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Adiponectin Promotes Neurogenesis After Transient Cerebral Ischemia Through STAT3 Mediated BDNF Upregulation in Astrocytes

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Abstract

Newborn neurons from the subventricular zone (SVZ) are essential to functional recovery following ischemic stroke. However, the number of newly generated neurons after stroke is far from enough to support a potent recovery. Adiponectin could increase neurogenesis in the dentate gyrus of hippocampus in neurodegenerative diseases. However, the effect of adiponectin on the neurogenesis from SVZ and the functional recovery after ischemic stroke was unknown, and the underlying mechanism was not specified either. The middle cerebral artery occlusion model of mice was adopted and adiponectin was administrated once a day from day 3 to 7 of reperfusion. The levels of BDNF and p-STAT3 were detected by western blotting on day 7 of reperfusion. The virus-encoded BDNF shRNA with GFAP promoter and a STAT3 inhibitor Stattic were used, respectively. Neurogenesis was evidenced by the expression of doublecortin and 5-bromo-2ʹ-deoxyuridine (BrdU) labelling and brain atrophy was revealed by Nissl staining on day 28 of reperfusion. Neurological functional recovery was assessed by the adhesive removal test and the forepaw grip strength. We found that adiponectin increased both the doublecortin-positive cells and NeuN/BrdU double-positive cells around the injured area on day 28 of reperfusion, along with the improved long-term neurological recovery. Mechanistically, adiponectin increased the protein levels of p-STAT3 and BDNF in astrocytes on day 7 of reperfusion, while silencing BDNF diminished the adiponectin-induced neurogenesis and functional recovery. Moreover, inhibition of STAT3 not only prevented the increase of BDNF but also the improved neurogenesis and functional recovery after stroke. In conclusion, adiponectin enhances neurogenesis and functional recovery after ischemic stroke via STAT3/BDNF pathway in astrocytes.

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Data Availability

The data that support the findings of the study are available from the corresponding author upon request.

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Acknowledgements

The authors are very grateful to Ms Yaoying Yu for her kind help.

Funding

This work was supported by the National Natural Science Foundation of China (81971226 to WGH), the Natural Science Foundation of Shaanxi province (2020JM-330 to SQW; 2021JQ-918 to XY), and the Fundamental Research Funds for the Central Universities (xzy022020041 to HDW). All funding bodies had no involvement in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Author notes

  1. Liang Yu, Jiajia Wang and Ying **a equally contributed to this work.

Authors and Affiliations

  1. Department of Information, The First Affiliated Hospital, The Fourth Military Medical University, **’an, 710032, Shaanxi, China

    Liang Yu

  2. Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital, The Fourth Military Medical University, **’an, 710032, Shaanxi, China

    Jiajia Wang, Wugang Hou, Yaru Guo, ** Wang & Shiquan Wang

  3. Department of Gastroenterology, The First Affiliated Hospital, The Fourth Military Medical University, **’an, 710032, Shaanxi, China

    Ying **a

  4. Department of Anesthesiology, Shaanxi Provincial People’s Hospital, **’an, 710068, Shaanxi, China

    ** Yao

  5. Department of Anesthesiology, The Second Affiliated Hospital of **’an Jiaotong University, **’an, 710004, Shaanxi, China

    Haidong Wei

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Contributions

SQW and HDW designed the experiment and wrote the manuscript. LY, JJW and YX performed the experiments. JW and YRG administrated ADPN and Stattic. WGH performed the statistical analysis. All authors approved the final manuscript.

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Correspondence to Haidong Wei or Shiquan Wang.

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Ethical Statement

This study was reviewed and approved by institutional Ethics Review Committee at Air Force Military Medical University on January 10, 2020 (20200151).

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Supplementary Information

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11064_2022_3790_MOESM1_ESM.tif

Supplementary file1 Fig. S1. The verification of Stattic on the activation of STAT3 after MCAO. A, Representative images of western blotting. B, Quantification of p-STAT3(Tyr705) protein. C, Quantification of p-STAT3(Ser727) protein. D, Quantification of total STAT3 protein. Data were presented as mean ± SD and analyzed by one way ANOVA test with Tukey’s post hoc test. *P < 0.05 vs. ADPN+DMSO, n = 4. (TIF 9259 kb)

11064_2022_3790_MOESM2_ESM.tif

Supplementary file2 Fig. S2. The efficiency of the virus encoding BDNF shRNA after MCAO. A, Western blotting analysis of BDNF. B, Representative images of mCherry/GFAP double positive cells. C, Quantification of mCherry/GFAP double positive cells. Data were presented as mean ± SD and analyzed by one way ANOVA test with Tukey’s post hoc test. *P < 0.05 vs. ADPN+ control virus, n = 4. (TIF 9160 kb)

11064_2022_3790_MOESM3_ESM.tif

Supplementary file3 Fig. S3. The effect of ADPN on neurogenesis in cortex. A, Representative images of Brdu/NeuN double positive cells. B, Quantification of Brdu/NeuN double positive cells. Data were presented as mean ± SD and analyzed by t test. *P < 0.05 vs. vehicle virus, n = 4. (TIF 1940 kb)

11064_2022_3790_MOESM4_ESM.tif

Supplementary file4 Fig. S4. The effect of ADPN on p-JAK1. A, Representative images of p-JAK1/GFAP double positive cells. B, Quantification of relative fluorescence intensity of p-JAK1 in astrocytes. C, Quantification of p-JAK1 protein level. Data were presented as mean ± SD and analyzed by one way ANOVA test with Tukey’s post hoc test. *P < 0.05 vs Sham, #P < 0.05 vs. Vehicle group, n = 4. (TIF 18281 kb)

11064_2022_3790_MOESM5_ESM.tif

Supplementary file5 Fig. S5 The effect of ADPN on ADIPOR1. A, Representative images of ADIPOR1/GFAP double positive cells. B, Quantification of relative fluorescence intensity of ADIPOR1 in astrocytes. C Quantification of ADIPOR1 protein level. Data were presented as mean ± SD and analyzed by one way ANOVA test with Tukey’s post hoc test. *P < 0.05 vs Sham, #P < 0.05 vs. Vehicle group, n = 4. (TIF 15246 kb)

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Yu, L., Wang, J., **a, Y. et al. Adiponectin Promotes Neurogenesis After Transient Cerebral Ischemia Through STAT3 Mediated BDNF Upregulation in Astrocytes. Neurochem Res 48, 641–657 (2023). https://doi.org/10.1007/s11064-022-03790-y

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