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Knockdown siRNA Targeting GPR55 Reveals Significant Differences Between the Anti-inflammatory Actions of KLS-13019 and Cannabidiol

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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-1β) 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. Pre-treatment 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-h 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.

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Data is provided within the manuscript.

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Funding

These studies were supported by grants from the National Institute on Neurological Disorders and Stroke (R42NS120548-02) and the National Institute on Drug Abuse (T32DA007237-33) at the National Institutes of Health.

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Authors and Affiliations

  1. Kannalife Sciences, Inc, Pennsylvania Biotechnology Center, 3805 Old Easton Road, Doylestown, PA, 18902, USA

    Douglas E. Brenneman, William A. Kinney & Mark E. McDonnell

  2. Department of Neural Science, Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA

    Michael J. Ippolito & Sara Jane Ward

Authors
  1. Douglas E. Brenneman
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  2. William A. Kinney
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  3. Mark E. McDonnell
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  4. Michael J. Ippolito
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  5. Sara Jane Ward
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Contributions

Douglas Brenneman designed and conducted all experiments using primary neuronal cultures and wrote the draft of the manuscript. William Kinney and Mark McDonnell chemically designed and provided the purified, structurally verified KLS-13019. Sara Jane Ward and Michael Ippolito provided intellectual input on study design pertaining to inflammation and GPR55 pharmacology. Editing contributions were made by all authors. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Douglas E. Brenneman.

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No animal or human subject data were done in this work. Animal tissues for primary cultures were purchased from a commercial source.

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Competing Interests

Douglas Brenneman, William Kinney, and Mark McDonnell are inventors of KLS-13019 and hold international patents on the technology described.

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Kannalife Sciences is a subsidiary of Neuropathix, Inc.

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Brenneman, D.E., Kinney, W.A., McDonnell, M.E. et al. Knockdown siRNA Targeting GPR55 Reveals Significant Differences Between the Anti-inflammatory Actions of KLS-13019 and Cannabidiol. J Mol Neurosci 74, 41 (2024). https://doi.org/10.1007/s12031-024-02217-3

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