SPECT/CT imaging reveals CNS-wide modulation of glymphatic cerebrospinal fluid flow by systemic hypertonic saline

• DOI: 10.1016/j.isci.2022.105250
• Publication Date: 2022-09-29T16:57:35Z
• Authors: Tuomas O. Lilius; Marko Rosenholm; Laura Klinger; Kristian Nygaard ...; Björn Sigurdsson; Frida Lind-Holm M...; Natalie L. Hauglund; Malthe Skytte Nor...; Tomi Rantamäki; Maiken Nedergaard
• Keywords: CLEARANCE; Science; Drug delivery system; Transport; Pharmacy; RAT-BRAIN; Article; PATHWAY; Central-nervous-system; DELIVERY; 03 medical and health sciences; 0302 clinical medicine; Blood-brain-barrier; BLOOD-BRAIN-BARRIER; CENTRAL-NERVOUS-SYSTEM; Q; Tc-99m-dtpa; Rat-brain; TRANSPORT; 3. Good health; TC-99M-DTPA; Clearance; Delivery; Small animal imaging; Pathway; Neuroscience

Intrathecal administration enables central nervous system delivery of drugs that do not bypass the blood-brain barrier. Systemic administration of hypertonic saline (HTS) enhances delivery of intrathecal therapeutics into the neuropil, but its effect on solute clearance from the brain remains unknown. Here, we developed a dynamic in vivo single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging platform to study the effects of HTS on whole-body distribution of the radiolabeled tracer 99mTc-diethylenetriaminepentaacetic acid (DTPA) administered through intracisternal, intrastriatal, or intravenous route in anesthetized rats. Co-administration of systemic HTS increased intracranial exposure to intracisternal 99mTc-DTPA by ∼80% during imaging. In contrast, HTS had minimal effects on brain clearance of intrastriatal 99mTc-DTPA. In sum, SPECT/CT imaging presents a valuable approach to study glymphatic drug delivery. Using this methodology, we show that systemic HTS increases intracranial availability of cerebrospinal fluid-administered tracer, but has marginal effects on brain clearance, thus substantiating a simple, yet effective strategy for enhancing intrathecal drug delivery to the brain.