Exploring of the Analgesic Effect of Emodin on Migraine Rat Model via the CREB/BDNF/TrkB Signaling Pathway: A Preliminary Study

Abstract

Background: Migraine is a prevalent neurovascular headache characterized by recurring pain episodes. Previous research indicates that managing the expression of the cAMP response element-binding protein/Brain-derived neurotrophic factor/Tyrosine receptor kinase B (CREB/BDNF/TrkB) pain signaling pathway may enhance migraine conditions. This study delves into the pharmacological effects and analgesic mechanisms of emodin in treating nitroglycerin-induced migraines in animal models, focusing on the CREB/BDNF/TrkB signaling pathway. Methods: Sixty-six male Sprague Dawley (SD) rats were randomly divided into six groups: Control, Model, positive control, and low, medium and high doses of emodin treatment groups. All groups, except the control, underwent the establishment of experimental migraine animal models and received treatment for seven consecutive days. Subsequently, behavioral evaluations and heat pain threshold assessments were conducted. Enzyme-linked immunosorbent assay (ELISA) was employed to measure the levels of Brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide (CGRP) in rat serum. Reverse Transcription-Quantitative Polymerase Chain Reaction (RT-qPCR) was performed to detect the mRNA expression levels of CGRP and cAMP response element-binding protein (CREB). Western blot analysis was utilized to assess the protein expression levels of Tyrosine receptor kinase B (TrkB) and Cyclooxygenase-2 (COX-2). Results: Behavioral assessment, measurement of thermal pain threshold, and mechanical pain thresholds indicated that, in comparison to the Model group, the emodin treatment group exhibited a significant improvement in abnormal behavior in migraine rats (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). Moreover, there was an increase in thermal pain threshold and mechanical pain thresholds in the emodin treatment group (p < 0.05, p < 0.01, p < 0.0001). ELISA experiments revealed that, when compared to the Model group, the emodin-high-dose (emodin-H) treatment group exhibited reduced serum levels of BDNF and CGRP (p < 0.01). Additionally, RT-qPCR and Western blot (WB) experiments demonstrated the downregulation of CGRP (p < 0.001) and CREB (p < 0.05) mRNA expression levels. Furthermore, there were decreased expression levels of TrkB and COX-2 proteins in the rat brainstem (p < 0.05, p < 0.01). Conclusion: This study confirms that emodin can markedly enhance abnormal behavioral activities and elevate the thermal pain threshold in the migraine rat model. Its effects appear to be mediated by the downregulation of upstream COX-2 and CGRP, along with the inhibition of the CREB/BDNF/TrkB pain signaling pathway.