CNS & Neurological Disorders-Drug Targets
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2020
·Vol. 19
·期 1
·66-82
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IF 0
Xianbin Wang,Wei Ma,Tongtong Wang,Jinwei Yang,Zhen Wu,Kuangpin Liu,Yunfei Dai,Chenghao Zang,Wei Liu,Jie Liu,Yu Liang,Jianhui Guo,Liyan Li
Background: Brain-Derived Neurotrophic Factor (BDNF) plays critical roles during development of the central and peripheral nervous systems, as well as in neuronal survival after injury. Although proBDNF induces neuronal apoptosis after injury in vivo, whether it can also act as a death factor in vitro and in vivo under physiological conditions and after nerve injury, as well as its mechanism of inducing apoptosis, is still unclear. Objective: In this study, we investigated the mechanisms by which proBDNF causes apoptosis in sensory neurons and Satellite Glial Cells (SGCs) in Dorsal Root Ganglia (DRG) After Sciatic Nerve Transection (SNT). Methods: SGCs cultures were prepared and a scratch model was established to analyze the role of proBDNF in sensory neurons and SGCs in DRG following SNT. Following treatment with proBDNF antiserum, TUNEL and immunohistochemistry staining were used to detect the expression of Glial Fibrillary Acidic Protein (GFAP) and Calcitonin Gene-Related Peptide (CGRP) in DRG tissue; immunocytochemistry and Cell Counting Kit-8 (CCK8) assay were used to detect GFAP expression and cell viability of SGCs, respectively. RT-qPCR, western blot, and ELISA were used to measure mRNA and protein levels, respectively, of key factors in BDNF-TrkB, proBDNF-p75NTR/sortilin, and apoptosis signaling pathways. Results: proBDNF induced mitochondrial apoptosis of SGCs and neurons by modulating BDNF-TrkB and proBDNF-p75NTR/sortilin signaling pathways. In addition, neuroprotection was achieved by inhibiting the biological activity of endogenous proBDNF protein by injection of anti-proBDNF serum. Furthermore, the anti-proBDNF serum inhibited the activation of SGCs and promoted their proliferation. Conclusion: proBDNF induced apoptosis in SGCs and sensory neurons in DRG following SNT. The proBDNF signaling pathway is a potential novel therapeutic target for reducing sensory neuron and SGCs loss following peripheral nerve injury.
研究领域:
神经生物学
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细胞生物学
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分子生物学
✓ 已验证
DOI
BEHAVIOURAL BRAIN RESEARCH
·
2019
·
IF 2.77
Jianguo Li,Jing Chen,Na Ma,Deping Yan,Ying Wang,Xin Zhao,Yu Zhang,Ce Zhang
Chronic stressor induces the release of glucocorticoid from the adrenal glands, the subsequent decrease of hippocampal volume, and the development of depression. Brain-derived neurotrophic factor (BDNF), composed of mature BDNF (mBDNF) and proBDNF, plays opposite roles in the structural integrity of the brain. However, the underlying mechanism of glucocorticoid-induced hippocampal atrophy remains unclear. Using the open field test, sucrose preference test, elevated plus maze test, and forced swimming test, we observed that the chronic (3 w) administration of corticosterone (CORT) (50 μg/ml) induced depressive-like behaviors in rats. Next, using Western blot assay, we showed that CORT exposure increased the proBDNF level in the ventral hippocampal dentate gyrus (DG), decreased the mBDNF level in the dorsal and ventral DG, and decreased the mBDNF/proBDNF ratio in the hippocampal DG. Furthermore, CORT administration differentially altered the expression of 11 Bdnf mRNA transcripts in the dorsal and ventral hippocampal DG. Our findings suggest an essential role for the mBDNF-proBDNF system in regulating the hippocampus of CORT-treated rats and present a new therapeutic mechanism for antidepressant treatments by targeting the Bdnf mRNA transcripts.
研究领域:
神经科学
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分子生物学
·
精神病学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2020
·
IF 3.292
Zuntao Wu,Lin Bai,Runqi Tu,Lijie Zhang,Yue Ba,Huizhen Zhang,Xing Li,Xuemin Cheng,Wenjie Li,Hui Huang
Lead (Pb) is recognized as a potent inducer of synaptic toxicity generally associated with reduced synaptic transmission and increased neuronal fiber excitability, becoming an environmental risk for neurodegenerative processes. Despite numerous toxicological studies on Pb have been directed to the developing brain, attention concerning long-term consequences of pubertal chronic Pb exposure on neuronal activity is still lacking. Thus, we exposed 4-week-old male mice to 0.2 % lead acetate solution for one month, then, conducted behavioral tests or extracted brain homogenate from mice prefrontal cortex (PFC) and hippocampus at the age of 4, 13 and 16-month-old respectively. Our results showed that treated mice exhibited an evident increase in latency to reach platform following pubertal Pb exposure and aging. The increase of 8-OHdG revealed evident neural DNA oxidative damage across time upon pubertal Pb exposure. In the hippocampus of lead exposed mice at three age nodes, the expression of brain-derived neurotrophic factor precursor (proBDNF) increased, while that of mature BDNF (mBDNF), cAMP-response element binding protein (CREB) and phosphorylated CREB (pCREB) decreased compared with the control group. Furthermore, the expression of BACE1 protein and tau phosphorylation level in PFC and hippocampus increased, APP mRNAs in PFC and prolonged induction of BACE1 in hippocampus. Our results show that chronic Pb exposure from pubertal stage onward can either initiate divergent synaptic-related gene expression patterns in adulthood or trigger time-course of neurodegenerative profile within the PFC or hippocampus, which can contribute consistent deficits of cognition across subsequent age-nodes.
研究领域:
神经毒理学
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神经科学
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分子生物学
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行为科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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