Evaluation of manganese uptake and toxicity in mouse brain during continuous MnCl2 administration using osmotic pumps.

Manganese is a vital element and cofactor of many key enzymes, but it is toxic at high levels, causing pronounced disturbances in the mammalian brain. Magnetic resonance imaging (MRI) studies using manganese ions as a paramagnetic contrast agent are often limited by the neurotoxicity of Mn2+. In this work, we have explored a new in vivo model to study Mn2+ uptake, distribution and neurotoxicity in mice by subcutaneous implantation of mini-osmotic pumps delivering MnCl2 continuously for 21 days. Fractionated injections can reduce the toxicity; however, constant administration at very low doses using osmotic pumps caused a substantial effect on the T1 contrast in MRI while reducing toxicity. Manganese-enhanced MRI documented fast but reversible Mn2+ deposition largely in glomerular and mitral cell layers of the olfactory bulb, in the CA3 area of the hippocampus, and in the gray matter of the cerebellum. Mn2+ accumulated as early as the first days after implantation, with a fast dispersal 9 days after stopping a 12-days Mn2+ exposure. Prominent Mn2+ accumulation was also seen in salivary glands and in the endocrine thyroid and posterior pituitary gland. These structures with enhanced Mn2+ accumulation correlated well with those showing high expression of the secretory pathway Ca2+/Mn2+-ATPase (SPCA1), i.e. a transporter that could take part in Mn2+ detoxification. Our new experimental model for continuous low-dosage administration of Mn2+ is an easy alternative for enhancing Mn2+-based contrast in MEMRI studies, and might provide insight into the etiology of neuropathologies resulting from chronic Mn2+ exposure in vivo. Copyright © 2012 John Wiley & Sons, Ltd.