Imaging the Transmembrane and Transendothelial Sodium Gradients in Gliomas

ABSTRACT 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, which reflect cell membrane potential ( V m ) and blood-brain barrier (BBB) integrity. We developed a sodium ( 23 Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic contrast agent to measure ΔNa + mem and ΔNa + end . In vitro 23 Na-MRSI established that the 23 Na signal is strongly shifted by the agent compared to biological factors. In vivo 23 Na-MRSI showed Na + i remained unshifted and Na + b was more shifted than Na + e , and these together created weakened ΔNa + mem and enhanced ΔNa + end in rat gliomas. Specifically, RG2 and U87 tumors maintained weakened ΔNa + mem (i.e., depolarized V m ) implying an aggressive state for proliferation, and RG2 tumors displayed elevated ΔNa + end suggesting altered BBB integrity. 23 Na-MRSI will allow explorations of perturbed Na + homeostasis in vivo for the tumor neurovascular unit.