Calcitonin gene-related peptide (CGRP) is a central mediator in migraine and an endogenous vasodilator in the trigeminovascular system. Its role in subarachnoid hemorrhage (SAH), remains uncertain, particularly in patients receiving CGRP-targeted migraine therapy at the time of hemorrhage. This study examined whether CGRP blockade administered shortly before experimental SAH affects outcome and whether early SAH is associated with altered trigeminovascular CGRP signaling. CGRP-mediated vasodilation was first assessed ex vivo in rat and mouse cerebral arteries using wire myography to identify the most suitable species for SAH experiments. Experimental pre-chiasmatic SAH was then induced in rats. At 24 h, body weight, rotating pole performance, mechanical sensitivity, and capsaicin evoked CGRP release from dura mater and trigeminal ganglion were evaluated in SAH and sham animals. In a separate intervention arm, rats received vehicle or the anti-CGRP monoclonal antibody fremanezumab, 30 mg/kg intravenously, 15 min before SAH. Functional outcome, neurological scoring, body weight, and survival were followed for 14 days. Rat basilar arteries showed markedly greater CGRP-induced dilation than mouse basilar arteries, supporting rat as the relevant model. At 24 h after SAH, body weight was reduced whereas periorbital and plantar von Frey thresholds were unchanged. Capsaicin-evoked CGRP release from dura mater was significantly reduced after SAH, while trigeminal ganglion release was unaffected, consistent with early peripheral trigeminovascular peptide release. Fremanezumab treated animals showed higher cerebral blood flow 5 min after SAH and improved rotating pole performance at 48 h compared with vehicle treated animals. No significant differences were observed in composite survival, defined as freedom from spontaneous death or euthanasia at humane endpoint, body weight trajectory, well-being score, or composite neurological score at the 14 day follow up. Experimental SAH is associated with early impairment of releasable CGRP in dura mater, supporting acute trigeminovascular involvement after hemorrhage. Pre-existing CGRP blockade did not worsen overall 14-day outcome in this model of SAH, but seemingly improved early functional recovery and the temporal pattern of disease progression. These findings suggest stage-dependent effects of CGRP signaling in SAH and support further study of CGRP-targeted therapies in cerebrovascular disease.
Fungbrant et al. (Fri,) studied this question.