title: Combination approaches to attenuate hemorrhagic transformation after tPA thrombolytic therapy in patients with poststroke hyperglycemia/diabetes.
abstract: To date, tissue type plasminogen activator (tPA)-based thrombolytic stroke therapy is the only FDA-approved treatment for achieving vascular reperfusion and clinical benefit, but this agent is given to only about 5% of stroke patients in the USA. This may be related, in part, to the elevated risk of symptomatic intracranial hemorrhage, and consequently limited therapeutic time window. Clinical investigations demonstrate that poststroke hyperglycemia is one of the most important risk factors that cause intracerebral hemorrhage and worsen neurological outcomes. There is a knowledge gap in understanding the underlying molecular mechanisms, and lack of effective therapeutics targeting the severe complication. This short review summarizes clinical observations and experimental investigations in preclinical stroke models of the field. The data strongly suggest that interactions of multiple pathogenic factors including hyperglycemia-mediated vascular oxidative stress and inflammation, ischemic insult, and tPA neurovascular toxicity in concert contribute to the BBB damage-intracerebral hemorrhagic transformation process. Development of combination approaches targeting the multiple pathological cascades may help to attenuate the hemorrhagic complication.
authors.affiliation: Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Fan
authors.affiliation: Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, PR China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Zhanyang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA; Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha, Hunan, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, PR China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA; Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha, Hunan, PR China.
authors.forename: Shuanglin
authors.initials: S
authors.lastname: Xiang
authors.affiliation: Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: wangxi@helix.mgh.harvard.edu.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
keywords: Blood–brain barrier; Combination therapy; Diabetes; Hyperglycemia; Intracerebral hemorrhage; Ischemic stroke; tPA