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.

Tobacco Use: A Major Risk Factor of Intracerebral Hemorrhage

“…136,139 Increased ROS/RNS release and increased activation of proinflammatory pathways and mitochondrial dysfunction are known to play a role in brain damage following hemorrhagic stroke. [140][141][142][143][144][145][146] Others also established the role of free radicals in sICH-induced brain damage. [147][148][149] Because nicotine exposure increases the activation of pathways involved in post-sICH brain damage, it is plausible that elevated activation of those pathways is enhanced post-sICH, which in turn leads to increased brain damage.…”

Neonatal Brain Hemorrhage (NBH) of Prematurity: Translational Mechanisms of the Vascular-Neural Network

“…In extension, recent therapeutic approaches using adult animals may one day prove useful in neonates [264] and vice-versa. Notably, proteasome inhibition using PS-519 was found to attenuate rodent brain inflammation, and related edema, through perihematomal modulation of nuclear factor-KB [267]. This intervention reduced expression of inflammatory astroglial iNOS; and improved functional recovery following the brain injury.…”

Scavenger receptor SRA attenuates microglia activation and protects neuroinflammatory injury in intracerebral hemorrhage

“…Much evidence suggests that microglia mediated inflammation plays a vital role in the ICH-induced brain injury (Kim et al, 2013;Hammond et al, 2012;Lei et al, 2013). After ICH, various stimuli could activate microglia and initiate inflammatory response, and subsequently release proinflammatory cytokines and chemokines to increase brain injury (Yao and Tsirka, 2012;Lin et al, 2012;Al-Senani et al, 2012). Therefore, the molecular mechanism to inhibit microglia activity might provide ideal strategy to treat inflammation induced brain injury after ICH.…”