Anti-central fatigue effects of myelophil in 5-HTergic hyperactivity mice model.

BACKGROUND: Myelophil is a standardized ethanol extract of Astragali Radix and Salviae Miltiorrhizae Radix, which has been developed based on clinical experience in traditional Korean medicine practices for patients with unexplained chronic fatigue, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our previous studies demonstrated Myelophil's clinical efficacy in ME/CFS, as well as its brain-related activities in animal models. However, the underlying pharmacological mechanisms remain unclear. Recently, we identified serotonergic hyperactivity as a key pathophysiological factor in central fatigue, such as ME/CFS. Therefore, in the present study, we aimed to investigate the mechanisms by which Myelophil exerts its effects, particularly in the context of a 5-HTergic hyperactivity model. METHOD: To verify the action mechanisms of Myelophil on serotonergic hyperactivity condition, we herein assessed its anti-central fatigue properties using a fluoxetine-treated mice model. Male C57BL/6 N mice (9 weeks old) were subjected to periodic intraperitoneal (IP) injections of fluoxetine for 4 weeks and the mice were simultaneously oral administered Myelophil (0, 50, or 100 mg/kg) or ascorbic acid (100 mg/kg). RESULT: Four-week injection of fluoxetine notably increased serotonin (5-hydroxytryptamine, 5-HT) activity, as evidenced by immunofluorescence staining and Western blot assays in the raphe nuclei (RN), and induced central fatigue-like behaviors in the nest building test, wheel running test, rota-rod test, plantar test, and open field test. Meanwhile, Myelophil (100 mg/kg) administration significantly ameliorated those fatigue-related behaviors including pain sensitivity. Furthermore, the anti-fatigue effects of Myelophil were corroborated by changes in serotonin-related parameters (serotonin transporter; 5-HTT and vesicular monoamine transporter 2; VMAT2), as well as neurotrophic markers including c-Fos and brain-derived neurotrophic factor (BDNF) in the RN. CONCLUSION: These results provide experimental evidence suggesting the potential mechanisms by which Myelophil may alleviate central fatigue associated with hyper-5-HTergic activity. CLINICAL TRIAL NUMBER: Not applicable.