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.

Automated summary

Under normal conditions, sodium distribution and gradients in different compartments are critical for membrane potential and blood-brain barrier integrity. A newly developed Na-23 magnetic resonance spectroscopic imaging (MRSI) method using a paramagnetic polyanionic agent allows for exploration of perturbed sodium homeostasis in vivo, revealing altered sodium ion distribution and gradients in rat gliomas compared to normal tissue. This suggests potential implications for aggressive proliferation and altered BBB integrity in tumor progression.