Anxiolytic effects of Formononetin in an inflammatory pain mouse model

Abstract

Chronic pain is commonly accompanied with anxiety disorder, which complicates treatment. In this study, we investigated the analgesic and anxiolytic effects of Formononetin (FMNT), an active component of traditional Chinese medicine red clover ( Trifolium pratense L.) that is capable of protecting neurons from N-methyl-D-aspartate (NMDA)-evoked excitotoxic injury, on mice suffering from complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain. The results show that FMNT administration significantly reduces anxiety-like behavior but does not affect the nociceptive threshold in CFA-injected mice. The treatment reverses the upregulation of NMDA, GluA1, and GABA A receptors, as well as PSD95 and CREB in the basolateral amygdala (BLA). The effects of FMNT on NMDA receptors and CREB binding protein (CBP) were further confirmed by the potential structure combination between these compounds, which was analyzed by in silico docking technology. FMNT also inhibits the activation of the NF-κB signaling pathway and microglia in the BLA of mice suffering from chronic inflammatory pain. Therefore, the anxiolytic effects of FMNT are partially due to the attenuation of inflammation and neuronal hyperexcitability through the inhibition of NMDA receptor and CBP in the BLA. Electronic supplementary material The online version of this article (10.1186/s13041-019-0453-4) contains supplementary material, which is available to authorized users.

Scopoletin ameliorates anxiety-like behaviors in complete Freund’s adjuvant-induced mouse model

“…Ionotropic glutamate receptors include AMPAR and NMDAR, such as GluA1, GluA2, GluN2A, and GluN2B, which play critical roles in regulating synaptic neurotransmission and plasticity as well as in anxiety [39]. In this study, CFA resulted in increased expression of GluA1, GluN2A, GluN2B, and PSD95, a postsynaptic anchor protein that binds to AMPA and NMDA receptors [40]. Treatment with SP down-regulated GluA1 and PSD95, but had no obvious effect on the levels of GluN2A and GluN2B.…”

Formononetin Attenuates Airway Inflammation and Oxidative Stress in Murine Allergic Asthma

“…We established OVA-induced murine model of allergic asthma and set doses of formononetin and dexamethasone based on previous studies with minor modification (Wang et al, 2016;Campa et al, 2018;Li et al, 2018;Luo et al, 2018;Wang X. S. et al, 2019). Sixty mice were randomly assigned to six groups (10 mice/group) as follows: normal control group; asthma group; asthma + formononetin 10 mg/kg group (Winherb Medical Science Co. Ltd, Shanghai, China); asthma + formononetin 20 mg/kg group; asthma + formononetin 40 mg/kg group; asthma + dexamethasone 2 mg/kg group.…”

“…FMT has a bioavailability of 21.8% and shows different absorption in all gastrointestinal segments ( Luo et al., 2018 ). An increasing body of evidence suggests that FMT exerts notable anti-inflammatory, anti-allergic, antioxidant, anti-hepatic steatosis, antiproliferative, and anticancer effects in vitro and animal models of many disease ( Wang et al., 2012 ; Xu and An, 2017 ; Fei et al., 2018 ; Li et al., 2018 ; Ong et al., 2019 ; Wang X. S. et al., 2019 ). Some reports demonstrate that FMT has neuroprotective effect in LPS-stimulated BV2 microglia and high-fat diet-induced cognitive disorder mice ( El-Bakoush and Olajide, 2018 ; Fu et al., 2019 ; Wang Y. et al., 2019 ).…”

Neuropharmacology of Secondary Metabolites from Plants with Anxiolytic and Antidepressant Properties

“…Another flavonoid known to have anxiolytic effects is formononetin, an active metabolite of traditional Chinese medicine red clover (Trifolium pratense L.). Wang et al [47] observed that administering 25 mg/kg of this metabolite to male mice once daily for 8 days blocked the anxiogenic effect on the open field test (OFT) produced by administering Freund's complete adjuvant (CFA), reduced the time spent and distance traveled in the central area, and decreased the time spent in the open arms of EPM [47]. Formononetin did not modify behavior compared to the control group on either test, indicating that it demonstrated an anxiolytic effect.…”

“…However, it seems that these results should be understood as a neuroprotective effect more than an anxiolytic one, at least under those study conditions. The notion of a neuroprotector effect is supported by the fact that the study found that formononetin attenuated inflammation and neuronal hyperexcitability by inhibiting NMDA receptors and the CREB signaling pathway in the basolateral amygdala (BLA) [47].…”