24-hydroxycholesterol prevents pronociceptive effects of ATP in the rat trigeminovascular system

Introduction. Cholesterol is a key element of cell cytoplasmic membranes. Cholesterol can oxidize into oxysterols, including 24-hydroxycholesterol (24-HC), which crosses the blood-brain barrier and affects various systems, embedded in cytoplasmic membranes or directly through membrane receptors. Meningeal afferents of trigeminal (TG) nerve is a site of nociceptive signaling origin in migraine headache. ATP which releases from endothelial cells and nerve endings plays a key role activation TG afferents directly and through degranulation of mast cells (MC). This work addresses the effect of 24-HC on trigeminal nerve afferent activity and MC in meninges of rats.

Methods. TG electrical activity and the morphology of MC were studied in a rat hemi-skull preparation (P30–40).

Results. Application of ATP (100 μM) increases frequency of TG action potentials (APs) 5 times compared to its baseline activity (n = 6). Incubation of hemiskull preparation in 24-HC (1 µM) for 20 or 40 min did not affect the background AP frequency, however decreased ATP effect (AP increased 3 times). MC degranulation promotes release of proinflammatory mediators which directly activate TG afferents or induce sensitization. ATP (100 µM) increased the degree of MC degranulation to 11±3.3% (n=10) compared to control values of 1.9±0.87 (n=5). Preincubation in 24-HC suppressed the ATP effect, reducing the fraction of degranulated mast cells to 5±1.26 (n=4).

Conclusion. 24-hydroxycholesterol reduces pronociceptive effects of ATP in TG afferents, and increases the stability of the MC in meninges thus providing protective properties in trigeminovascular system.

The work was carried out with funds from the Strategic Academic Leadership Program (PRIORITY 2030)."