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

Abstract

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 Mn(2+) . In this work, we have explored a new in vivo model to study Mn(2+) uptake, distribution and neurotoxicity in mice by subcutaneous implantation of mini-osmotic pumps delivering MnCl(2) 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 T(1) contrast in MRI while reducing toxicity. Manganese-enhanced MRI documented fast but reversible Mn(2+) 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. Mn(2+) accumulated as early as the first days after implantation, with a fast dispersal 9 days after stopping a 12-days Mn(2+) exposure. Prominent Mn(2+) accumulation was also seen in salivary glands and in the endocrine thyroid and posterior pituitary gland. These structures with enhanced Mn(2+) accumulation correlated well with those showing high expression of the secretory pathway Ca(2+) /Mn(2+) -ATPase (SPCA1), i.e. a transporter that could take part in Mn(2+) detoxification. Our new experimental model for continuous low-dosage administration of Mn(2+) is an easy alternative for enhancing Mn(2+) -based contrast in MEMRI studies, and might provide insight into the etiology of neuropathologies resulting from chronic Mn(2+) exposure in vivo.

4D MEMRI atlas of neonatal FVB/N mouse brain development

“…Additionally, in this study no injections were performed to the developing pups and instead lactating females were injected every other day from P0 to P10 (6x) or P1 to P9 (5x). The pups received Mn with milk, which is more similar to continuous Mn delivery via osmotic pumps that have been reported to have fewer side effects than acute IP injections (Eschenko et al, 2010; Mok et al, 2012; Sepulveda et al, 2012). Also relevant are studies reporting that fractionated Mn delivery can reduce toxicity (Bock et al, 2008; Grunecker et al, 2010).…”

High levels of Mn2+ inhibit secretory pathway Ca2+/Mn2+‐ATPase (SPCA) activity and cause Golgi fragmentation in neurons and glia

“…This is also supported by in vivo studies reporting that brain areas with high SPCA1 expression also show enhanced Mn 2+ accumulation upon continuous systemic MnCl 2 infusion in mice (Sepulveda et al . ) and by the observation that a gain‐of‐function mutation of SPCA1, which specifically enhances Golgi Mn 2+ transport, improves survival of Mn 2+ ‐exposed cells (Mukhopadhyay and Linstedt ).…”

Environmental enrichment is associated with rapid volumetric brain changes in adult mice

“…The MnCl 2 -solution was distributed equally across two injections administered 1 h apart to minimize potential adverse effects from peak MnCl 2 -concentration (Sepúlveda et al, 2012). Mice were anesthetized with 4% isoflurane.…”