NAD replenishment with nicotinamide mononucleotide protects blood-brain barrier integrity and attenuates delayed tissue plasminogen activator-induced haemorrhagic transformation after cerebral ischaemia

Autor:	Pei Wang, Xia Hua, Si-Li Zheng, Yuan-Yuan Kong, Chun-Chun Wei, Guo-Qiang Li, Ming-He Cheng, Chao-Yu Miao
Rok vydání:	2017
Předmět:	0301 basic medicine Pharmacology integumentary system Chemistry Ischemia Blood–brain barrier medicine.disease Occludin Tissue plasminogen activator Brain ischemia 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Edema medicine medicine.symptom 030217 neurology & neurosurgery Neuroinflammation medicine.drug Nicotinamide mononucleotide
Zdroj:	British Journal of Pharmacology. 174:3823-3836
ISSN:	0007-1188
Popis:	Background and Purpose Tissue plasminogen activator (tPA) is the only approved pharmacological therapy for acute brain ischemia; however, a major limitation of tPA is the haemorrhagic transformation followed by tPA treatment. Here, we determine whether nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide biosynthesis, would affect tPA-induced haemorrhagic transformation. Experimental Approach Middle cerebral artery occlusion (MCAO) was achieved in CD1 mice by introducing a filament to the left MCA for 5 hours. When the filament was removed for reperfusion, tPA was infused from tail vein. NMN was injected intraperitoneally with a single dose (300 mg/kg). Mice were euthanized at 24 hours post ischemia and their brains were evaluated for brain infarction, edema, hemoglobin content, apoptosis, neuroinflammation, blood-brain barrier (BBB) permeability, tight junction proteins (TJPs) expression and matrix metalloproteinases (MMPs) activities/expression. Key Results In the mice infused with tPA at 5 hours post ischemia, there were significant increases in mortality, brain infarction, brain edema, brain hemoglobin level, neural apoptosis, Iba-1 staining (microglia activation) and MPO staining (neutrophil infiltration). All these tPA-induced alterations were significantly prevented by NMN administration. Mechanistically, the delayed tPA treatment induced BBB permeability by downregulating tight junction proteins, including claudin-1, occludin and ZO-1, and enhancing the activities and protein expression of MMP9 and MMP2. Similarly, NMN administration partly blocked these tPA-induced molecular changes. Conclusions and Implications Our results demonstrate that NMN ameliorates tPA-induced haemorrhagic transformation in brain ischemia by maintaining BBB integrity.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::1f2c68d2ee491753c8feb5928cc703ba https://doi.org/10.1111/bph.13979 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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