TY - JOUR
T1 - SPECT/CT imaging reveals CNS-wide modulation of glymphatic cerebrospinal fluid flow by systemic hypertonic saline
AU - Lilius, Tuomas O
AU - Rosenholm, Marko
AU - Klinger, Laura
AU - Mortensen, Kristian Nygaard
AU - Sigurdsson, Björn
AU - Mogensen, Frida Lind-Holm
AU - Hauglund, Natalie L
AU - Nielsen, Malthe Skytte Nordentoft
AU - Rantamäki, Tomi
AU - Nedergaard, Maiken
N1 - Acknowledgements
This work was supported by NIH, National Institute of Neurological Disorders and Stroke (R01NS100366 and RF1AG057575, M.N.), U.S. Army Research Office (MURI W911NF1910280, M.N.), Fondation Leducq Transatlantic Networks of Excellence Program (M.N.), The Adelson Foundation (M.N.), EU Horizon 2020 research and innovation programme (grant no. 666881; SVDs@target, M.N. and grant no 798944, GLYMPHARMA, T.O.L.), Novo Nordisk Foundation (M.N.), Lundbeck Foundation (M.N. and M.R.), University of Helsinki Research Funding (T.O.L.), Finnish Medical Foundation (T.O.L.), and Paulo Foundation (T.O.L.). We gratefully acknowledge Mette Møller Jørgensen for radiotracer production, Dan Xue for graphical design and illustrations, Natalie Beschorner, Palle Koch, Ryszard Gomolka, Merja Voutilainen, and Daniel Persson for technical assistance, and Gitte Moos Knudsen and Paul Cumming for expert comments on the manuscript.
PY - 2022/10/21
Y1 - 2022/10/21
N2 - 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 SPECT/CT imaging platform to study the effects of HTS on whole-body distribution of the radiolabeled tracer 99mTc-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 CSF-administered tracer, but has marginal effects on brain clearance, thus substantiating a simple, yet effective strategy for enhancing intrathecal drug delivery to the brain.
AB - 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 SPECT/CT imaging platform to study the effects of HTS on whole-body distribution of the radiolabeled tracer 99mTc-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 CSF-administered tracer, but has marginal effects on brain clearance, thus substantiating a simple, yet effective strategy for enhancing intrathecal drug delivery to the brain.
UR - https://pubmed.ncbi.nlm.nih.gov/36274948
U2 - 10.1016/j.isci.2022.105250
DO - 10.1016/j.isci.2022.105250
M3 - Article
C2 - 36274948
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 10
M1 - 105250
ER -