Endogenous zinc protoporphyrin formation critically contributes to hemorrhagic stroke-induced brain damage

Abstract

Hemorrhagic stroke is a leading cause of death. The causes of intracerebral hemorrhage (ICH)-induced brain damage are thought to include lysis of red blood cells, hemin release and iron overload. These mechanisms, however, have not proven very amenable to therapeutic intervention, and so other mechanistic targets are being sought. Here we report that accumulation of endogenously formed zinc protoporphyrin (ZnPP) also critically contributes to ICH-induced brain damage. ICH caused a significant accumulation of ZnPP in brain tissue surrounding hematoma, as evidenced by fluorescence microscopy of ZnPP, and further confirmed by fluorescence spectroscopy and supercritical fluid chromatography-mass spectrometry. ZnPP formation was dependent upon both ICH-induced hypoxia and an increase in free zinc accumulation. Notably, inhibiting ferrochelatase, which catalyzes insertion of zinc into protoporphyrin, greatly decreased ICH-induced endogenous ZnPP generation. Moreover, a significant decrease in brain damage was observed upon ferrochelatase inhibition, suggesting that endogenous ZnPP contributes to the damage in ICH. Our findings reveal a novel mechanism of ICH-induced brain damage through ferrochelatase-mediated formation of ZnPP in ICH tissue. Since ferrochelatase can be readily inhibited by small molecules, such as protein kinase inhibitors, this may provide a promising new and druggable target for ICH therapy.

Prior statin and short‐term outcomes of primary intracerebral hemorrhage: From a large‐scale nationwide longitudinal registry

“…In addition, endogenously formed zinc protoporphyrin can induce ICH‐related damage, including the lysis of red blood cells and brain edema. Hence, ferrochelatase, a catalyst that inserts zinc into protoporphyrin, may be beneficial for reducing brain edema 40 . Compared to the advances in therapeutic agents for ischemic stroke, 41–43 progress in ICH research is limited and drugs targeted to brain edema, including statins, may be promising.…”

“…Hence, ferrochelatase, a catalyst that inserts zinc into protoporphyrin, may be beneficial for reducing brain edema. 40 Compared to the advances in therapeutic agents for ischemic stroke, [41][42][43] progress in ICH research is limited and drugs targeted to brain edema, including statins, may be promising.…”