Xiongshao Zhitong Recipe Attenuates Nitroglycerin-Induced Migraine-Like Behaviors via the Inhibition of Inflammation Mediated by Nitric Oxide Synthase

Abstract

Migraine is a major cause of disability worldwide, particularly in young adults and middle-aged women. Xiongshao Zhitong Recipe (XZR) is a traditional Chinese medicine prescription used for treating migraine, but its bioactive components and therapeutic mechanisms remain unclear. We aimed to confirm the therapeutic effect of XZR on migraine and to determine the possible mechanism and bioactive components of XZR. Here, a sensitive UHPLC-LTQ-Orbitrap MS assay was carried out to analyze the ingredients of XZR, and a total of 62 components were identified, including coumarins, phenolic acids, phthalides, flavonoids, and terpenoids; among them, 15 components were identified in the serum samples after XZR treatment. We established a rat model of migraine via nitroglycerin (NTG) injection. The in vivo experiments demonstrated that XZR attenuated allodynia and photophobia in rats with NTG-induced migraine, and XZR also demonstrated analgesic effects. XZR reversed the abnormal levels of nitric oxide, 5-hydroxytryptamine (5-HT), calcitonin gene-related peptide (CGRP), and substance P (SP) to normal levels. XZR also downregulated inflammatory reactions, including mast cell degranulation and serum IL-1β, IL-6, and TNF-α levels. In terms of mechanism, we revealed that XZR treated NTG-induced migraine through the inhibition of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) expression in both the trigeminal nucleus caudalis (TNC) and periaqueductal gray matter (PAG), as well as the total NOS enzyme activity, which regulated the NF-κB signaling pathway. Additionally, imperatorin and xanthotoxin, two major ingredients of XZR, showed a high binding affinity to nNOS (Gly468-Leu616). In vitro, XZR, imperatorin, and xanthotoxin inhibited the nNOS expression and the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated PC12 cells. In conclusion, we demonstrated the therapeutic effects of XZR and provided evidence that XZR played a critical anti-inflammatory role by suppressing NOS and NF-κB signaling pathway activation. Imperatorin and xanthotoxin were potential bioactive components of XZR. The findings from this study supported that XZR was a candidate herbal drug for migraine therapy.

Regulating Neuroinflammatory Biomarkers in Nitroglycerine induced Migraine in Rats: A Therapeutic role of Chrysanthemum indicum extract

“…Our results suggesting that the CIHE attenuates the biomarkers such as MMP9[16], TNF-α[26], NFkB [27], IL-1β[28], CGRP [29], and iNOS [30] are involved in the migraine attack which represented in (Fig. 1).…”

New perspectives on migraine treatment: a review of the mechanisms and effects of complementary and alternative therapies

“…Herbal treatment has the advantages of holistic conditioning, multi-targeting, and long-lasting effects, which are conducive to individualized and fine-tuned treatment for migraine patients (58)(59)(60). In 22 years, Yang et al (61) showed that in a rat model of nitroglycerin (NTG)-induced migraine, the Chinese herbal formula Xiongshao Zhitongfang (XZR) regulated NO, 5-HT, CGRP, and SP to normal levels, while inhibiting mast cell degranulation and the release of inflammatory factors, which resulted in attenuation of migraine symptoms. In addition, in a homozygous rat model, rhubarb extract from the traditional Chinese medicine Rheum palmatum also downregulated the inflammatory response and alleviated migraine via the cGMP-PKG pathway (62).…”

Potential analgesic effect of Foshousan oil-loaded chitosan-alginate nanoparticles on the treatment of migraine

“…Radix Angelica Sinensis and Chuanxiong Rhizoma as major herbal ingredients of the FSS formula possessed blood nourishment, wind elimination, and pain alleviation in TCM perspectives (Huang et al, 2020). Furthermore, modern medical studies reported that these two Chinese medicines had anti-nociceptive and anti-inflammatory activities (Wang et al, 2020;Li C. et al, 2022). Tetramethylpyrazine (ligustrazine) from Chuanxiong Rhizoma showed an anti-inflammatory effect on cells by regulating related signaling pathways such as nuclear factor kappa-B (NF-κB) and PI3K/AKT (Zheng et al, 2013;Zhang et al, 2020;Huang et al, 2021).…”

“…In this research, a single emulsion solvent evaporation method was used to prepare CS-AL NPs containing FSSO. In the nano-emulsion, AL was one type of hydrophilic polymer functioning as a wall-forming material for protecting loaded volatile substances; moreover, CS and calcium chloride (CaCl 2 ) are crosslinked with AL to produce hydrogel for gelification (Li S. et al, 2022).…”