Neuroprotective Effects of Fasudil, a Rho-Kinase Inhibitor, After Spinal Cord Ischemia and Reperfusion in Rats.

Abstract

Excessive Rho/Rho-kinase pathway activation occurs subsequent to stroke. We examined the neuroprotective effects of pre- and posttreatment with fasudil (a Rho-kinase inhibitor) in a rat transient spinal cord ischemia-reperfusion model under normothermic conditions. After approval by our animal research committee, male Sprague-Dawley rats were assigned to 1 of 6 groups: pre- and postcontrol (C); pre- and postfasudil (F); and pre- and postsham (S). Fasudil (10 mg/kg) or normal saline was administered intravenously over 30 minutes before ischemia in the pre-F or pre-C groups, and over 30 minutes after reperfusion in the post-F or post-C groups. Sham groups were not subjected to ischemia. Ischemia was induced by aortic occlusion using a balloon catheter combined with hypotension for 10 minutes. Neurologic deficit scores (NDS; 0-8 points) were assessed 1, 7, and 14 days after ischemia, and then histopathologic outcomes were assessed. NDS 7 and 14 days after ischemia in the pre-F group (median [range]; 3.5 [2-6] and 2.5 [0-6]) were lower than those in the pre-C group (5.5 [4-7] and 4.5 [4-6]; P = .046 and P = .049), whereas NDS in the post-F group and in the post-C group were not different. The numbers of intact neurons in the gray matter in the pre- and post-F groups (mean ± standard deviation [95% confidence interval]: 25 ± 7 [20-30] and 16 ± 5 [12-19]) were greater than those in the pre- and post-C groups (11 ± 5 [7-14] and 9 ± 3 [7-11]; P < .001 and P = .002). The number of intact neurons in the post-F group (16 ± 5 [12-19]) was lower than the number in the post-S group (26 ± 2 [24-29]; P < .001). The percentages of vacuolation in the white matter in the pre- and post-F groups (21.5 ± 8.4 [15.5-27.5] and 13.6 ± 7.4 [8.3-18.9]) were lower than those in the pre- and post-C groups (43.7 ± 10.4 [36.3-51.1] and 40.6 ± 12.3 [31.8-49.4]; P < .001 and P < .001). Our results demonstrated that intravenous fasudil administered before ischemia improved both neurologic and histopathologic outcomes even 14 days after ischemia, while fasudil administered postinsult improved histopathologic outcomes only in normothermic rats. Fasudil may be a relevant pretreatment paradigm for planned procedures at risk for spinal cord ischemia.