Results showing neuroprotection with sovesudil (PHP-201) was presented at the World Glaucoma Congress Annual Meeting June 30th – July 3rd, 2021 (WGC 2021). This study was conducted at The University of Melbourne as a collaboration with pH Pharma. The study demonstrated the potential of sovesudil in providing neuroprotection to neurons in the eye.
Sovesudil provides neuroprotection in a rat ON crush model
- Lower IOP
- Better retinal function
- A trend for higher RGC density
“Sovesudil provides neuroprotection against optic nerve injury” (link)
Presenter: Da Zhao, Ph.D., E-Poster #P-160
Purpose: Rho-associated protein kinases (ROCK) are known to regulate the shape and movement of cells and as such ROCK inhibitors modulate aqueous outflow via the trabecular meshwork to lower intraocular pressure. Here we consider whether sovesudil (a ROCK inhibitor alternatively known as PHP-201) also has neuroprotective properties. This study seeks to determine whether topical application of sovesudil protects the optic nerve from injury induced by optic nerve crush.
Methods: In anesthetised P18 male and female Sprague Dawley rats, optic nerve crush was performed in one eye for 5 seconds using number 5 tweezers placed 1.5 mm behind the globe. Perfusion of the eye and vasculature was confirmed to be unaffected by the crush. Rats were randomly assigned to 4 groups: vehicle (Group 1,n=9), low (0.5%, Group 2,n=12), moderate (0.75%, Group 3,n=12) or high dose of sovesudil (1%, Group 4,n=7) 3 times per day for 14 days. Intraocular pressure was monitored on Days 3, 6, 9 and 12. On day 14 rats were anesthetised (ketamine and xylazine mixture) and underwent in vivo functional (electroretinography) and structural assessment (optical coherence tomography). Following in vivo assessment, eyes were enucleated and the retinas were dissected for retinal ganglion cell (RGC) staining with antibodies against RBPMS. Stained retinas were used to quantify numbers of RGCs.
Results: Electroretinography of the vehicle treated group showed that optic nerve transection resulted in significantly smaller ganglion cell (RGC -88±3), bipolar cell (BC -42±6%) and photoreceptor (Ph -32±7%) responses. Treatment with sovesudil significantly improved retinal function for low (RGC -73±4%, BC -22±4%, Ph -13±5%) and moderate (RGC -51 ±18%, BC -2 ±23%, Ph +10±25%) doses. The high (1.0%) dose also provide some benefit (RGC -69 ±11%, BC -27 ±8%, Ph -16±9%). OCT analysis in the vehicle treat the group revealed a significant reduction in retinal nerve fibre (-25±3%) and ganglion cell layer thickness (-12±3%), but no overall difference in total retinal thickness (+2±2%). Comparison across groups showed that there was no structural difference between groups (two-way ANOVA treatment groups (treatment effects p>0.05). A trend for higher RGC density was observed with higher doses of sovesudil (vehicle 155±61, 0.5% 428±232, 0.75% 736±386, 1% 991±521).
Conclusions: Whilst there was no clear improvement in retinal structure measured using OCT, the ROCK- inhibitor, sovesudil, provided robust functional neuroprotection.