The Natural Flavonoid Naringenin Elicits Analgesia through Inhibition of NaV1.8 Voltage-Gated Sodium Channels

Autor: May Khanna, Song Cai, David D. Scott, Yuan Zhou, Zhiming Shan, Aubin Moutal, Angie Dorame, Marcel Patek, Samantha Perez-Miller, Nancy Yen Ngan Pham, Rajesh Khanna, Liberty François-Moutal, Maria J. Serafini, Jie Yu, Kimberly Gomez, Cynthia L. Madura
Rok vydání: 2019
Předmět:
Male
Models
Molecular
Nociception
Naringenin
Protein Conformation
Physiology
Pharmacology
Biochemistry
Rats
Sprague-Dawley
Mice
chemistry.chemical_compound
0302 clinical medicine
Dorsal root ganglion
Ganglia
Spinal
Protein Interaction Mapping
Analgesics
Pain
Postoperative
0303 health sciences
Voltage-dependent calcium channel
food and beverages
General Medicine
Specific Pathogen-Free Organisms
medicine.anatomical_structure
Hyperalgesia
Flavanones
Tetrodotoxin
Intercellular Signaling Peptides and Proteins
Female
medicine.symptom
Acetylcholine
Sodium Channel Blockers
medicine.drug
Sensory Receptor Cells
Cognitive Neuroscience
Nerve Tissue Proteins
NAV1.8 Voltage-Gated Sodium Channel
Structure-Activity Relationship
03 medical and health sciences
medicine
Animals
Calcium Signaling
030304 developmental biology
Calcium channel
Sodium channel
Sodium
Excitatory Postsynaptic Potentials
Cell Biology
Rats
Mechanism of action
chemistry
Neuralgia
Calcium Channels
030217 neurology & neurosurgery
Zdroj: ACS Chemical Neuroscience. 10:4834-4846
ISSN: 1948-7193
Popis: Naringenin (2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one is a natural flavonoid found in fruits from the citrus family. Because (2S)-naringenin is known to racemize, its bioactivity might be related to one or both enantiomers. Computational studies predicted that (2R)-naringenin may act on voltage-gated ion channels, particularly the N-type calcium channel (CaV2.2) and the NaV1.7 sodium channel-both of which are key for pain signaling. Here we set out to identify the possible mechanism of action of naringenin. Naringenin inhibited depolarization-evoked Ca2+ influx in acetylcholine-, ATP-, and capsaicin-responding rat dorsal root ganglion (DRG) neurons. This was corroborated in electrophysiological recordings from DRG neurons. Pharmacological dissection of each of the voltage-gated Ca2+ channels subtypes could not pinpoint any selectivity of naringenin. Instead, naringenin inhibited NaV1.8-dependent and tetrodotoxin (TTX)-resistant while sparing tetrodotoxin sensitive (TTX-S) voltage-gated Na+ channels as evidenced by the lack of further inhibition by the NaV1.8 blocker A-803467. The effects of the natural flavonoid were validated ex vivo in spinal cord slices where naringenin decreased both the frequency and amplitude of sEPSC recorded in neurons within the substantia gelatinosa. The antinociceptive potential of naringenin was evaluated in male and female mice. Naringenin had no effect on the nociceptive thresholds evoked by heat. Naringenin's reversed allodynia was in mouse models of postsurgical and neuropathic pain. Here, driven by a call by the National Center for Complementary and Integrative Health's strategic plan to advance fundamental research into basic biological mechanisms of the action of natural products, we advance the antinociceptive potential of the flavonoid naringenin.
Databáze: OpenAIRE
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