Andrea Nehr-Majoros, Lajos Karakai, Maja Payrits, Noémi Bencze, Ágnes Kemény, György Sétáló, Rita Börzsei, Csaba Hetényi, Zsuzsanna Helyes, Éva Szőke
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引用次数: 0
Abstract
The nociceptive Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) channels are predominantly expressed on peptidergic sensory nerves, being involved in pain sensation and neurogenic inflammation induced by local release of pro-inflammatory neuropeptides in the innervation area. Their activation is facilitated by cholesterol-rich lipid microdomains (lipid rafts) in the plasma membrane. Cyclodextrin (CD) derivatives deplete cholesterol from membrane rafts, reducing receptor activation in vitro, anticipating in vivo analgesic effects. We compared three different CD derivatives selected based on our previous results: random methylated β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin and sulfobutylether-β-cyclodextrin. The effects of the topical CD pretreatments were evaluated in acute pain and neurogenic vasodilatation models in mice 30 minutes after TRPV1 (resiniferatoxin) or TRPA1 (formalin or mustard oil) receptor agonist administration. Intraplantar CD pretreatments significantly reduced the duration of nocifensive behaviors during the neurogenic inflammatory phase of the formalin test, as well as mechanical, but not thermal hyperalgesia following resiniferatoxin injection. CD-pretreatment significantly reduced mustard oil-induced acute neurogenic vasodilatation in the mouse ear and decreased the total cholesterol content in the plantar skin and ear tissues. Cholesterol depletion was restored by cholesterol loaded CDs. However, overloading cells with cholesterol did not significantly affect the cholesterol depletion. In silico modeling showed that the methylated derivative RAMEB has different cholesterol binding mode compared to HPBCD and SBECD. We present the first in vivo results showing that these CD derivatives are promising agents for exerting peripheral analgesia and anti-inflammation via cholesterol depletion, also supported by our in vitro and in silico findings.
期刊介绍:
The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.