title: Peroxynitrite decomposition catalyst prevents matrix metalloproteinase-9 activation and neurovascular injury after hemoglobin injection into the caudate nucleus of rats.
abstract: Hemoglobin (Hb) is a major constituent of blood and a potent mediator of oxidative or nitrative stress after intracerebral hemorrhage (ICH). Our previous study demonstrated that Hb could induce abundant peroxynitrite (ONOO(-)) formation in vivo, which may be involved in the blood-brain barrier (BBB) disruption, however, the drug intervention is absent and also the underlying mechanism. Using an experimental stroke model by injecting Hb into the caudate nucleus of male Sprague-Dawley rats, we assessed the role of ONOO(-) decomposition catalyst, 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron(III) [FeTPPS] in the activation of MMP-9 and Hb-induced neurovascular injuries. 3-Nitrotyrosine (3-NT, as an index of ONOO(-) formation) and NF-κB expression was measured by western blot (WB) and immunohistochemistry (IHC)/immunofluorescence (IF). Activity of MMP was evaluated by in situ zymography. Neurovascular injury was assessed using zonula occludens-1 (ZO-1) by WB and IF, fibronectin (FN) and neuron-specific nuclear protein (NeuN) IHC. Perihematomal cell death was determined by TUNEL assay. Behavioral outcome was measured by modified neurological severity score (mNSS) test. At the injured striata, profuse 3-NT was produced and mainly expressed in neutrophils and microglia/macrophages. 3-NT formation significantly colocalized with nuclear factor-κB (NF-κB) expression. In situ zymography showed that gelatinase activity was mostly co-localized with neurons and blood vessel walls and partly with neutrophils and microglia/macrophages. Enhanced 3-NT production, NF-κB induction and MMP-9 activation were obviously reduced after FeTPPS treatment. Hb-induced injury to tight junction protein (ZO-1), basal lamina of FN-immunopositive microvasculature and neural cells was evidently ameliorated by FeTPPS. In addition, apoptotic cell numbers as well as behavioral deficits were also improved. The present study shows that the administration of the ONOO(-) decomposition catalyst FeTPPS protects against Hb-induced neurovascular injuries and improves neurological function, which possibly in part by suppressing MMP-9 activation.
authors: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors: R
authors: R
authors: Ding
authors: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors: L
authors: L
authors: Feng
authors: Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors: L
authors: L
authors: He
authors: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China. Electronic address: yizhao_chen@hotmail.com.
authors: Y
authors: Y
authors: Chen
authors: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors: P
authors: P
authors: Wen
authors: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors: Z
authors: Z
authors: Fu
authors: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors: C
authors: C
authors: Lin
authors: Department of Neurosurgery, Gaoqing Campus of Central Hospital of Zibo, Gaoqing People's Hospital, Gaoqing, Zibo 256300, Shandong, China.
authors: S
authors: S
authors: Yang
authors: Department of Neurosurgery, 999 Brain Hospital, Jinan University, Guangzhou 510510, China.
authors: X
authors: X
authors: Deng
authors: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors: J
authors: J
authors: Zeng
authors: Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China.
authors: G
authors: G
authors: Sun
mesh_terms: D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects* / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000139:chemically induced*; D053331:Ectodysplasins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006454:Hemoglobins / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011166:Porphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism; D013997:Time Factors; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D053331:Ectodysplasins; D005353:Fibronectins; D005904:Glial Fibrillary Acidic Protein; D006454:Hemoglobins; D016328:NF-kappa B; D011166:Porphyrins; D062826:Zonula Occludens-1 Protein; D030421:Peroxynitrous Acid; C016136:tetraphenylporphine sulfonate; D020780:Matrix Metalloproteinase 9; D010751:Phosphopyruvate Hydratase
keywords: hemoglobin; intracerebral hemorrhage; matrix metalloproteinases; neurovascular injury; oxidative or nitrative stress; peroxynitrite