Neuroprotective and Anti-inflammatory Effects of a Dodecamer Peptide Harboring Ninjurin 1 Cell Adhesion Motif in the Postischemic Brain

Autor: Seung Woo Kim, Hahnbie Lee, Lidan Luo, Il-Doo Kim, Ja-Kyeong Lee, Hye-Kyung Lee
Rok vydání: 2017
Předmět:
Male
rac1 GTP-Binding Protein
0301 basic medicine
Small interfering RNA
Neutrophils
Cell Adhesion Molecules
Neuronal
Amino Acid Motifs
Anti-Inflammatory Agents
Neuroscience (miscellaneous)
HL-60 Cells
Cell Communication
Motor Activity
Biology
Brain Ischemia
Proinflammatory cytokine
Rats
Sprague-Dawley
Brain ischemia
Phosphatidylinositol 3-Kinases
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Immune system
Cell Movement
Cell Adhesion
Human Umbilical Vein Endothelial Cells
medicine
Animals
Humans
Amino Acid Sequence
Nerve Growth Factors
Cell adhesion
Inflammation
Innate immune system
Tumor Necrosis Factor-alpha
Cell adhesion molecule
Brain
Infarction
Middle Cerebral Artery
Recovery of Function
medicine.disease
Molecular biology
Cell biology
Disease Models
Animal
Neuroprotective Agents
030104 developmental biology
Neurology
Gene Knockdown Techniques
Peptides
Infiltration (medical)
030217 neurology & neurosurgery
Zdroj: Molecular Neurobiology. 55:6094-6111
ISSN: 1559-1182
0893-7648
DOI: 10.1007/s12035-017-0810-1
Popis: It has been reported that the innate immune response plays important roles in brain ischemia and that the infiltration of blood-derived immune cells is a key initiator of this response. Nerve injury-induced protein 1 (Ninjurin 1, Ninj1) is a cell adhesion molecule responsible for cell-to-cell interactions between immune cells and endothelial cells. In the present study, we investigated the proinflammatory and neuroprotective effects of Ninj1 and a dodecamer peptide harboring Ninj1 N-terminal adhesion motif (N-NAM, Pro26~Asn37) in a rat middle cerebral artery occlusion (MCAO) model of stroke. Ninj1 was predominantly induced in neutrophils and endothelial cells in the ischemic hemispheres around 12 h to 1 day post-MCAO, which coincided with a massive neutrophil influx. We demonstrated that intranasal administration of Ninj1 small interfering RNA (siRNA) or N-NAM significantly blocked neutrophil infiltration in postischemic brains. In addition, intranasal administration of Ninj1 siRNA or N-NAM reduced the mean infarct volume to 46.5 ± 9.2 or 30.6 ± 11.7% of that of the PBS-treated MCAO controls, respectively, which was accompanied by significant amelioration of neurological and motor deficits. We showed that N-NAM or Ninj1 siRNA effectively blocked the adhesion and transendothelial migration of TNF-α-stimulated human myelocytic leukemia cells to human umbilical vein endothelial cells and similarly suppressed adhesion and migration of monocytes. Activations of phosphoinositide 3-kinase and Ras-related C3 botulinum toxin substrate 1 are involved in these Ninj1-mediated processes and can be inhibited by N-NAM or Ninj1 siRNA. These results indicate that Ninj1 plays an important role in neutrophil infiltration in the postischemic brain and N-NAM confers robust neuroprotective and anti-inflammatory effects by inhibiting Ninj1-mediated infiltration of neutrophils.
Databáze: OpenAIRE
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