Lithium Accumulates in Neurogenic Brain Regions as Revealed by High Resolution Ion Imaging

Abstract

Lithium (Li) is a potent mood stabilizer and displays neuroprotective and neurogenic properties. Despite extensive investigations, the mechanisms of action have not been fully elucidated, especially in the juvenile, developing brain. Here we characterized lithium distribution in the juvenile mouse brain during 28 days of continuous treatment that result in clinically relevant serum concentrations. By using Time-of-Flight Secondary Ion Mass Spectrometry- (ToF-SIMS) based imaging we were able to delineate temporospatial lithium profile throughout the brain and concurrent distribution of endogenous lipids with high chemical specificity and spatial resolution. We found that Li accumulated in neurogenic regions and investigated the effects on hippocampal neurogenesis. Lithium increased proliferation, as judged by Ki67-immunoreactivity, but did not alter the number of doublecortin-positive neuroblasts at the end of the treatment period. Moreover, ToF-SIMS revealed a steady depletion of sphingomyelin in white matter regions during 28d Li-treatment, particularly in the olfactory bulb. In contrast, cortical levels of cholesterol and choline increased over time in Li-treated mice. This is the first study describing ToF-SIMS imaging for probing the brain-wide accumulation of supplemented Li in situ. The findings demonstrate that this technique is a powerful approach for investigating the distribution and effects of neuroprotective agents in the brain.

Lithium protects hippocampal progenitors, cognitive performance and hypothalamus-pituitary function after irradiation to the juvenile rat brain

“…The intra- and extracellular lithium concentrations required to obtain the observed effects in the brain are not known, but we recently showed that serum concentrations of 1.2 mM in mice yielded brain tissue concentrations in the range of 0.82 - 0.05 mM, where the highest concentrations were observed in the neurogenic regions [34]. Lithium did not appear to protect medulloblastoma cells from radiation-induced cell death in vitro .…”

Lithium treatment reverses irradiation-induced changes in rodent neural progenitors

“…was sufficient to yield a lithium serum concentration of 0.7-0.9 mM in mice (Zanni et al 2017), which is equivalent to the commonly used 0.6-1.2 mM therapeutic range in humans.…”

“…Female littermates (5-6 animals in each cage) were randomly assigned to lithium chow ( Netherlands). This regimen was determined in our previous study (Zanni et al 2017) and…”

“…Immunohistochemistry and quantification were performed as previously described (Zanni et al 2017). The following primary antibodies were used: rat anti-BrdU (1:500, AbD Serotec, Kidlington, UK) and goat anti-DCX (1:100, Santa Cruz Biotechnology Inc., CA, USA Only cells with an entire, clearly visible cell body were counted.…”

Action Plan for Prolongation of Nephrogenesis in Preterm and Growth Restricted Babies: Explore Ultrastructure of the Nephrogenic Zone, Identify a Molecular Target, Select a Viable Drug and Find a Path for Administration

“…For years lithium (Li + ) is known as a potent mood stabilizer. Actual experiments show in this connection that the ion accumulates in neurogenic brain regions [122]. However, in earlier culture experiments it was demonstrated that Li + ions can also elicit the early stages of epithelial differentiation in isolated nephrogenic mesenchyme [123].…”