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Long-term administration of salvianolic acid A promotes endogenous neurogenesis in ischemic stroke rats through activating Wnt3a/GSK3β/β-catenin signaling pathway

Abstract

Stroke is the major cause of death and disability worldwide. Most stroke patients who survive in the acute phase of ischemia display various extents of neurological deficits. In order to improve the prognosis of ischemic stroke, promoting endogenous neurogenesis has attracted great attention. Salvianolic acid A (SAA) has shown neuroprotective effects against ischemic diseases. In the present study, we investigated the neurogenesis effects of SAA in ischemic stroke rats, and explored the underlying mechanisms. An autologous thrombus stroke model was established by electrocoagulation. The rats were administered SAA (10 mg/kg, ig) or a positive drug edaravone (5 mg/kg, iv) once a day for 14 days. We showed that SAA administration significantly decreased infarction volume and vascular embolism, and ameliorated pathological injury in the hippocampus and striatum as well as the neurological deficits as compared with the model rats. Furthermore, we found that SAA administration significantly promoted neural stem/progenitor cells (NSPCs) proliferation, migration and differentiation into neurons, enhanced axonal regeneration and diminished neuronal apoptosis around the ipsilateral subventricular zone (SVZ), resulting in restored neural density and reconstructed neural circuits in the ischemic striatum. Moreover, we revealed that SAA-induced neurogenesis was associated to activating Wnt3a/GSK3β/β-catenin signaling pathway and downstream target genes in the hippocampus and striatum. Edaravone exerted equivalent inhibition on neuronal apoptosis in the SVZ, as SAA, but edaravone-induced neurogenesis was weaker than that of SAA. Taken together, our results demonstrate that long-term administration of SAA improves neurological function through enhancing endogenous neurogenesis and inhibiting neuronal apoptosis in ischemic stroke rats via activating Wnt3a/GSK3β/β-catenin signaling pathway. SAA may be a potential therapeutic drug to promote neurogenesis after stroke.

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Fig. 1: Chemical structure of SAA and the schematic diagram of the experimental protocols.
Fig. 2: The effects of SAA on neurological function and body weight in ischemic stroke rats.
Fig. 3: The effects of SAA on infarct volume, vascular thrombosis and histopathology after stroke.
Fig. 4: The effect of SAA on the proliferation of NSPCs around the SVZ at 14 d after stroke.
Fig. 5: The effects of SAA on neuronal density and neurogenesis at 14 d after stroke.
Fig. 6: The effect of SAA on Wnt3a/GSK3β/β-catenin signaling pathway at 14 d after stroke.
Fig. 7: The effect of SAA on neuronal apoptosis at 14 d after stroke.
Fig. 8: Schematic diagram of the enhancement of SAA on endogenous neurogenesis via activating of Wnt3a/GSK3β/β-catenin signaling pathway during the recovery after ischemic stroke.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Grant No. 82004071); Beijing Municipal Natural Science Foundation (Grant No. 7182113); Fundamental Research Funds for the Central Universities (Grant No. 3332020038).

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SZ, GHD, and LLK conceptualized the study. SZ, DWK, GDM, YJY, SL, and ZRP contributed to the animal experiments. SZ, CDL, NJ, and WZ contributed to the molecular biology experiments. SZ contributed to the data collection and statistical analysis. SZ, GHD, and LLK drafted and finalized the paper.

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Correspondence to Ling-lei Kong or Guan-hua Du.

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Zhang, S., Kong, Dw., Ma, Gd. et al. Long-term administration of salvianolic acid A promotes endogenous neurogenesis in ischemic stroke rats through activating Wnt3a/GSK3β/β-catenin signaling pathway. Acta Pharmacol Sin 43, 2212–2225 (2022). https://doi.org/10.1038/s41401-021-00844-9

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Keywords

  • ischemic stroke
  • salvianolic acid A
  • neurogenesis
  • Wnt3a/GSK3β/β-catenin signaling
  • hippocampus
  • striatum

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