title: Proteasome Inhibitor Reduces Astrocytic iNOS Expression and Functional Deficit after Experimental Intracerebral Hemorrhage in Rats.
abstract: Intracerebral hemorrhage (ICH) is associated with perihematoma inflammation and edema. We have recently shown cell death and a robust activation of the proinflammatory transcription factor, nuclear factor-κB (NF-κB) in brain areas adjacent to the hematoma. Proteasome represents a key component necessary for the activation of NF-κB. The aim of our present study was to examine if selective proteasome inhibition with a clinically relevant agent, PS-519, might influence the ICH pathogenesis, and improve functional outcome. ICH was induced in Sprague-Dawley rats by the double blood injection method. PS-519 was administered intravenously 4 h and 15 min after induction of ICH. Behavioral testing was performed 3, 5, and 7 days later. The animals were sacrificed on day 7, and their brains were evaluated for hemorrhage size and inflammation using immunohistochemistry with antibody to various inflammatory markers. Treatment with PS-519 significantly (p < 0.05) reduced behavioral impairment post-ICH as determined by the footfault test. This effect was not due to difference in ICH volume. The improved functional status of PS-519 treated animals correlated positively (p < 0.01) with reduced expression of astroglial iNOS in areas adjacent to the hemorrhage 7 days post-ICH. No delayed changes in expression of OX-42 and ED-1 (microglia/macrophages marker), or vimentin (intermediate filament; marker of astroglia activation) were detected in animals treated with PS-519. This data suggests that modulation of proteasome-activated processes may represent a strategic target for treatment of ICH in humans.
authors: Department of Neurology, Stroke Program, University of Texas Medical School-Houston, 6431 Fannin, Suite 7.210, Houston, TX, 77030, USA.
authors: Fahmi M
authors: FM
authors: Al-Senani
authors: Xiurong
authors: X
authors: Zhao
authors: James C
authors: JC
authors: Grotta
authors: Ali
authors: A
authors: Shirzadi
authors: Roger
authors: R
authors: Strong
authors: Jaroslaw
authors: J
authors: Aronowski