Thrombopoietin protects the brain and improves sensorimotor functions: reduction of stroke-induced MMP-9 upregulation and blood-brain barrier injury.
This study was conducted to determine the protective efficacy and mechanisms of thrombopoietin (TPO) intervention in experimental focal stroke. Male rats underwent 2 hours of left middle cerebral artery occlusion (MCAO) followed by 22 hours of reperfusion. Vehicle or TPO (0.03 to 1.00 μg/kg) was administered intravenously immediately after reperfusion. Brain infarct and swelling, neurologic deficits, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), TPO and c-Mpl (TPO receptor) mRNA, MMP-9 enzyme activity and protein expression, and the integrity of the blood-brain barrier (BBB) were subsequently measured. MCAO reperfusion produced a large infarct and swelling after stroke. Thrombopoietin significantly reduced these in a dose-dependent manner. The most effective TPO dose, 0.1 μg/kg, when administrated immediately or 2 hours after reperfusion, significantly reduced infarct and swelling and ameliorated neurologic deficits after stroke. Stroke-induced increases in cortical MMP-9 mRNA, enzyme activity and protein expression, TIMP-1 mRNA, and Evans blue extravasation were reduced by TPO intervention. Thrombopoietin did not alter cortical TPO or c-Mpl mRNA expression, blood pressure, heart rate, blood hematocrit, or platelets. This is the first demonstration of TPO's efficacy in reducing ischemic brain injury and improving functional outcome, partly by inhibiting the stroke-induced increase in MMP-9 and the early, negative effects on the BBB.
Zhou
Jin
J
Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York 11203-2098, USA. jin.zhou@downstate.edu
Li
Jie
J
Rosenbaum
Daniel M
DM
Barone
Frank C
FC
D000818:Animals; D001794:Blood Pressure; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001831:Body Temperature; D001921:Brain / Q000187:drug effects*; D001929:Brain Edema / Q000209:etiology / Q000473:pathology; D002544:Cerebral Infarction / Q000150:complications / Q000473:pathology; D003199:Computer Systems; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects*; D009422:Nervous System Diseases / Q000209:etiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010976:Platelet Count; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D012677:Sensation / Q000187:drug effects*; D020521:Stroke / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D013926:Thrombopoietin / Q000008:administration & dosage*; D015854:Up-Regulation / Q000187:drug effects
D006454:Hemoglobins; D018696:Neuroprotective Agents; D013926:Thrombopoietin; D020780:Matrix Metalloproteinase 9