[ANA- 12 inhibits spinal inflammation and alleviates acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling]

doi:10.12122/j.issn.1673-4254.2022.02.09

. 2022 Feb 20;42(2):232-237.

doi: 10.12122/j.issn.1673-4254.2022.02.09.

[ANA- 12 inhibits spinal inflammation and alleviates acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling]

[Article in Chinese]

J Zhao¹, H Yang¹, Z Wang¹, H Zhu¹, M Xie¹

Affiliations

PMID: 35365447
PMCID: PMC8983361
DOI: 10.12122/j.issn.1673-4254.2022.02.09

[ANA- 12 inhibits spinal inflammation and alleviates acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling]

[Article in Chinese]

J Zhao et al. Nan Fang Yi Ke Da Xue Xue Bao. 2022.

. 2022 Feb 20;42(2):232-237.

doi: 10.12122/j.issn.1673-4254.2022.02.09.

Authors

J Zhao¹, H Yang¹, Z Wang¹, H Zhu¹, M Xie¹

Affiliation

¹ School of Pharmacy, Hubei University of Science and Technology, Xianning 437100, China.

PMID: 35365447
PMCID: PMC8983361
DOI: 10.12122/j.issn.1673-4254.2022.02.09

Abstract
in English, Chinese

Objective: To investigate the inhibitory effect of ANA-12 that blocks brain-derived neurotrophic factor (BDNF)/ tropomyosin receptor kinase B (TrkB) signaling on inflammatory pain in rats and explore the underlying mechanism.

Methods: Forty-two adult SD rats were randomized into BDNF-induced acute pain group (n=24) and CFA-induced chronic pain group. The former group were randomly divided into 4 subgroups, including a control group, ANA-12 treatment group, BDNF treatment group, and BDNF+ANA-12 treatment group; the latter group were subgrouped into control group, CFA treatment group (CFA) and CFA + ANA-12 treatment group. The effects of ANA-12 treatment on pain behaviors of the rats with BDNF-induced acute pain and CFA-induced chronic inflammatory pain were observed. Western blotting was used to examine TrkB signaling and expressions of microglia marker protein Iba1 and TNF-α in the spinal cord of the rats.

Results: BDNF injection into the subarachnoid space significantly increased the number of spontaneous paw withdrawal of the rats (P < 0.05), which was obviously reduced by ANA-12 treatment (P < 0.05). The rats with intraplantar injection of CFA, showed significantly increased ipsilateral mechanical stimulation sensitivity (P < 0.05), and ANA-12 treatment obviously increased the ipsilateral foot withdrawal threshold (P < 0.05). Treatment with either BDNF or CFA significantly increased the phosphorylation level of TrkB (Y705) in the spinal cord of the rats (P < 0.05), which was significantly lowered by ANA-12 treatment (P < 0.05). Treatment with BDNF and CFA both significantly up-regulated the expressions of Iba1 and TNF-α in the spinal cord (P < 0.05), but ANA-12 significantly reduced their expression levels (P < 0.05).

Conclusion: ANA-12 can reduce spinal cord inflammation and relieve acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling.

目的: 探讨ANA-12靶向阻断脑源性神经营养因子（BDNF）/原肌球蛋白受体激酶B（TrkB）信号对炎症痛的抑制作用及机制。

方法: 将42只大鼠随机分为7组（6只/组）：BDNF处理下的对照组、ANA-12处理组、BDNF处理组以及BDNF和ANA-12联合处理组（BDNF+ANA-12）；炎症痛模型下的对照组、CFA处理组以及CFA和ANA-12联合处理组（CFA+ANA-12）。给药完毕后，对各组大鼠进行痛觉行为学检测，记录ANA-12处理对BDNF-急性痛和CFA-慢性炎症痛大鼠痛觉行为的影响；采用免疫印迹法检测各组大鼠脊髓组织TrkB信号、小胶质细胞标记蛋白Iba1和促炎细胞因子TNF-α以及炎症因子IL-1β、Caspase-1、NLRP3的表达水平。

结果: 与对照组相比，BDNF增加自发缩足次数（P < 0.05）；与BDNF组相比，ANA-12降低自发缩足次数（P < 0.05）。与对照组相比，CFA增加同侧机械刺激敏感性（P < 0.05）；与CFA组相比，ANA-12增加同侧缩足阈值（P < 0.05）。与对照组相比，BDNF和CFA增加磷酸化TrkB（Y705）水平（P < 0.05）；与BDNF或CFA组相比，ANA-12降低TrkB（Y705）磷酸化水平（P < 0.05）。与对照组相比，BDNF和CFA上调Iba1、TNF-α以及炎症因子表达（P < 0.05）；与BDNF或CFA组相比，ANA-12降低Iba1、TNF-α以及炎症因子表达水平（P < 0.05）。

结论: ANA-12靶向阻断BDNF/TrkB信号可降低脊髓炎症并缓解急性痛和慢性痛。

Keywords: brain-derived neurotrophic factor; microglia; pathological pain; tropomyosin receptor kinase B; tumor necrosis factor-α.

PubMed Disclaimer

Figures

**图 1**
ANA-12有效缓解BDNF诱导的急性痛 ANA-12 effectively relieves BDNF-induced acute pain in rats (*Mean* ± SE, n=6). ^*P < 0.05 vs Control group; ^#P < 0.05 vs BDNF group.

**图 2**
ANA-12降低CFA诱导的炎性痛 ANA-12 reduces CFA-induced inflammatory pain in rats (*Mean*±SE, n=6). ^*P < 0.05 vs Control group; ^#P < 0.05 vs CFA group.

