In recent years, neurovascular unit (NVU) which is composed of neurons, astrocytes (Ast), microglia (MG), vascular cells and extracellular matrix (ECM), has become an attractive field in ischemic stroke. As the important component of NVU, Ast closely interacts with other constituents, which has been playing double-edged sword roles, beneficial or detrimental after ischemic stroke. Based on the pathophysiological changes, we evaluated some strategies for targeting Ast in treating ischemic stroke. The present review is focused on the roles of Ast in NVU and its complex signaling molecular network after ischemic stroke, which may be a prospective approach to the treatment of ischemic diseases in central nervous system.

In the process of ischemic stroke (IS), cellular macroautophagy/autophagy and apoptosis play a vital role in neuroprotection against it. Therefore, regulating their balance is a potential therapeutic strategy. It has been proved that hydroxysafflor yellow A (HSYA) has anti-inflammatory and antioxidant effects, which can both protect neurons. By exploring bioinformatics combined with network pharmacology, we found that HIF1A and CASP3, key factors regulating autophagy and apoptosis, may be important targets of HSYA for neuroprotection in an oxygen glucose deprivation and reperfusion (OGD/R) model. In this study, we explored a possible new mechanism of HSYA neuroprotection in the OGD/R model. The results showed that OGD/R increased the expression of HIF1A and CASP3 in SH-SY5Y cells and induced autophagy and apoptosis, while HSYA intervention further promoted the expression of HIF1A and inhibited the level of CASP3, accompanied by an increase in autophagy and a decrease in apoptosis in SH-SY5Y cells. The inhibition of HIF1A diminished the activation of autophagy induced with HSYA, while the inhibition of autophagy increased cell apoptosis and blocked the neuroprotective effect of HSYA, suggesting that the neuroprotective effect of HSYA should be mediated by activating the HIF1A/BNIP3 signaling pathway to induce autophagy. These results demonstrate that HSYA may be a promising agent for treating IS.

Alzheimer’s disease (AD) is characterized by cognitive decline stemming from the accumulation of beta-amyloid (Aβ) plaques and the propagation of tau pathology through synapses. Exosomes, crucial mediators in neuronal development, maintenance, and intercellular communication, have gained attention in AD research. Yet, the molecular mechanisms involving exosomal miRNAs in AD remain elusive. In this study, we treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice, a model for AD, with either vehicle (ADNS) or fasudil (ADF), while C57BL/6 (control) mice received vehicle (WT). Cognitive function was evaluated using the Y-maze test, and AD pathology was confirmed through immunostaining and western blot analysis of Aβ plaques and phosphorylated tau. Exosomal RNAs were extracted, sequenced, and analyzed from each mouse group. Our findings revealed that fasudil treatment improved cognitive function in AD mice, as evidenced by increased spontaneous alternation in the Y-maze test and reduced Aβ plaque load and phosphorylated tau protein expression in the hippocampus. Analysis of exosomal miRNAs identified three miRNAs (mmu-let-7i-5p, mmu-miR-19a-3p, mmu-miR-451a) common to both ADNS vs ADF and WT vs ADNS groups. Utilizing miRTarBase software, we predicted and analyzed target genes associated with these miRNAs. Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of miRNA target genes indicated that mmu-miR-19a-3p and mmu-miR-451a are implicated in signal transduction, immune response, cellular communication, and nervous system pathways. Specifically, mmu-miR-19a-3p targeted genes involved in the sphingolipid signaling pathway, such as Pten and Tnf, while mmu-miR-451a targeted Nsmaf, Gnai3, and Akt3. Moreover, mmu-miR-451a targeted Myc in signaling pathways regulating the pluripotency of stem cells. In conclusion, fasudil treatment enhanced cognitive function by modulating exosomal MicroRNAs, particularly mmu-miR-451a and mmu-miR-19a-3p. These miRNAs hold promise as potential biomarkers and therapeutic targets for novel AD treatments. Graphical Abstract

Astragaloside IV (AST IV), a major saponin component and active ingredient isolated from Astragalus membranaceus, has been well known to exhibit neuroprotective effects on diverse models of neurological diseases. Accumulating evidence suggests that dynamic balance of microglia/macrophages and...