OBJECTIVE: To investigate recombinant human TIMP-1 ((125)I-rhTIMP-1) half-life in blood and its distribution in rat brain tissue after cerebral ischemia/reperfusion as part of a therapeutic development paradigm. METHOD: A suture model of the middle cerebral artery occlusion was used. (125)I-labeled rhTIMP-1 at 60 μg/kg (11.23 μCi/μg) was administered to rats intravenously at the beginning of reperfusion. Blood and brain tissue were collected. The radioactivity was detected with a gamma counter and analyzed by autoradiography. RESULTS: The blood half-life T(1/2) of (125)I-rhTIMP-1 was 42.2 hours. Thirty minutes after (125)I-rhTIMP-1 administration, an increased accumulation of (125)I-rhTIMP-1 in the ischemic hemisphere was observed. The maximum brain tissue concentration C(max) was 26.1 ng/g at 1.5 hours in the striatum and 13.9 ng/g at 5 hours in the cortex when the uptake percentage of brain tissue to blood was 6.1±0.4 and 6.7±2.1%, respectively. The cortex and striatum elimination half-lives T(1/2) were 45.3 and 39.2 hours, respectively. Electrophoretic analysis of ischemic samples for (125)I-rhTIMP-1 showed a clear 28 kDa band 1.5 hours after (125)I-rhTIMP-1 administration in the cortex and striatum. The intensity of the 28 kDa band decreased after 3.0 hours of the administration. Some (125)I-rhTIMP-1 maintained its molecular integrity for 8.5 hours in ischemic striatum after reperfusion. DISCUSSION: (125)I-labeled rhTIMP-1 was distributed quickly into ischemic brain tissue and had a slow elimination in both blood and brain tissue. These results, along with other studies suggesting therapeutic benefits, will aid in the development of TIMP-1 for protecting ischemic stroke.
OBJECTIVE: To investigate recombinant humanTIMP-1 ((125)I-rhTIMP-1) half-life in blood and its distribution in rat brain tissue after cerebral ischemia/reperfusion as part of a therapeutic development paradigm. METHOD: A suture model of the middle cerebral artery occlusion was used. (125)I-labeled rhTIMP-1 at 60 μg/kg (11.23 μCi/μg) was administered to rats intravenously at the beginning of reperfusion. Blood and brain tissue were collected. The radioactivity was detected with a gamma counter and analyzed by autoradiography. RESULTS: The blood half-life T(1/2) of (125)I-rhTIMP-1 was 42.2 hours. Thirty minutes after (125)I-rhTIMP-1 administration, an increased accumulation of (125)I-rhTIMP-1 in the ischemic hemisphere was observed. The maximum brain tissue concentration C(max) was 26.1 ng/g at 1.5 hours in the striatum and 13.9 ng/g at 5 hours in the cortex when the uptake percentage of brain tissue to blood was 6.1±0.4 and 6.7±2.1%, respectively. The cortex and striatum elimination half-lives T(1/2) were 45.3 and 39.2 hours, respectively. Electrophoretic analysis of ischemic samples for (125)I-rhTIMP-1 showed a clear 28 kDa band 1.5 hours after (125)I-rhTIMP-1 administration in the cortex and striatum. The intensity of the 28 kDa band decreased after 3.0 hours of the administration. Some (125)I-rhTIMP-1 maintained its molecular integrity for 8.5 hours in ischemic striatum after reperfusion. DISCUSSION: (125)I-labeled rhTIMP-1 was distributed quickly into ischemic brain tissue and had a slow elimination in both blood and brain tissue. These results, along with other studies suggesting therapeutic benefits, will aid in the development of TIMP-1 for protecting ischemic stroke.
Authors: Aigang Lu; Joseph F Clark; Joseph P Broderick; Gail J Pyne-Geithman; Kenneth R Wagner; Pooja Khatri; Thomas Tomsick; Frank R Sharp Journal: Exp Neurol Date: 2009-01-07 Impact factor: 5.330
Authors: Aigang Lu; Joseph F Clark; Joseph P Broderick; Gail J Pyne-Geithman; Kenneth R Wagner; Ruiqiong Ran; Pooja Khatri; Thomas Tomsick; Frank R Sharp Journal: Exp Neurol Date: 2007-12-15 Impact factor: 5.330
Authors: Emiri Tejima; Shuzhen Guo; Yoshihiro Murata; Ken Arai; Josephine Lok; Klaus van Leyen; Anna Rosell; Xiaoying Wang; Eng H Lo Journal: J Neurotrauma Date: 2009-11 Impact factor: 5.269
Authors: Kyung-Pil Park; Anna Rosell; Christian Foerch; Changhong Xing; Woo Jean Kim; Seoul Lee; Ghislain Opdenakker; Karen L Furie; Eng H Lo Journal: Stroke Date: 2009-06-25 Impact factor: 7.914