accumulation during a fractionated application scheme over 8 days of 30 mg/kg MnCl2 , as well as on the clearance of manganese chloride over the course of several weeks after the termination of the whole application protocol supplying an accumulative dose of 240 mg/kg MnCl2 . Our data show most rapid accumulation in the superior and inferior colliculi, amygdala, bed nucleus of the stria terminalis, cornu ammonis of the hippocampus and globus pallidus. The data suggest that no ceiling effects occur in any region using the proposed application protocol. Therefore, a comparison of basal neuronal activity differences in different animal groups based on locally specific manganese accumulation is possible using fractionated application. Half-life times of manganese clearance varied between 5 and 7 days, and were longest in the periaqueductal gray, amygdala and entorhinal cortex. As the hippocampal formation shows one of the highest T1 -weighted signal intensities after manganese application, and manganese-induced memory impairment has been suggested, we assessed hippocampus-dependent learning as well as possible manganese-induced atrophy of the hippocampal volume. No interference of manganese application on learning was detected after 4 days of Mn(2+) application or 2 weeks after the application protocol. In addition, no volumetric changes induced by manganese application were found for the hippocampus at any of the measured time points. For longitudinal measurements (i.e. repeated manganese applications), a minimum of at least 8 weeks should be considered using the proposed protocol to allow for sufficient clearance of the paramagnetic ion from cerebral tissue.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Grünecker
authors.forename: S F
authors.initials: SF
authors.lastname: Kaltwasser
authors.forename: A C
authors.initials: AC
authors.lastname: Zappe
authors.forename: B T
authors.initials: BT
authors.lastname: Bedenk
authors.forename: Y
authors.initials: Y
authors.lastname: Bicker
authors.forename: V I
authors.initials: VI
authors.lastname: Spoormaker
authors.forename: C T
authors.initials: CT
authors.lastname: Wotjak
authors.forename: M
authors.initials: M
authors.lastname: Czisch
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002712:Chlorides / Q000493:pharmacokinetics* / Q000633:toxicity; D007089:Image Enhancement; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D017895:Manganese Compounds / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D002712:Chlorides; D017895:Manganese Compounds; C025340:manganese chloride