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Fig. 4 | The Journal of Headache and Pain

Fig. 4

From: Efficacy profile of noninvasive vagus nerve stimulation on cortical spreading depression susceptibility and the tissue response in a rat model

Fig. 4

nVNS attenuates CSD-triggered neuroinflammation and trigeminovascular system activation. A CSD-induced ipsilateral cortical cyclooxygenase-2 (COX-2) expression in naïve, sham control, and rats receiving CSD induction for 2 h following sham VNS, single 2-minute nVNS at low (1 V), medium (11.4 V), or high intensity (24.4 V). CSD increased ipsilateral cortical COX-2 expression (*P=0.0083 versus naïve group; +P=0.0137 versus sham control), which were intensity-dependently reduced by nVNS (#P=0.0167 high intensity×1 VNS+CSD versus sham VNS+CSD group, n=6) (B) Cortical COX-2 levels in rats receiving sham VNS or VNS (11.4 V, 2\(\times\)2-minute) followed by CSD induction for 2 h. CSD-induced upregulation of COX-2 attenuated by VNS (+P=0.0042 versus sham control; #P=0.0207 versus sham VNS+CSD group, n=4). C Confocal images of CGRP expression in ipsilateral TG of rats receiving sham VNS or VNS (11.4 V, 2 × 2-minute) followed by CSD induction for 1 h and the TG were harvested at 2 h. Scale bar indicates 50 μm. CSD upregulated CGRP expression in the TG (+P=0.0004 for CGRP+ cell, +P=0.0028 for percentage of neuronal CGRP, compared to sham control), which was attenuated by VNS (#P=0.0002 for CGRP+ cell; #P=0.0012 for percentage of neuronal CGRP, compared to sham VNS+CSD group, n=3). Immunohistochemistry images show c-Fos in lamina I and II of TNC ipsilateral to CSD induction site from rats receiving sham VNS or VNS (11.4 V, 2\(\times\)2-minute) followed by CSD induction for 1 h and TNC was harvested at 2 h. Inset rectangles show the magnified images. Scale bar indicates 100 μm. CSD increased c-Fos immunoreactivity in the lamina I~II of TNC (+P=0.0282 versus sham control group), which was attenuated by VNS (#P=0.0263 versus sham VNS+CSD group, n=3). Data are presented as whisker–box plots with all points (whisker: full range; line: median; cross: mean). Kruskal-Wallis test followed by post hoc Dunn’s test (A) and one-way ANOVA followed by post hoc Bonferroni test (B-D) were used for statistical analysis

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