**图 3**
ANA-12处理阻断脊髓组织中BDNF/TrkB信号 ANA-12 treatment blocks BDNF/TrkB signaling in the spinal cord of rats (*Mean* ± SD, n=3). ^*P < 0.05 vsControl group; ^#P < 0.05 vs BDNF or CFA group.

**图 4**
ANA-12处理降低脊髓中小胶质细胞的激活和炎症信号上调 ANA-12 treatment reduces activation of microglia and up-regulation of TNF-α in the spinal cord of rats (*Mean*±SD, n=3). ^*P < 0.05 vs Control group; ^#P < 0.05 vs BDNF or CFA group.

**图 5**
炎症小体组分及炎症因子的表达 ANA-12 lowers BNDF- or CFA- induced up- regulation of inflammatory factors and components of inflammasomes in the spinal cord of the rats (*Mean*±SD, n=3). ^*P < 0.05 vs Control group; ^#P < 0.05 vs BDNF or CFA group.

See this image and copyright information in PMC

Cited by

EA participates in pain transition through regulating KCC2 expression by BDNF-TrkB in the spinal cord dorsal horn of male rats.
Shi M, Zhou J, Hu R, Xu H, Chen Y, Wu X, Chen B, Ma R. Shi M, et al. Neurobiol Pain. 2023 Jan 5;13:100115. doi: 10.1016/j.ynpai.2023.100115. eCollection 2023 Jan-Jul. Neurobiol Pain. 2023. PMID: 36875547 Free PMC article.

References

1. Numakawa T, Odaka H. Brain-derived neurotrophic factor signaling in the pathophysiology of Alzheimer's disease: beneficial effects of flavonoids for neuroprotection. Int J Mol Sci. 2021;22(11):5719–27. doi: 10.3390/ijms22115719. - DOI - PMC - PubMed
1. Lima Giacobbo B, Doorduin J, Klein HC, et al. Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation. Mol Neurobiol. 2019;56(5):3295–312. doi: 10.1007/s12035-018-1283-6. - DOI - PMC - PubMed
1. Liu SM. Neurotrophic factors in enteric physiology and pathophysiology. Neurogastroenterol Motil. 2018;30(10):e13446-57. doi: 10.1111/nmo.13446. - DOI - PMC - PubMed
1. Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223–50. doi: 10.1007/978-3-642-45106-5_9. - DOI - PubMed
1. Lin YT, Ro LS, Wang HL, et al. Up-regulation of dorsal root Ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitro study. J Neuroinflammation. 2011;8:126–37. doi: 10.1186/1742-2094-8-126. - DOI - PMC - PubMed

MeSH terms

Substances

Actions
Actions

Grants and funding

国家自然科学基金（81901149）；湖北科技学院校级团队项目（2020TD02）；湖北省教育厅项目（Q20192807）

LinkOut - more resources

Full Text Sources
- Europe PubMed Central
- PubMed Central
Medical
- MedlinePlus Health Information

[1] Numakawa T, Odaka H. Brain-derived neurotrophic factor signaling in the pathophysiology of Alzheimer's disease: beneficial effects of flavonoids for neuroprotection. Int J Mol Sci. 2021;22(11):5719–27. doi: 10.3390/ijms22115719. - DOI - PMC - PubMed

[2] Numakawa T, Odaka H. Brain-derived neurotrophic factor signaling in the pathophysiology of Alzheimer's disease: beneficial effects of flavonoids for neuroprotection. Int J Mol Sci. 2021;22(11):5719–27. doi: 10.3390/ijms22115719. - DOI - PMC - PubMed

[3] Lima Giacobbo B, Doorduin J, Klein HC, et al. Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation. Mol Neurobiol. 2019;56(5):3295–312. doi: 10.1007/s12035-018-1283-6. - DOI - PMC - PubMed

[4] Lima Giacobbo B, Doorduin J, Klein HC, et al. Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation. Mol Neurobiol. 2019;56(5):3295–312. doi: 10.1007/s12035-018-1283-6. - DOI - PMC - PubMed

[5] Liu SM. Neurotrophic factors in enteric physiology and pathophysiology. Neurogastroenterol Motil. 2018;30(10):e13446-57. doi: 10.1111/nmo.13446. - DOI - PMC - PubMed

[6] Liu SM. Neurotrophic factors in enteric physiology and pathophysiology. Neurogastroenterol Motil. 2018;30(10):e13446-57. doi: 10.1111/nmo.13446. - DOI - PMC - PubMed

[7] Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223–50. doi: 10.1007/978-3-642-45106-5_9. - DOI - PubMed

[8] Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223–50. doi: 10.1007/978-3-642-45106-5_9. - DOI - PubMed

[9] Lin YT, Ro LS, Wang HL, et al. Up-regulation of dorsal root Ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitro study. J Neuroinflammation. 2011;8:126–37. doi: 10.1186/1742-2094-8-126. - DOI - PMC - PubMed

[10] Lin YT, Ro LS, Wang HL, et al. Up-regulation of dorsal root Ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitro study. J Neuroinflammation. 2011;8:126–37. doi: 10.1186/1742-2094-8-126. - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

[ANA- 12 inhibits spinal inflammation and alleviates acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling]

Affiliation

[ANA- 12 inhibits spinal inflammation and alleviates acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling]

Authors

Affiliation

Abstract
in English, Chinese

Figures

Similar articles

Cited by

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract in English, Chinese

Figures

Similar articles

Cited by

References

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract
in English, Chinese