Imaging the Transmembrane and Transendothelial Sodium Gradients in Gliomas

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 (Delta Na-mem(+)) and weak transendothelial (Delta Na-end(+)) gradients respectively, and these manifest the cell membrane potential (V-m) as well as blood-brain barrier (BBB) integrity. We developed a sodium (Na-23) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic polyanionic agent to measure Delta Na-mem(+) and Delta Na-end(+). In vitro Na-23-MRSI established that the Na-23 signal is intensely shifted by the agent compared to other biological factors (e.g., pH and temperature). In vivo Na-23-MRSI showed Na-i(+) remained unshifted and Na-b(+) was more shifted than Na-e(+), and these together revealed weakened Delta Na-mem(+) and enhanced Delta Na-end(+) in rat gliomas (vs. normal tissue). Compared to normal tissue, RG2 and U87 tumors maintained weakened Delta Na-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 Na-23-MRSI will allow biomedical explorations of perturbed Na+ homeostasis in vivo.