Brain distribution and elimination of recombinant human TIMP-1 after cerebral ischemia and reperfusion in rats
To investigate recombinant human TIMP-1 (125I-rhTIMP-1) half-life in blood and its distribution in rat brain tissue after cerebral ischemia/reperfusion as part of a therapeutic development paradigm.
A suture model of the middle cerebral artery occlusion was used. 125I-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.
The blood half-life T1/2 of 125I-rhTIMP-1 was 42.2 hours. Thirty minutes after 125I-rhTIMP-1 administration, an increased accumulation of 125I-rhTIMP-1 in the ischemic hemisphere was observed. The maximum brain tissue concentration Cmax 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 T1/2 were 45.3 and 39.2 hours, respectively. Electrophoretic analysis of ischemic samples for 125I-rhTIMP-1 showed a clear 28 kDa band 1.5 hours after 125I-rhTIMP-1 administration in the cortex and striatum. The intensity of the 28 kDa band decreased after 3.0 hours of the administration. Some 125I-rhTIMP-1 maintained its molecular integrity for 8.5 hours in ischemic striatum after reperfusion.
125I-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.
Sa, Y., Hao, J., Samineni, D., Clark, J., Pyne-Geithman, G., Broderick, J., & Lu, A. (2011). Brain distribution and elimination of recombinant human TIMP-1 after cerebral ischemia and reperfusion in rats. Neurological Research, 33(4), 433-438.