Absence of Transient Receptor Potential Vanilloid-1 Accelerates Stress-Induced Axonopathy in the Optic Projection

Abstract

How neurons respond to stress in degenerative disease is of fundamental importance for identifying mechanisms of progression and new therapeutic targets. Members of the transient receptor potential (TRP) family of cation-selective ion channels are candidates for mediating stress signals, since different subunits transduce a variety of stimuli relevant in both normal and pathogenic physiology. We addressed this possibility for the TRP vanilloid-1 (TRPV1) subunit by comparing how the optic projection of Trpv1 Ϫ / Ϫ mice and age-matched C57 controls responds to stress from elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma. Over a 5 week period of elevated pressure induced by microbead occlusion of ocular fluid, Trpv1Ϫ / Ϫ accelerated both degradation of axonal transport from retinal ganglion cells to the superior colliculus and degeneration of the axons themselves in the optic nerve. Ganglion cell body loss, which is normally later in progression, occurred in nasal sectors of Trpv1 Ϫ / Ϫ but not C57 retina. Pharmacological antagonism of TRPV1 in rats similarly accelerated ganglion cell axonopathy. Elevated ocular pressure resulted in differences in spontaneous firing rate and action potential threshold current in Trpv1 Ϫ / Ϫ ganglion cells compared with C57. In the absence of elevated pressure, ganglion cells in the two strains had similar firing patterns. Based on these data, we propose that TRPV1 may help neurons respond to disease-relevant stressors by enhancing activity necessary for axonal signaling.

Nanosponge-Mediated Drug Delivery Lowers Intraocular Pressure

“…This increase in IOP is similar to other studies using this model in C57 mice. [41][42][43] Brimonidine Ocular pressure in C57 mice before microbead injection averaged 14.44 6 0.10 mm Hg (Fig. 2).…”

“…As an initial step, we wanted to show efficacy of our NS in a well characterized animal model of glaucoma. 41,42,48 Moving forward with our NS drug delivery system will require multiple animal models, including those more suited for intravitreal pharmacokinetic studies, so that all aspects of treatment (safety, potential side effects, less invasive delivery methods) can be examined thoroughly. Injection of Neuro-DiO loaded NS was an extension of this proof-of-concept to determine if the NS could deliver a payload to the retinal surface and to RGCs.…”

“…41 Using this model, we induced ocular pressure elevations of 30% for 23 days and 33% for 36 days in C57 mice following one 1.0 lL injection. 41,42 Injection of 1.5 lL of microbeads in C57 mice has produced ocular pressure elevations of 31% to 34% for up to 7 weeks. 43 The IOP was measured in anesthetized mice using a Tono-Pen (Reichert, Inc., Depew, NY) as described.…”

Activation of transient receptor potential vanilloid-1 (TRPV1) influences how retinal ganglion cell neurons respond to pressure-related stress

“…We discovered recently in testing our initial hypothesis that both knock-out and pharmacological antagonism of TRPV1 accelerated RGC degeneration with exposure to elevated intraocular pressure in an inducible model of glaucoma. 34 Furthermore, RGCs from Trpv1-/-retina lacked a compensatory, transient increase in spontaneous action potentials with elevated pressure and required greater depolarization to reach firing threshold. 34 Thus, we proposed that TRPV1 in response to pressure-related stress in vivo acts to boost excitatory activity as a way of promoting RGC survival in glaucoma.…”

Correction

“…Over the past few years, there has been a surge in our understanding about which RGCs are most vulnerable in early-stage glaucoma 8,9 , and of the ion channels required to translate intraocular pressure increases into RGC degradation and death 10 . The current study provides a solid molecular foundation on which to integrate these findings.…”