Potential for intranasal drug delivery to alter cerebrospinal fluid outflow via the nasal turbinate lymphatics

Harold Kim,Sara A Moore,Miles G Johnston

doi:10.1186/2045-8118-11-4

Harold Kim, Sara A Moore + Show 1 more

Open Access

https://doi.org/10.1186/2045-8118-11-4

Copy DOI

Abstract

BackgroundCerebrospinal fluid absorption (CSF) at the cribriform plate is mediated by direct extracranial connections to the lymphatic system. Given the accessibility of these pharmacologically responsive vessels we hypothesized that the rate of CSF outflow can be modulated via the intranasal delivery of drugs known to affect lymphatic contractile activity.FindingsFluid was infused into the lateral ventricle of anesthetized sheep and inflow rate and CSF pressure measured during intranasal administration of pharmacological agents. CSF absorption was calculated at steady-state CSF pressures. The ability of a pharmacological agent to alter CSF absorption was related to the steady-state intracranial pressure (ICP), the concentration and the class of pharmacological agent delivered. An increase in drug concentration correlated with an increase in CSF absorption at high ICP (45 cm H2O, r = 0.42, p = 0.0058). Specifically, the delivery of NG-monomethyl L-arginine (L-NMMA) significantly increased CSF absorption by 2.29 fold over no treatment (2.29 ± 0.34 mL/min), while the thromboxane A2 analogue U46619 resulted in a 2.44 fold increase in CSF absorption over no treatment (2.44 ± 0.55 mL/min). Saline delivery did not significantly increase CSF absorption (0.88 ± 0.097 mL/min). A trend of increased CSF absorption upon noradrenaline delivery was observed: however, this did not reach statistical significance. Increasing drug concentrations inversely correlated with CSF outflow resistance across all drug classes (r = -0.26, p = 0.046).ConclusionsThe administration of nebulized pharmacological agents intranasally has the potential to provide an alternate method to non-invasively modulate CSF absorption and outflow resistance.

Highlights

The regulation of intracranial homeostasis is strictly controlled due to the finite space offered by the fixed volume of the skull
Intranasal administration of drug shifts intracranial pressure versus cerebrospinal fluid curves to the right Given the direct connection between the Cerebrospinal fluid absorption (CSF) compartment and the extracranial lymphatics within the nasal turbinate region, we hypothesized that the nebulization of pharmacological agents into the nasal cavity may increase CSF absorption (Figure 1)
While the delivery of saline (n = 5) did not alter CSF absorption, we observed that the delivery of agents such as noradrenaline (NA, n = 5), L-NMMA (n = 4) and U46619 (n = 5) at steady state intracranial pressures increased CSF absorption in a dose dependent manner relative to no drug treatment

Summary

Introduction

The regulation of intracranial homeostasis is strictly controlled due to the finite space offered by the fixed volume of the skull. The primary mechanism to control intracranial pressure (ICP) is via regulation of CSF production and absorption within the ventricular and subarachnoid spaces [1]. Strong evidence supports a mechanism where the absorption of CSF occurs extracranially at the cribriform plate via the ethmoid turbinate lymphatics [2,3,4]. A significant portion of CSF absorption occurs through the foramina and directly into the extracranial lymphatics. Restriction of this pathway results in increased resistance, decreased outflow and raised ICP [5,6,7]. Cerebrospinal fluid absorption (CSF) at the cribriform plate is mediated by direct extracranial connections to the lymphatic system. Given the accessibility of these pharmacologically responsive vessels we hypothesized that the rate of CSF outflow can be modulated via the intranasal delivery of drugs known to affect lymphatic contractile activity

Results

Discussion

Conclusion