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Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa

Michelle G. Pedler, View ORCID ProfileJ. Mark Petrash, View ORCID ProfilePrem S. Subramanian
doi: https://doi.org/10.1101/2021.03.02.433537
Michelle G. Pedler
1Departments of Ophthalmology, University of Colorado School of Medicine, Aurora, CO, USA
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J. Mark Petrash
1Departments of Ophthalmology, University of Colorado School of Medicine, Aurora, CO, USA
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Prem S. Subramanian
1Departments of Ophthalmology, University of Colorado School of Medicine, Aurora, CO, USA
2Departments of Neurology, University of Colorado School of Medicine, Aurora, CO, USA
3Departments of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA
4Division of Ophthalmology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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  • ORCID record for Prem S. Subramanian
  • For correspondence: prem.subramanian@cuanschutz.edu
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Abstract

Introduction Cerebrospinal fluid (CSF) outflow has been demonstrated along nasal lymphatics via olfactory nerve projections; flow may be increased by stimulating lymphatic contractility using agents such as noradrenaline and the thromboxane A2 analog U46619. Lymphatics elsewhere in the body show increased contractility upon exposure to the prostaglandin F2alpha analog isoprostane-8-epi-prostaglandin. We investigated the ability of ophthalmic prostaglandin F2alpha analogs to increase CSF outflow when applied to the nasal mucosa by inhalation.

Methods Latanoprost (0.1, 0.5, or 1mg/ml), bimatoprost (0.3 or 3mg/ml), travoprost (0.04 or 0.4mg/ml), latanoprostene bunod (0.24 or 2.4mg/ml), tafluprost (0.25 or 2.5mg/ml), or vehicle (10% DMSO) was administered to awake adult C57B/6 mice by nasal inhalation of 2μl droplets. A total of 67 animals were studied including controls. General anesthesia was induced by injection, and fluorescent tracer (AlexaFluor647-labelled ovalbumin) was injected under stereotaxic guidance into the right lateral ventricle. Nasal turbinate tissue was harvested and homogenized after 1 hour for tracer detection by ELISA and fluorometric analysis.

Results Inhalation of latanoprost 0.5mg/ml and 1mg/ml led to a 11.5-fold increase in tracer recovery from nasal turbinate tissues compared to controls (3312 pg/ml vs 288 pg/ml, p<0.001 for 0.5mg/ml; 3355 pg/ml vs 288 pg/ml, p<0.001 for 1mg/ml), while latanoprost 0.1 mg/ml enhanced recovery 6-fold (1713 pg/ml vs 288 pg/ml, p<0.01). Tafluprost 0.25mg/ml and bimatoprost 0.3mg/ml showed a modest (1.4x, p<0.05) effect, and the remaining agents showed no significant effect on tracer recovery.

Conclusions Prostaglandin F2alpha analogs delivered by nasal inhalation resulted in increased nasal recovery of a CSF fluorescent tracer, implying increased CSF outflow via the nasal lymphatics. The greatest effect, partially dose-dependent, was observed using latanoprost. Further studies are needed to determine the efficacy of these agents in reducing ICP in short and long-term applications.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted March 02, 2021.
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Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa
Michelle G. Pedler, J. Mark Petrash, Prem S. Subramanian
bioRxiv 2021.03.02.433537; doi: https://doi.org/10.1101/2021.03.02.433537
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Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa
Michelle G. Pedler, J. Mark Petrash, Prem S. Subramanian
bioRxiv 2021.03.02.433537; doi: https://doi.org/10.1101/2021.03.02.433537

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