# Knockdown siRNA targeting GPR55 reveals significant differences between the anti-inflammatory actions of KLS-13019 and cannabidiol

## TL;DR

This study shows that KLS-13019, but not cannabidiol, effectively reduces inflammation in a mouse model of chemotherapy-induced nerve pain by targeting GPR55.

## Contribution

The study reveals distinct anti-inflammatory mechanisms of KLS-13019 versus cannabidiol through GPR55 knockdown.

## Key findings

- KLS-13019 reversed paclitaxel-induced inflammation, but this effect was reduced by GPR55 siRNA.
- CBD showed low efficacy in reversing inflammation and was poorly affected by GPR55 siRNA.
- The anti-inflammatory actions of KLS-13019 and CBD differ significantly, possibly explaining their differing effects on nerve pain.

## Abstract

KLS-13019 was reported previously to reverse paclitaxel-induced mechanical allodynia in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). Recent studies demonstrated that paclitaxel-induced increases in inflammatory markers (GPR55, NLRP3 and IL-1b) of dorsal root ganglion (DRG) cultures were shown to be reversed by KLS-13019 treatment. The mechanism of action for KLS-13019-mediated reversal of paclitaxel-induced neuroinflammation now has been explored using GPR55 siRNA. Pretreatment of DRG cultures with GPR55 siRNA produced a 21% decrease of immunoreactive (IR) area for GPR55 in cell bodies and a 59% decrease in neuritic IR area, as determined by high content imaging. Using a 24-hour reversal treatment paradigm, paclitaxel-induced increases in the inflammatory markers were reversed back to control levels after KLS-3019 treatment. Decreases in these inflammatory markers produced by KLS-13019 were significantly attenuated by GPR55 siRNA co-treatment, with mean IR area responses being attenuated by 56% in neurites and 53% in cell bodies. These data indicate that the percentage decreases in siRNA-mediated attenuation of KLS-13019-related efficacy on the inflammatory markers were similar to the percentage knockdown observed for neuritic GPR55 IR area. Similar studies conducted with cannabidiol (CBD), the parent compound of KLS-13019, produced low efficacy (25%) reversal of all inflammatory markers that were poorly attenuated (29%) by GPR55 siRNA. CBD was shown previously to be ineffective in reversing paclitaxel-induced mechanical allodynia. The present studies indicated significant differences between the anti-inflammatory properties of KLS-13019 and CBD which may play a role in their observed differences in the reversibility of mechanical allodynia in a mouse model of CIPN.