Neuroprotective effect of KR-31378, a novel potassium channel activator, on spinal cord ischemic injury in rabbits.
Neurologic deficits after the surgical repair of thoracic and thoracoabdominal aortic disease are devastating complications. Recently, pharmacologic preconditioning with potassium channel openers was reported to protect the spinal cord against neurologic injury in a model of spinal cord ischemia. A novel benzopyran derivative with an N-cyanoguanidine group, KR-31378, has been synthesized as a new therapeutic agent against ischemic injury. In the present study, we evaluated the protective effects of KR-31378 on spinal cord ischemic injury and compared its neuroprotective activities and hemodynamic stabilities with those of diazoxide. Thirty-four New Zealand white rabbits were randomly divided into four groups: ischemia group (n = 10, 25 min of aortic cross-clamping without any intervention), diazoxide group (n = 8, diazoxide [5 mg/kg] intravenously 15 min before the 25-min cross-clamping), KR20 group (n = 8, KR-31378 [20 mg/kg] intravenously 30 min before the 25-min cross-clamping), and the KR50 group (n = 8, KR-31378 [50 mg/kg] intravenously 30 min before the 25-min cross-clamping). Neurologic functions were evaluated for 72 h postoperatively using modified Tarlov's scores. All rabbits were sacrificed for histopathologic observations after finally scoring neurologic function. All rabbits but three survived. The rest were completely evaluated 72 h postoperatively. Unlike diazoxide-treated rabbits, KR-31378-treated rabbits showed relatively stable hemodynamics. Tarlov's score outcomes showed a marked improvement in the diazoxide group, in the KR20 group, and in the KR50 group compared to the ischemia group (p = .005, .002, and .001, respectively). However, Tarlov's scores in the KR50 group were not significantly different from those of the diazoxide group. Histopathologic data were not significantly different between the groups, but the degree of degenerative change in motor neurons showed a significant correlation with Tarlov's scores 3 days postoperatively (gamma = -.378, p = .036). Thus, the administration of KR-31378 before the aortic cross-clamping resulted in a significant improvement in neurologic outcome with stable hemodynamics in this rabbit model.
Lee
Chang-Ha
CH
Department of Cardiac Surgery, Sejong General Hospital, Bucheon, Korea.
Choi
Ki Young
KY
Kim
Yong Jin
YJ
Kim
Won Gon
WG
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D019194:Ischemic Preconditioning; D008297:Male; D009460:Neurologic Examination; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D015221:Potassium Channels / Q000819:agonists*; D011714:Pyrans / Q000627:therapeutic use*; D011817:Rabbits; D020760:Spinal Cord Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control
D006146:Guanidines; C438686:N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine; D018696:Neuroprotective Agents; D015221:Potassium Channels; D011714:Pyrans; D003981:Diazoxide