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

Tuomas O Lilius; Marko Rosenholm; Laura Klinger; Kristian Nygaard Mortensen; Björn Sigurdsson; Frida Lind-Holm Mogensen; Natalie L Hauglund; Malthe Skytte Nordentoft Nielsen; Tomi Rantamäki; Maiken Nedergaard

doi:10.1016/j.isci.2022.105250

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

iScience. 2022 Sep 29;25(10):105250. doi: 10.1016/j.isci.2022.105250. eCollection 2022 Oct 21.

Authors

Tuomas O Lilius^{1

2

3

4}, Marko Rosenholm^{1

2}, Laura Klinger¹, Kristian Nygaard Mortensen¹, Björn Sigurdsson¹, Frida Lind-Holm Mogensen^{1

5

6}, Natalie L Hauglund¹, Malthe Skytte Nordentoft Nielsen¹, Tomi Rantamäki^{7

8}, Maiken Nedergaard^{1

9}

Affiliations

¹ Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
² Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
³ Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁴ Department of Emergency Medicine and Services, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
⁵ Neuro-immunology Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
⁶ Doctoral School of Science and Technology, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
⁷ Laboratory of Neurotherapeutics, Doctoral Program in Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
⁸ SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁹ Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Box 645, Rochester, NY 14642, USA.

Abstract

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.

Keywords: Drug delivery system; Neuroscience; Small animal imaging.

Associated data

figshare/10.6084/m9.figshare.21150415

Abstract

Associated data

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