Abstract

The oxysterol 24-hydroxycholesterol (24-HC) is a major cholesterol metabolite, primarily known for its role in cholesterol homeostasis and neuronal signaling in the central nervous system. However, its potential modulatory effects on peripheral neuro-immune interactions, particularly in the context of nociception and inflammation, remain poorly understood. This study investigates the impact of 24-HC on the purinergic signaling pathway in the trigeminovascular system, a key area involved in headache and migraine pathophysiology. Specifically, we examined the effect of 24-HC on the ATP-induced electrical activity of trigeminal nerve afferents and the concurrent degranulation of resident mast cells (MCs) in rat meninges. Using electrophysiological recordings and fluorescence microscopy, we demonstrate that extracellular ATP significantly increases the firing rate of trigeminal afferents and promotes MC degranulation. Crucially, pre-treatment with 24-HC was found to significantly suppress both the ATP-induced electrical activity and the percentage of degranulated MCs. These findings suggest that 24-HC acts as a novel negative modulator of the ATP-mediated neuro-immune axis in the trigeminovascular system. The observed inhibitory effect on mast cell degranulation and subsequent neuronal excitation highlights a potential therapeutic role for 24-HC or its derivatives in the management of neuroinflammatory pain conditions like migraine.