Novel Pharmacological Treatments

Recently, the Meniere’s research laboratory has been exploring the development of a novel treatment for endolymphatic hydrops. The premise is that if a chemical could be applied to the inner ear which temporarily increased the permeability of the endolymphatic compartment, it may provide hydrostatic relief of hydrops (kind of like deflating a balloon for a while). Currently, there are a host of chemicals that are used in pharmacology, and are FDA and TGA approved, which provide such a temporary (i.e. hours) increase in the permeability of membranes.

We began trialing ‘sodium caprate’, which is often used to temporarily permeabilize the lining of the intestines, but has recently been used to increase the fluid permeability of inner ear tissues. At moderate concentrations, sodium caprate certainly increases the permeability of membranes like the vasculature overlying the cochlea:

Right) The outer vasculature of the cochlea imaged using our Light Sheet Microscope, with fluorescent contrast agents perfused through blood. Left) In an ear where 20mM sodium caprate has been applied to the middle ear, demonstrating the blood vessels are permeabilized and leak blood onto the cochlear wall. Images are presented in low-resolution.

Moreover, sodium caprate can be applied at lower concentrations, directly to the endolymphatic compartment, increasing its permeability, and allowing perilymph and endolymph to mix temporarily. However, we have yet to perfect methods of applying sodium caprate via and intra-tympanic approach (which would be used clinically), enabling endolymph compartment to be temporarily permeabilized. We currently believe this is due to the complex pharmacokinetics of the inner ear, which make drug delivery to the inner ear a tricky business.

 

 

August 2016 Update

Our recent publication: “Endolymph movement visualized with light sheet fluorescence microscopy in an acute hydrops model“, used our Light Sheet Fluorescence Microscope to suggest that at some stage during endolymphatic hydrops, some mechanism ‘triggers’ the rapid uptake of endolymph into the endolymphatic sac, and most likely the utricle and semicircular canals. This mechanism may explain the sudden vertigo attacks observed in Meniere’s.

Moreover, the result highlight that there is an apparent uptake of endolymph into the micro-vasculature surrounding the endolymphatic duct. This uptake appears (at first glance) to be a ‘paracellular’ uptake (i.e. the endolymph fluid flows directly into the microvasculature, rather than flowing through cells). 7
Figure from Brown et al., 2016 showing uptake of fluorescent fluid marker into the microcanals surrounding the endolymphatic duct.

This is a remarkable possibility, because it suggests that the endolymphatic compartment isn’t actually a ‘closed’ compartment as it is typically viewed, but rather this pathway normally allows endolymph to ‘leak’ out into either trabeculated bone or blood. Interestingly, there was a series of histological studies performed by Prof. Fred Linthicium between 2010-2014, where they noted the abnormal morphology of the microcanals surrounding the endolymphatic compartment in Meniere’s sufferers as compared to non-Meniere’s ears. Currently, the link between these microcanals and Meniere’s disease is unclear, although their apparent involvement in endolymph volume regulation makes them prime candidates for further study and pharmacological targeting.

Linthicum et al

Figure from Linthicium et al., 2014, showing a 3D reconstruction of the microcanals in human temporal bones. In previous studies by this research group, they have noted that the canals appear to be decellularized in Meniere’s sufferers.