Imaging the transmembrane and transendothelial sodium gradients in gliomas

Abstract

Abstract Under normal conditions, high sodium (Na+) in extracellular (Na+ e) and blood (Na+ b) compartments and low Na+ in intracellular milieu (Na+ i) produce strong transmembrane (ΔNa+ mem) and weak transendothelial (ΔNa+ end) gradients respectively, and these manifest the cell membrane potential (V m ) as well as blood–brain barrier (BBB) integrity. We developed a sodium (23Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic polyanionic agent to measure ΔNa+ mem and ΔNa+ end. In vitro 23Na-MRSI established that the 23Na signal is intensely shifted by the agent compared to other biological factors (e.g., pH and temperature). In vivo 23Na-MRSI showed Na+ i remained unshifted and Na+ b was more shifted than Na+ e, and these together revealed weakened ΔNa+ mem and enhanced ΔNa+ end in rat gliomas (vs. normal tissue). Compared to normal tissue, RG2 and U87 tumors maintained weakened ΔNa+ mem (i.e., depolarized V m ) implying an aggressive state for proliferation, whereas RG2 tumors displayed elevated ∆Na+ end suggesting altered BBB integrity. We anticipate that 23Na-MRSI will allow biomedical explorations of perturbed Na+ homeostasis in vivo.