Intracerebroventricular delivery of recombinant NAMPT deters inflammation and protects against cerebral ischemia
| Autor: | Fenghua Chen, Steven H. Graham, Lihong Han, Zhongfang Weng, Guodong Cao, Qinghai Xia, Catherine Cao, Jian Xiao, Rehana K. Leak |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Ischemia Nicotinamide phosphoribosyltransferase Macrophage polarization Inflammation Pharmacology Neuroprotection Article Brain Ischemia Brain ischemia 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine medicine Extracellular Animals Nicotinamide Phosphoribosyltransferase Microglia business.industry General Neuroscience Macrophages Infarction Middle Cerebral Artery Cerebral Infarction medicine.disease Recombinant Proteins Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Infusions Intraventricular Neuroprotective Agents chemistry Blood-Brain Barrier Neurology (clinical) medicine.symptom Cardiology and Cardiovascular Medicine business 030217 neurology & neurosurgery |
| Zdroj: | Transl Stroke Res |
| Popis: | Our previous study indicated that nicotinamide phosphoribosyltransferase (NAMPT) is released from cells and might be an important extracellular neuroprotective factor in brain ischemia. Here we tested whether NAMPT protects against ischemic brain injury when administered directly into the intracerebroventricular (ICV) compartment of the cranium. Recombinant NAMPT protein (2 μg) was delivered ICV in mice subjected to 45-min middle cerebral artery occlusion (MCAO), and the effects on infarct volume, sensorimotor function, microglia/macrophage polarization, neutrophil infiltration, and BBB integrity were analyzed. The results indicate that ICV administration of NAMPT significantly reduced infarct volume, retained its beneficial properties even when ICV administration was delayed by 6 hours after MCAO, and improved neurological outcomes. NAMPT treatment inhibited pro-inflammatory microglia/macrophages, promoted microglia/macrophage polarization toward the anti-inflammatory phenotype, and reduced the infiltration of neutrophils into the perilesional area after brain ischemia. In vitro studies indicated that multiple pro-inflammatory microglial markers/cytokines were downregulated while multiple anti-inflammatory microglial markers/cytokines were induced in primary microglial cultures treated with NAMPT protein. NAMPT treatment also fortified the blood-brain barrier (BBB), as shown by reduced extravascular leakage of the small-molecule tracer Alexa Fluor 555 Cadaverine and larger-sized endogenous IgGs into brain parenchyma. Thus, NAMPT may protect against ischemic brain injury partly through a novel anti-inflammatory mechanism, which in turn maintains BBB integrity and reduces the infiltration of peripheral inflammatory cells. Taken together, these results provide validation of recombinant NAMPT delivery into the extracellular space as a potential neuroprotective strategy for stroke. |
| Databáze: | OpenAIRE |
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