Votucalis, a Novel Centrally Sparing Histamine-Binding Protein, Attenuates Histaminergic Itch and Neuropathic Pain in Mice.

Autor: Alrashdi I; School of Pharmacy, Newcastle University, Newcastle-upon-Tyne, United Kingdom.; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom., Alsubaiyel A; School of Pharmacy, Newcastle University, Newcastle-upon-Tyne, United Kingdom.; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom., Chan M; School of Pharmacy, Newcastle University, Newcastle-upon-Tyne, United Kingdom.; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom., Battell EE; School of Pharmacy, Newcastle University, Newcastle-upon-Tyne, United Kingdom., Ennaceur A; School of Pharmacy, University of Sunderland, Sunderland, United Kingdom., Nunn MA; Akari Therapeutics Plc, London, United Kingdom., Weston-Davies W; Akari Therapeutics Plc, London, United Kingdom., Chazot PL; Department of Biosciences, Durham University, Durham, United Kingdom., Obara I; School of Pharmacy, Newcastle University, Newcastle-upon-Tyne, United Kingdom.; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
Jazyk: angličtina
Zdroj: Frontiers in pharmacology [Front Pharmacol] 2022 Mar 08; Vol. 13, pp. 846683. Date of Electronic Publication: 2022 Mar 08 (Print Publication: 2022).
DOI: 10.3389/fphar.2022.846683
Abstrakt: Votucalis is a biologically active protein in tick ( R. appendiculatus ) saliva, which specifically binds histamine with high affinity and, therefore, has the potential to inhibit the host's immunological responses at the feeding site. We hypothesized that scavenging of peripherally released endogenous histamine by Votucalis results in both anti-itch and anti-nociceptive effects. To test this hypothesis, adult male mice were subjected to histaminergic itch, as well as peripheral nerve injury that resulted in neuropathic pain. Thus, we selected models where peripherally released histamine was shown to be a key regulator. In these models, the animals received systemic (intraperitoneal, i.p.) or peripheral transdermal (subcutaneous, s.c. or intraplantar, i.pl.) administrations of Votucalis and itch behavior, as well as mechanical and thermal hypersensitivity, were evaluated. Selective histamine receptor antagonists were used to determine the involvement of histamine receptors in the effects produced by Votucalis. We also used the spontaneous object recognition test to confirm the centrally sparing properties of Votucalis. Our main finding shows that in histamine-dependent itch and neuropathic pain models peripheral (s.c. or i.pl.) administration of Votucalis displayed a longer duration of action for a lower dose range, when compared with Votucalis systemic (i.p.) effects. Stronger anti-itch effect was observed after co-administration of Votucalis (s.c.) and antagonists that inhibited peripheral histamine H 1 and H 2 receptors as well as central histamine H 4 receptors indicating the importance of these histamine receptors in itch. In neuropathic mice, Votucalis produced a potent and complete anti-nociceptive effect on mechanical hypersensitivity, while thermal (heat) hypersensitivity was largely unaffected. Overall, our findings further emphasize the key role for histamine in the regulation of histaminergic itch and chronic neuropathic pain. Given the effectiveness of Votucalis after peripheral transdermal administration, with a lack of central effects, we provide here the first evidence that scavenging of peripherally released histamine by Votucalis may represent a novel therapeutically effective and safe long-term strategy for the management of these refractory health conditions.
Competing Interests: Authors MN and WW-D were employed by the company Akari Therapeutics Plc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Alrashdi, Alsubaiyel, Chan, Battell, Ennaceur, Nunn, Weston-Davies, Chazot and Obara.)
Databáze: MEDLINE
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