Peimine, an Anti-Inflammatory Compound from Chinese Herbal Extracts, Modulates Muscle-Type Nicotinic Receptors.

Armando Alberola-Die,José Antonio Encinar,Gregorio Fernández-Ballester,Raúl Cobo,Isabel Ivorra,Andrés Morales,José Manuel González-Ros

doi:10.3390/ijms222011287

Armando Alberola-Die, José Antonio Encinar + Show 5 more

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https://doi.org/10.3390/ijms222011287

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Abstract

Fritillaria bulbs are used in Traditional Chinese Medicine to treat several illnesses. Peimine (Pm), an anti-inflammatory compound from Fritillaria, is known to inhibit some voltage-dependent ion channels and muscarinic receptors, but its interaction with ligand-gated ion channels remains unexplored. We have studied if Pm affects nicotinic acetylcholine receptors (nAChRs), since they play broad functional roles, both in the nervous system and non-neuronal tissues. Muscle-type nAChRs were incorporated to Xenopus oocytes and the action of Pm on the membrane currents elicited by ACh (IAChs) was assessed. Functional studies were combined with virtual docking and molecular dynamics assays. Co-application of ACh and Pm reversibly blocked IACh, with an IC50 in the low micromolar range. Pm inhibited nAChR by: (i) open-channel blockade, evidenced by the voltage-dependent inhibition of IAch, (ii) enhancement of nAChR desensitization, revealed by both an accelerated IACh decay and a decelerated IACh deactivation, and (iii) resting-nAChR blockade, deduced from the IACh inhibition elicited by Pm when applied before ACh superfusion. In good concordance, virtual docking and molecular dynamics assays demonstrated that Pm binds to different sites at the nAChR, mostly at the transmembrane domain. Thus, Pm from Fritillaria bulbs, considered therapeutic herbs, targets nAChRs with high affinity, which might account for its anti-inflammatory actions.

Highlights

The active ingredients of Traditional Chinese medicines (TCMs) plants include: (i) alkaloids, such as peimine (Pm), found in Fritillaria bulbs (Fb), which are commonly used to treat cough and asthma [1,2], (ii) terpenoids, as ginsenoides from Panax ginseng, which might reverse multidrug resistance of certain chemotherapeutic drugs [3], (iii) phenols and flavonoids, which are common in medicinal plants and own strong antioxidant and anti-inflammatory activities [4], tannic acid-related gallotannins and polyphenols, which are relatively abundant in green tea, inhibit TMEM16A, a calcium-activated chloride channel [5] and some flavonoids, as quercetin or genistein, act as positive allosteric modulators of α7 nicotinic receptors [6], and (iv) other compounds, as cinnamaldehyde, obtained from cinnamon cortex, which is known to activate TMEM16A [7]
We have assessed the effect of Pm, an isosteroidal alkaloid found in Fb, on purified and reconstituted nicotinic acetylcholine receptors (nAChRs) microtransplanted to the Xenopus oocyte membrane
Pm exerted a powerful inhibition of muscle-type nAChRs acting by different mechanisms: (i) open-channel blockade, as evidenced by its voltagedependent inhibition of IACh, (ii) enhancement of nAChR desensitization, as supported by three observables: first, the acceleration of the IACh decay, second, the slowing down of

Summary

Introduction

(ii) terpenoids, as ginsenoides from Panax ginseng, which might reverse multidrug resistance of certain chemotherapeutic drugs [3], (iii) phenols and flavonoids (polyphenolic compounds), which are common in medicinal plants and own strong antioxidant and anti-inflammatory activities [4], tannic acid-related gallotannins and polyphenols, which are relatively abundant in green tea, inhibit TMEM16A, a calcium-activated chloride channel [5] and some flavonoids, as quercetin or genistein, act as positive allosteric modulators of α7 nicotinic receptors [6], and (iv) other compounds, as cinnamaldehyde, obtained from cinnamon cortex, which is known to activate TMEM16A [7]. Known as verticine, has been related to diverse therapeutic actions [8], including: (i) anti-inflammatory and analgesic, (ii) antitumor, inhibiting proliferation of human leukemia or lung cancer, (iii) expectorant, (iv) sedative, besides its analgesic action, (v) antihypertensive, (vi) a blocker of voltage-dependent ion channels, including both Na+ and

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