CNB-001 reduces paraplegia in rabbits following spinal cord ischemia

Abstract

Spinal cord ischemia associated with trauma and surgical procedures including thoraco-abdominal aortic aneurysm repair and thoracic endovascular aortic repair results in devastating clinical deficits in patients. Because spinal cord ischemia is inadequately treated, we studied the effects of [4-((1E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1H-pyrazoyl-3-yl) vinyl)-2-methoxy-phenol)] (CNB-001), a novel curcumin-based compound, in a rabbit SCI model. CNB-001 is known to inhibit human 5-lipoxygenase and 15-lipoxygenase and reduce the ischemia-induced inflammatory response. Moreover, CNB-001 can reduce the level of oxidative stress markers and potentiate brain-derived neurotrophic factor and brain-derived neurotrophic factor receptor signaling. The Tarlov scale and quantal analysis technique results revealed that CNB-001 administered as an intravenous dose (bolus) 30 minutes prior to spinal cord ischemia improved the behaviors of female New Zealand White rabbits. The improvements were similar to those produced by the uncompetitive N-methyl-D-aspartate receptor antagonist memantine. At 48 hours after aortic occlusion, there was a 42.7% increase (P < 0.05) in tolerated ischemia duration (n = 14) for rabbits treated with CNB-001 (n = 16), and a 72.3% increase for rabbits treated with the positive control memantine (P < 0.05) (n = 23) compared to vehicle-treated ischemic rabbits (n = 22). CNB-001 is a potential important novel treatment for spinal cord ischemia induced by aortic occlusion. All experiments were approved by the CSMC Institutional Animal Care and Use Committee (IACUC #4311) on November 1, 2012.

Keywords: curcumin analog; motor function; neuroprotection; neurorepair; spinal cord injury; spinal cord ischemia; thoracic endovascular aortic repair; thoraco-abdominal aortic aneurysm.

Figure 1

Experimental design temporal profile. Female rabbits underwent the aortic occlusion procedure for various durations as shown in the figure. Rabbits were pretreated by intravenous bolus of 10 mg/kg CNB-001/vehicle 30 minutes before aortic occlusion. Behavior was assessed at 24 and 48 hours. CNB-001: 4-((1E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1H-pyrazoyl-3-yl) vinyl)-2-methoxy-phenol).

Figure 2

CNB-001 pre-treatment prevents paraplegia in female rabbits subjected to aortic occlusion. Rabbits were pretreated by intravenous vehicle (30% Solutol HS15 in saline, n = 14) or CNB-001 (10 mg/mL, n = 16) 30 minutes (min) before aortic occlusion. CNB-001 (red line, red X) significantly increased the P₅₀ value (ischemia duration by 5.8 minutes) measured at 48 hours after aortic occlusion (unpaired t-test, *P < 0.05) compared to vehicle control (black line, black circle), and improved rabbit behaviors. For the superimposed graphs, behaviorally normal animals are plotted on the y-axis at 0 and abnormal animals are plotted at 100. CNB-001: 4-((1E)-2-(5-(4-hydroxy-3-methoxystyryl-)- 1-phenyl-1H-pyrazoyl-3-yl) vinyl)-2-methoxy-phenol).

Figure 3

Memantine pre-treatment prevents paraplegia in female rabbits subjected to aortic occlusion. Female rabbits underwent the aortic occlusion procedure for various durations as shown in the figure. Rabbits were pretreated with intravenous either vehicle (saline, black line, black circle, n = 22) or memantine (20 mg/kg; red line, red X, n = 23) 30 minutes (min) before aortic occlusion. Memantine significantly increased the P₅₀ value (ischemia duration by 9.45 minutes) measured at 48 hours after aortic occlusion (unpaired t-test, *P < 0.05), and improved rabbit behaviors. For graphical analysis, normal animal data are plotted on the y-axis at 0 and abnormal animal data are plotted at 100.