(-)-Naringenin 4',7-dimethyl Ether Isolated from Nardostachys jatamansi Relieves Pain through Inhibition of Multiple Channels

  • Molecules. 2022 Mar 7;27(5):1735. doi: 10.3390/molecules27051735.
Ru-Rong Gu  1  2 ,  Xian-Hua Meng  3 ,  Yin Zhang  2 ,  Hai-Yan Xu  2 ,  Li Zhan  2 ,  Zhao-Bing Gao  1  2  4  5 ,  Jun-Li Yang  3 ,  Yue-Ming Zheng  2
Affiliations
  • 1. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2. Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. CAS Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China.
  • 4. Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 5. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
PMID: 35268839 DOI: 10.3390/molecules27051735
Abstract

(-)-Naringenin 4',7-dimethyl ether ((-)-NRG-DM) was isolated for the first time by our lab from Nardostachys jatamansi DC, a traditional medicinal plant frequently used to attenuate pain in Asia. As a natural derivative of analgesic, the current study was designed to test the potential analgesic activity of (-)-NRG-DM and its implicated mechanism. The analgesic activity of (-)-NRG-DM was assessed in a formalin-induced mouse inflammatory pain model and mustard oil-induced mouse colorectal pain model, in which the mice were intraperitoneally administrated with vehicle or (-)-NRG-DM (30 or 50 mg/kg) (n = 10 for each group). Our data showed that (-)-NRG-DM can dose dependently (30~50 mg/kg) relieve the pain behaviors. Notably, (-)-NRG-DM did not affect motor coordination in mice evaluated by the rotarod test, in which the Animals were intraperitoneally injected with vehicle or (-)-NRG-DM (100, 200, or 400 mg/kg) (n = 10 for each group). In acutely isolated mouse dorsal root ganglion neurons, (-)-NRG-DM (1~30 μM) potently dampened the stimulated firing, reduced the action potential threshold and amplitude. In addition, the neuronal delayed rectifier potassium currents (IK) and voltage-gated sodium currents (INa) were significantly suppressed. Consistently, (-)-NRG-DM dramatically inhibited heterologously expressed Kv2.1 and Nav1.8 channels which represent the major components of the endogenous IK and INa. A pharmacokinetic study revealed the plasma concentration of (-)-NRG-DM is around 7 µM, which was higher than the effective concentrations for the IK and INa. Taken together, our study showed that (-)-NRG-DM is a potential analgesic candidate with inhibition of multiple neuronal channels (mediating IK and INa).

Keywords
(−)-Naringenin 4′,7-dimethyl ether; analgesic candidate; delayed rectifier potassium currents; ion channels; mechanism study.
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