Molecular neurochemistry of the lanthanides

Lanthanides, once termed rare-earth elements, are not as sparce in the environment as their traditional name suggests. Mean litospheric concentrations are in fact comparable to the physiologically fundamental elements such as iodine, cobalt, and selenium. Recent advances in medical technology have resulted in accumulation of lanthanides presenting potential exposure to both our central and peripheral nervous systems. Extensive and detailed studies on these peculiar active metals in the context of their influence on neural functions are therefore urgently required. Almost all neurochemical effects of trivalent lanthanide ions appear to result from the similarity of their radii to the key signaling ion calcium. Lanthanides, especially La³⁺ and Gd³⁺ block different types of calcium, potassium, and sodium channels in human and animal neurons, regulate neurotransmitter turnover and release, as well as synaptic activity. Lanthanides also act as modulators of several ionotropic receptors, e.g., GABA, NMDA, and kainate and can also affect numerous signaling mechanisms including NF-κB and apoptotic-related endoplasmic reticulum IRE1-XBP1, PERK, and ATF6 pathways. Several lanthanide ions may cause oxidative neuronal injuries and functional impairment by promoting reactive oxygen species production. However, cerium and yttrium oxides have some unique and promising neuroprotective properties, being able to decrease free radical cell injury and even alleviate motor impairment and cognitive function in animal models of multiple sclerosis and mild traumatic brain damage, respectively. In conclusion, lanthanides affect various neurophysiological processes, altering a large spectrum of brain functions. Thus, a deeper understanding of their potential mechanistic roles during disease and as therapeutic agents requires urgent elucidation.