Down-regulation of Nogo receptor promotes functional recovery by enhancing axonal connectivity after experimental stroke in rats

• Published in: Brain research Vol. 1360; pp. 147 - 158
• Main Authors: Wang, Tianzhu, Wang, Jing, Yin, Cheng, Liu, Ruen, Zhang, John H, Qin, Xinyue
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 11-11-2010; Elsevier
• Subjects: Adenoviridae - genetics; Adenovirus-mediated RNAi; Animals; Axonal connectivity; Axonogenesis; Axons - physiology; Behavior, Animal - physiology; Biological and medical sciences; Biotin - analogs & derivatives; Blotting, Western; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Dextrans; Down-Regulation - physiology; Fluorescent Dyes; GPI-Linked Proteins; Hippocampus - metabolism; Hippocampus - pathology; Infarction, Middle Cerebral Artery - pathology; Male; MCAO; Medical sciences; Myelin Proteins; Neural Pathways - physiology; Neurology; NgR; Nogo Receptor 1; Psychomotor Performance - physiology; Pyramidal Tracts - pathology; Pyramidal Tracts - physiology; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Peptide - genetics; Receptors, Peptide - physiology; Recovery of Function - physiology; Reperfusion Injury - pathology; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Stereotaxic Techniques; Stroke - pathology; Stroke - physiopathology; Vascular diseases and vascular malformations of the nervous system; TTC; RNA interference; CNS; BSA; myelin-associated glycoprotein; RT-PCR; NgR; biotinylated dextran amine; nogo receptor; MCAO; OMgp; RNAi; CST; Axonal connectivity; adenovirus-associated virus; NEP1–40; central nervous system; reverse transcriptase-polymerase chain reaction; MAG; oligodendrocyte myelin glycoprotein; Adenovirus-mediated RNAi; AAV; corticospinal tract; nogo extracellular peptide 1–40; 2,3,5-triphenyltetrazolium chloride; BDA; bovine serum albumin; middle cerebral artery occlusion; Nervous system diseases; Stroke; Adenoviridae; Rat; Rodentia; Cardiovascular disease; Cerebral disorder; Vascular disease; Virus; Vertebrata; Mammalia; Functional recovery; Animal; Central nervous system disease; Cerebrovascular disease; Biological receptor
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2010.08.101

Abstract The inability of axons in central nervous system (CNS) to regenerate after injury is related partly to multiple endogenous axon growth inhibitors including Nogo receptor (NgR). This study tested the hypothesis that silencing NgR expression by adenovirus-mediated RNA interference (RNAi) (AD-NgR) may permit axonal connectivity after focal cerebral ischemia in rats. Male Sprague–Dawley rats (250–280 g, n = 97) were assigned into seven groups: sham, MCAO (24 h and 2 weeks), MCAO plus AD-NgR (24 h and 2 weeks), and MCAO plus AD-HK (control oligonucleotides) (24 h and 2 weeks). After cerebral ischemia, NgR mRNA and protein in the cortex and hippocampus were significantly increased at 24 h and 2 weeks. However, in AD-NgR treated rats, NgR mRNA and protein were reduced by 40–60% in the cortex and hippocampus at both time points as compared to controls. Although there was no significant difference in the infarct volume between the two groups, the number of midline-crossing fibers projecting to the contralateral red nucleus and corticostriatal fibers in the dorsolateral striatum were increased in AD-NgR injected rats, accompanied by improved behavioral outcomes. Taken together, these results suggest that NgR knockdown may promote CNS axonal regeneration and functional recovery after ischemic cerebral injury.