Cyclodextrin derivatives decrease Transient Receptor Potential vanilloid 1 and Ankyrin 1 ion channel activation via altering the surrounding membrane microenvironment by cholesterol depletion

Front Cell Dev Biol. 2024 Feb 28:12:1334130. doi: 10.3389/fcell.2024.1334130. eCollection 2024.

Abstract

Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) are nonselective cation channels expressed in primary sensory neurons and several other non-neuronal structures such as immune cells, keratinocytes, and vascular smooth muscle cells. They play important roles in nociception, pain processing and their chanellopathies are associated with the development of several pathological conditions. They are located in cholesterol- and sphingolipid-rich membrane lipid raft regions serving as platforms to modulate their activations. We demonstrated earlier that disruption of these lipid rafts leads to decreased TRP channel activation and exerts analgesic effects. Cyclodextrins are macrocyclic molecules able to form host-guest complexes with cholesterol and deplete it from the membrane lipid rafts. The aim of this study was to investigate 8 structurally different (methylated and non-methylated) CD derivatives on cell viability, mitochondrial membrane potential, membrane composition and activation abilities of the TRPV1 and TRPA1 channels. We showed that non-methylated derivatives have preferable safety profiles compared to methylated ones. Furthermore, methylated derivatives reduced mitochondrial membrane potential. However, all investigated derivatives influence the ordered cell membrane structure depleting membrane cholesterol and inhibit the TRPV1 agonist capsaicin- and the TRPA1 agonist allyl isothiocyanate-induced Ca2+-influx. This mechanism of action might provide novel perspectives for the development of peripherally acting analgesics via indirectly decreasing the generation and transmission of nociceptive signals.

Keywords: TRPA1; TRPV1; cholesterol; cyclodextrin; lipid raft; neurogenic inflammation; pain.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by research grants No. TKP2021-EGA-13, TKP2021-EGA-16 grants which have been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the EGA 13 and EGA 16 funding scheme co-financed by the EU. J. E. was supported by TKP2021-EGA-17 provided by the National Research, Development, and Innovation Fund of Hungary, financed under the EGA 17 funding scheme. The work was supported by PTE-ÁOK-KA-2021-09 and OTKA-138936. This work was also supported by the Hungarian Research Network (HUN-REN), Chronic Pain Research Group and by The National Research, Development and Innovation Office (PharmaLab, RRF-2.3.1-21-2022-00015). Supported by the ÚNKP-22-3 New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund.