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ORIGINAL RESEARCH ARTICLE

Functional Neuroprotective Effect of CGS 26303, a Dual ECE Inhibitor, on Ischemic-Reperfusion Spinal Cord Injury in Rats

An-Kuo Chou^*,, Tai-I Chen, William Winardi, Ming-Hong Dai^||, Shih-Chieh Chen^¶, Shen-Long Howng, Chun-Po Yen, Tzu-Kan Lin^#, Arco Y. Jeng^** and Aij-Lie Kwan^,1

^* Department of Anesthesiology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Anesthesiology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung 807, Taiwan; Department of Neurosurgery, Kaohsiung Medical University, Kaohsiung 807, Taiwan; ^|| Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; ^¶ Department of Anatomy, Kaohsiung Medical University, Kaohsiung 807, Taiwan; ^# Department of Neurosurgery, Chang Gung Memorial Hospital, Tao Yen, Taiwan; ^** Cardiovascular Diseases Research, Novartis Institutes for BioMedical Research, East Hanover, New Jersey; and Department of Neurosurgery, University of Virginia, Charlottesville, Virginia

To whom requests for reprints should be addressed at ¹ Department of Neurosurgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, Taiwan, Republic of China. E-mail: A_LKWAN{at}yahoo.com

Endothelin-1 (ET-1) has been implicated in many neurological diseases, including subarachnoid hemorrhage (SAH) and cerebral ischemia. ET-1 is also proved to deteriorate the ischemia-reperfusion injury in many organs. Our previous studies demonstrated that the endothelin-converting enzyme (ECE) inhibitor, CGS 26303, possessed beneficial effects for the treatment of SAH and transient middle cerebral artery occlusion. In this study, we investigated the neuroprotective effect of CGS 26303 on the locomotor function and mRNA expression of heme-oxygenase-1 (HO-1) in rats subjected to a 15-min spinal cord ischemia. The results showed that pretreatment with CGS 26303 significantly preserved the locomotor function and decreased the paraplegia rate at Days 1 and 3 as compared with a saline-treated group. Furthermore, rats pretreated with CGS 26303 had a significant increase in the levels of HO-1 mRNA expression at Day 3 when compared with animals pretreated with saline after spinal cord ischemia and the sham operation group. These results suggest that CGS 26303 may have a promising neuroprotective effect in the spinal cord after ischemia-reperfusion injury, and beneficial result may be due to an adaptive mechanism involved by HO-1 overexpression.

Key Words: CGS 26303 • dual inhibitor • ischemia-reperfusion injury • heme-oxygenase