Systemic hemin therapy attenuates blood–brain barrier disruption after intracerebral hemorrhage

Abstract

Injury to the blood-brain barrier (BBB) is a key feature of intracerebral hemorrhage (ICH) and may contribute to perihematomal cell injury. Pretreatment with the heme oxygenase (HO)-1 inducer hemin improves barrier function and neurological outcome in experimental models of traumatic and ischemic CNS injury. Since hemin is already in clinical use to treat acute porphyrias, this translational study was designed to test its effect on BBB function when initiated after ICH in two mouse models. At a dose similar to those used in most preconditioning studies (26 mg/kg i.p.), post-hemorrhage treatment with hemin reduced parenchymal extravasation of Evans blue by about three-quarters in both the blood injection and collagenase ICH models. Similar efficacy was observed when treatment was begun at one or three hours. At the lower dose that is currently in clinical use (4 mg/kg beginning at 3 hours), hemin also improved barrier function in both models, as assessed by both Evans blue and FITC-dextran leakage; however, it was somewhat less potent, reducing Evans blue leakage by about half. This dose was nevertheless sufficient to attenuate striatal cell loss and accelerate neurological recovery. Consistent with prior observations, striatal HO-1 expression was increased by hemin, and was localized to perivascular cells. These results suggest that hemin may be an effective therapy for ICH with a clinically relevant time window. Further study of the repurposing of this old drug seems warranted.

Astrocyte Overexpression of Heme Oxygenase-1 Improves Outcome After Intracerebral Hemorrhage

“…21 Since astrocyte HO-1 overexpression is particularly prominent in GFAP.HMOX1 mice adjacent to vessels (Fig 2), blood-brain barrier integrity was assessed 24 hours after striatal blood injection. Evans blue leakage into the striatal parenchyma at this time point in GFAP.HMOX1 mice was less than half of that in WT mice (Fig.…”

“…In prior studies from this laboratory, mortality in Swiss-Webster or C57BL/6 × 129 mice has ranged from 0–4%, which is comparable to that reported in multiple other studies. 2, 21, 37, 38 The 34% mortality rate in WT FVB mice was unexpected and highlights the prominent influence of strain on vulnerability to hemorrhagic CNS injury. FVB mice have been used infrequently in acute CNS injury models, but reported results have been largely consistent with the present observations.…”

“…21, 24 Both of these therapies increase CNS HO-1 expression, but also have pleiotropic effects on signaling pathways and gene expression that limit their utility as mechanistic probes. The present findings provide more specific evidence that HO-1 overexpression per se is sufficient to manifest protection.…”

“…Functional outcome was assessed as previously described, 21 via: 1) quantification of spontaneous cage activity in 1 hour videos, using Homecage Scan (CleverSys., Reston, VA USA); 2) adhesive removal test; 3) elevated body swing test.…”

Eff ects of hemin, a heme oxygenase-1 inducer in L-arginine-induced acute pancreatitis and associated lung injury in adult male albino rats

“…Th is could be explained by the fact that hemin requires a preconditioning interval of several hours, which is mediated in part by induction of HO-1 to mediate its protective eff ect (Lu et al 2014). In vivo, systemic pre-treatment with hemin was protective in multiple acute injury models, including brain (Zhang et al 2008), heart (Hangaishi et al 2000), kidney (Demirogullari et al 2006), liver (Xue et al 2007), and gut ischemia/reperfusion (Attuwaybi et al 2004) and colitis (Zhong et al 2010), and pancreatitis (Habtezion et al 2011).…”