Mechanistic investigation of HMGB1 in an in vitro model of the trigeminovascular system under migraine-like conditions
Abstract
BACKGROUND: Migraine is a complex neurovascular disorder driven by abnormal activation of the trigeminovascular system (TVS), neurogenic inflammation and excessive release of calcitonin gene-related peptide (CGRP). While CGRP-targeted therapies have demonstrated clinical efficacy, the upstream molecular mechanisms sustaining CGRP dysregulation remain incompletely understood. High-mobility group box 1 (HMGB1), a pro-inflammatory damage-associated molecule implicated in neuroinflammation, has emerged as a potential contributor to migraine pathophysiology. However, its role in neuron-endothelial interactions within the TVS under migraine -relevant conditions remains unclear. METHODS: To model inflammatory and hypoxic stress associated with migraine, SH-SY5Y neuron-like cells were stimulated with lipopolysaccharide (LPS) and cobalt chloride (CoCl₂). HMGB1 expression was silenced using siRNA to evaluate its role in regulating CGRP and NF-κB signaling. Conditioned medium from stimulated neuronal cells was applied to human umbilical vein endothelial cells (HUVECs) to investigate neuron-endothelial interactions, and CGRP signaling was inhibited using a receptor antagonist. Protein expression of HMGB1, CGRP, and NF-κB pathway components was assessed by Western Blot. In addition, neuronal migration and intracellular reactive oxygen species (ROS) were assessed to evaluate cellular activation under inflammatory stress conditions. RESULTS: Inflammatory and hypoxic stimulation increased…
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