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Knockdown siRNA targeting GPR55 reveals significant differences between the anti-inflammatory actions of KLS-13019
Douglas E Brenneman1, William A Kinney1, Mark E McDonnell1
1Kannalife Sciences, Inc* Pennsylvania Biotechnology Center.
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.
Insights
KLS-13019 effectively reverses chemotherapy-induced peripheral neuropathy (CIPN) by reducing neuroinflammation. This study confirms KLS-13019
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting side effect of neurotoxic cancer treatments.
- Paclitaxel, a widely used chemotherapy agent, can induce mechanical allodynia, a form of neuropathic pain.
- KLS-13019 has shown promise in reversing paclitaxel-induced mechanical allodynia, with recent studies linking this effect to the modulation of inflammatory markers in dorsal root ganglion (DRG) cultures.
Approach:
- Investigated the mechanism of KLS-13019's anti-neuroinflammatory effects in paclitaxel-treated DRG cultures using GPR55 siRNA.
- Quantified the knockdown of GPR55 expression and its impact on KLS-13019's ability to reverse paclitaxel-induced increases in inflammatory markers (GPR55, NLRP3, IL-1b).
- Compared the efficacy of KLS-13019 with its parent compound, cannabidiol (CBD), in reversing neuroinflammation and mechanical allodynia.
Key Points:
- GPR55 siRNA significantly reduced GPR55 expression in DRG cultures, confirming successful knockdown.
- KLS-13019 treatment reversed paclitaxel-induced increases in inflammatory markers to control levels.
- GPR55 siRNA co-treatment attenuated KLS-13019's anti-inflammatory efficacy, indicating GPR55's role in KLS-13019's mechanism of action.
- KLS-13019 demonstrated superior anti-inflammatory properties compared to CBD, which showed low efficacy in reversing these markers.
Conclusions:
- The anti-inflammatory effects of KLS-13019 in paclitaxel-induced neuroinflammation are mediated, at least in part, through GPR55.
- KLS-13019 exhibits significantly different and more potent anti-inflammatory properties than CBD.
- These distinct anti-inflammatory profiles may explain the observed differences in their ability to reverse mechanical allodynia in CIPN models.
