Dihydromyricetin Modulates Neuropathic Pain and Depression: A Correlation with Hippocampal Vascular Endothelial Growth Factor in Mice

Introduction: Neuropathic pain (NP) is a multidisciplinary problem of medicine, psychology, sociology and economics. The emotional disorders caused by neuropathic pain are seriously underestimated. The dynamic interaction between the NP and emotional disorders greatly increasing the difficulty in clinical treatment, highlighting the importance of finding an effective treatment for neuropathic pain combined with depression. Dihydromyricetin (DHM) has been shown to be effective in improving neurological diseases due to its potent anti-inflammatory and neuroprotective effects. Methods: In this study, through network pharmacology and bioinformatics, the potential targets and signaling pathways of DHM in the treatment of neuropathic pain (NP) and depression (DP) comorbidities were predicted. Further animal experiments utilized the spared nerve injury (SNI) model in mice. Mice received daily intraperitoneal injections of DHM (20 mg kg − 1 ) or vehicle for 14 days. Mechanical sensitivity was assessed with the paw withdrawal mechanical threshold (PWMT), and depressive-like behaviors were assessed by tail suspension test immobility time, open field test total distance moved and central time. Hippocampal levels of vascular endothelial growth factor (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), IL-1β, and TNF-α were quantified by Western blot and immunofluorescence staining. Results: VEGFA was found to have the high “degree” value after ranking by target correlation based on the analysis from network pharmacology. SNI model evoked persistent the pain and depressive-like behavior that were paralleled by marked hippocampal down-regulation of VEGFA/VEGFR2 and a concomitant surge in IL-1β and TNF-α. However, the pain and depressive-like behavior can be relieved by DHM treatment. Both VEGFA and VEGFR2 were up-regulated in the hippocampus, and the changes of IL-1β and TNF-α were improved after DHM treatment. Discussion: This study elucidates that DHM alleviates neuropathic pain and depressive-like behavior, potentially be related to the upregulation of the VEGFA/VEGFR2 signaling pathway and subsequent attenuation of neuroinflammation. Keywords: neuropathic pain, depression, vascular endothelial growth factor