Astragaloside IV Exerts Cognitive Benefits and Promotes Hippocampal Neurogenesis in Stroke Mice by Downregulating Interleukin-17 Expression via Wnt Pathway

Abstract

Background: Stroke remains a leading cause of adult disability and the demand for stroke rehabilitation services is growing, and Astragaloside IV (As IV), a primary bioactive compound of Radix Astragali: Astragalus mongholicus Bunge (Fabaceae), may be a promising stroke therapy. Methods: To access the effect of As IV on adult mice after ischemic stroke, a photochemical ischemia model was established on C57BL/6 mice, which were intravenously administered As IV for three consecutive days later. And then the cognitive benefits and hippocampal neurogenesis were evaluated by Morris Water Maze (MWM) test, Golgi staining, and immunohistochemical staining in vivo and in vitro. Furthermore, to find out the underlying mechanism, interleukin-17 (IL-17) knockout (KO) mice were used, through RNA sequence (RNA-seq) analysis and immunohistochemistry. Then the mechanism of neurogenesis promoted by As IV was observed by western blot both in vivo and in vitro. Specifically, As IV, recombinant mouse IL-17A and IL-17F, and Wingless/integrated (Wnt)-expressing virus was administered respectively in neural stem cells (NSCs), and then their diameters and protein expression of Nestin, IL-17, and Wnt pathway relevant protein, were measured in vitro. Results: Administering As IV resulted in significant amelioration of stroke-induced cognitive deficits. And more hippocampal neurons with normal morphology, significant increments in the length of the apical dendrites, and the density of their spines were observed in As IV-treated mice. Furthermore, the immunohistochemistry staining of DCX/ BrdU and Sox2/Nestin showed As IV could promote hippocampal neurogenesis and NSC proliferation after ischemic stroke, as well as in vitro. For the mechanism underlying, IL-17 expression was downregulated significantly by As IV treatment and knocking out IL-17 was associated with nervous regeneration and synapse repair according to the analysis of RNA-seq. Consistent to As IV treatment, knocking out IL-17 showed some promotion on hippocampal neurogenesis and proliferation of NSCs, with activating Wnt pathway after

Antagonistic effects of IL-17 and Astragaloside IV on cortical neurogenesis and cognitive behavior after stroke in adult mice through Akt/GSK-3β pathway

“…In our previous study, As-IV exerts cognitive benefits and promotes hippocampal neurogenesis and synaptic plasticity in stroke mice via Wnt pathway. IL-17 expression is downregulated by administering As-IV 29 , which is consistent with the results in other acute diseases [30][31][32] . Therefore, it seems that As IV could be a promising strategy in the therapeutic arsenal against ischemic cortex after stroke for its effect on activating proliferation and promoting neurogenesis.…”

Interleukine-17 Modulates Neurogenesis and Behavior Following Exposure to Trauma in Mice

“…Indeed, previous studies have demonstrated the inhibitory effect of IL-17 on neurogenesis, in particular, on neural progenitor proliferation in vivo and in vitro [23,34,[42][43][44][45].…”

Inhibiting Brd4 alleviated PTSD‐like behaviors and fear memory through regulating immediate early genes expression and neuroinflammation in rats

“…The rats were randomly (simple randomization with computer‐generated random numbers) divided into different experimental groups. No sample calculation was performed in advance, and the sample sizes were based on previous studies (Sun et al., 2020; Wang et al., 2020). Before the IFS procedure, all rats were conducted with 1‐week adaptation for the new environment.…”