Trigeminovascular Calcitonin Gene-Related Peptide Release and Peripheral Vascular Responses in a Mouse Model of Accelerated Aging: Implications for Migraine

Objective Understanding age-related changes in migraine is pivotal, considering the increasing global life expectancy. In addition, both aging and migraine are prominent cardiovascular risk factors. It remains unclear whether calcitonin gene-related peptide (CGRP) release changes with age across trigeminovascular components, and how this relates to peripheral responses to migraine-related vasodilatory molecules. The primary aim was to investigate age-related effects on CGRP release from the trigeminovascular system by studying a mouse model of combined accelerated neuronal and vascular aging, the DNA repair-deficient Ercc1 ^Δ/− mice. Second, we assessed the effects of aging on isolated coronary vasodilatory responses to CGRP and forskolin. Methods Experiments were conducted using DNA repair-deficient Ercc1 ^Δ/− mice and their wild type controls. After sacrifice, the trigeminal nucleus caudalis (TNC), trigeminal ganglion (TG), and dura mater (DM) were isolated. Ex vivo KCl-induced CGRP release was measured, and CGRP release was compared between Ercc1 ^Δ/− and wild type mice. In a subset of mice, concentration-response curves to CGRP and forskolin were generated in isolated coronary arteries. The pEC ₅₀ (negative log of the molar concentration of an agonist needed to reach half of its maximal effect) and E _max (maximum relaxation response) values were compared between both groups. Results CGRP release (expressed as ratio compared to baseline release) of the DM was significantly lower in Ercc1 ^Δ/− (2.01±0.24) versus wild type mice (3.22±0.48) ( P =0.040). No differences were observed in CGRP release between Ercc1 ^Δ/− and wild type mice in the TNC (8.07±1.15 versus 6.10±0.57, P =0.364) or the TG (4.84±0.92 versus 4.41±0.60, P =0.838). In addition, there were no differences in pEC ₅₀ and E _max values in response to CGRP and forskolin. Conclusion Our findings suggest that aging is linked to reduced CGRP release of the DM, potentially partly explaining the reduction in migraine attacks in elderly. This decreased CGRP release is not accompanied by altered peripheral vascular reactivity to CGRP.