Astrocyte heme oxygenase-1 reduces mortality and improves outcome after collagenase-induced intracerebral hemorrhage.
Pharmacotherapies that increase CNS expression of heme oxygenase-1 (HO-1) and other antioxidant proteins have improved outcome in experimental models of spontaneous intracerebral hemorrhage (ICH). In order to more specifically investigate the relationship between HO-1 and ICH outcome, mice expressing human HO-1 driven by the glial fibrillary acidic protein (GFAP) promoter (GFAP·HMOX1 mice) were tested in a model of in situ parenchymal hemorrhage. Injection of collagenase into the striata of wild-type (WT) mice resulted in a 26.3% mortality rate, with deaths equally distributed between males and females. Mortality was reduced to 4.48% in GFAP·HMOX1 mice. Cell viability in the injected striata of surviving WT mice was reduced by about half at one week and was significantly increased in transgenics; this benefit persisted over a 22day observation period. Cell counts guided by design-based stereology indicated loss of ~40% of neurons in WT hemorrhagic striata at one week, which was decreased by half in transgenics; no significant differences in microglia or astrocyte numbers were observed. Blood-brain barrier disruption and short-term neurological deficits were also mitigated in GFAP·HMOX1 mice, but long-term outcome did not differ from that of WT survivors. These results suggest that astrocyte HO-1 overexpression provides robust neuroprotection after acute intracerebral hemorrhage. Further investigation of drug or genetic therapies that selectively increase astrocyte HO-1 is warranted.
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Jing
J
Chen-Roetling
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Pramod
P
Kamalapathy
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Yang
Y
Cao
Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
Wei
W
Song
Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Hyman M
HM
Schipper
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: Raymond.Regan@jefferson.edu.
Raymond F
RF
Regan
D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002543:Cerebral Hemorrhage / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000523:psychology; D017364:Collagenases; D003342:Corpus Striatum / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000066829:Neuroprotection / Q000502:physiology
D005904:Glial Fibrillary Acidic Protein; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D017364:Collagenases
Glia; Intracerebral hemorrhage; Nrf2; Stroke; Subarachnoid hemorrhage