Nogo-A/Pir-B/TrkB Signaling Pathway Activation Inhibits Neuronal Survival and Axonal Regeneration After Experimental Intracerebral Hemorrhage in Rats
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Intracerebral hemorrhage (ICH) leads to widespread pathological lesions in the brain, especially impacting neuronal survival and axonal regeneration. This study aimed to elucidate whether the Nogo-A (a myelin-related protein)/paired immunoglobulin-like receptor B (Pir-B)/tropomyosin receptor kinase B (TrkB) pathway could exert a regulatory effect in ICH. An ICH model was first established in Sprague Dawley rats, followed by different administrations of vehicle, k252a, or NSC 87877. The Morris water maze test was performed to observe ICH-induced cognitive dysfunction in rats. Rats in the ICH + NSC 87877 group showed better cognitive performance compared with those injected with vehicle or k252a. Neurobehavioral scores were identical. By harvesting brain tissues at different time points after ICH, we detected the expression levels of Nogo-A and PirB with western blot and immunofluorescence and found that they were markedly upregulated at 48 h after ICH. TUNEL and Fluoro-Jade B staining showed that NSC 87877 treatment attenuated ICH-induced apoptosis and neuronal death, whereas k252a treatment aggravated these pathological changes. The expression levels of growth-associated protein 43 (GAP43) and neurofilament 200 (NF200) were higher in the ICH + NSC 87877 group compared with the ICH + vehicle group, but were lower in the ICH + k252a group. Finally, we confirmed the protective role of p-TrkB/TrkB in ICH by western blot. To sum up, our study identified the inhibitory role of the Nogo-A/PirB/TrkB pathway in ICH; however, p-TrkB/TrkB may serve as a potential target for secondary brain injury post-ICH.
KeywordsIntracerebral hemorrhage Nogo-A Tropomyosin receptor kinase B Axonal regeneration Neuron cell death Growth-associated protein 43
J.W and X.F conceived and designed the study. Y.L and C.M performed the experiments and wrote the paper. H.L and H.S helped conduct the literature review. X.L and G.C reviewed and edited the manuscript. Yinlong Liu and Chao Ma contributed equally to this work. All authors read and approved the manuscript.
This work was supported by the Project of Jiangsu Provincial Medical Innovation Team (No. CXTDA2017003), Suzhou Key Medical Centre (No. Szzx201501), Scientific Department of Jiangsu Province (No. BE2017656), Suzhou Government (No. LCZX201601), Youth Science Foundation of Suzhou China (No. KJXW2017038), Science and Technology - Basic Research Project of Medical and Health Application of Suzhou China (No. SYS2018089), and the National Key R&D Program of China (No. 2018YFC1312600 & No. 2018YFC1312601).
Compliance with Ethical Standards
All procedures were approved by the Animal Protection Committee of Soochow University and were performed in accordance with the National Institutes of Health’s guidelines on the care and use of animals and the Animal Research: Reporting In Vivo Experiments guidelines. All efforts were made to minimize animal suffering and the number of animals used.
Conflict of Interest
The authors declare that they have no conflict of interest.
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