LAUSR

Spreading depolarization (SD) is assumed to be the pathophysiological correlate of migraine aura, leading to spreading depression of activity and a long-lasting vasoconstriction known as spreading oligemia. Further, cerebrovascular reactivity is reversibly impaired after SD. Here, we explored the progressive restoration of impaired neurovascular coupling to somatosensory activation during spreading oligemia. Also, we evaluated whether nimodipine treatment accelerated the recovery of impaired neurovascular coupling after SD. Male, 4-9 months old C57BL/6 mice (n=11) were anesthetized with isoflurane (1-1.5%), and SD was triggered with KCl through a burr hole made at the caudal parietal bone. EEG and cerebral blood flow (CBF) were recorded minimally-invasively with a silver ball electrode and transcranial laser-Doppler flowmetry, rostral to SD elicitation. The L-type voltage-gated Ca2+ channel blocker nimodipine was administered i.p. (10 mg/kg). Whisker stimulation-related evoked potentials (EVPs) and functional hyperemia were assessed under isoflurane (0.1%) - medetomidine (0.1 mg/kg i.p.) anesthesia before, and repeatedly after SD, at 15 min intervals for 75 minutes. Nimodipine accelerated the recovery of CBF from spreading oligemia (time to full recovery, 52±13 vs. 70±8 min, nimodipine vs. control) and exhibited a tendency to shorten the duration of the SD-related EGG depression duration. The amplitudes of EVP and functional hyperemia were markedly reduced after SD, and progressively recovered over an hour post-SD. Nimodipine exerted no impact on EVP amplitude but consistently increased the absolute level of functional hyperemia from 20 min post-CSD (93±11 vs. 66±13 %, nimodipine vs. control). A linear, positive correlation between EVP and functional hyperemia amplitude was skewed by nimodipine. In conclusion, nimodipine facilitated CBF restoration from spreading oligemia and the recovery of functional hyperemia post-SD, which were linked to a tendency of an accelerated return of spontaneous neural activity after SD. The use of nimodipine in migraine prophylaxis is suggested to be re-visited.