Dual regulation of microglia and neurons by Astragaloside IV‐mediated mTORC1 suppression promotes functional recovery after acute spinal cord injury

Abstract

Inflammation and neuronal apoptosis contribute to the progression of secondary injury after spinal cord injury (SCI) and are targets for SCI therapy; autophagy is reported to suppress apoptosis in neuronal cells and M2 polarization may attenuate inflammatory response in microglia, while both are negatively regulated by mTORC1 signalling. We hypothesize that mTORC1 suppression may have dual effects on inflammation and neuronal apoptosis and may be a feasible approach for SCI therapy. In this study, we evaluate a novel inhibitor of mTORC1 signalling, Astragaloside IV (AS‐IV), in vitro and in vivo. Our results showed that AS‐IV may suppress mTORC1 signalling both in neuronal cells and microglial cells in vitro and in vivo. AS‐IV treatment may stimulate autophagy in neuronal cells and protect them against apoptosis through autophagy regulation; it may also promote M2 polarization in microglial cells and attenuate neuroinflammation. In vivo, rats were intraperitoneally injected with AS‐IV (10 mg/kg/d) after SCI, behavioural and histological evaluations showed that AS‐IV may promote functional recovery in rats after SCI. We propose that mTORC1 suppression may attenuate both microglial inflammatory response and neuronal apoptosis and promote functional recovery after SCI, while AS‐IV may become a novel therapeutic medicine for SCI.

Astragaloside IV alleviates liver injury in type 2 diabetes due to promotion of AMPK/mTOR‑mediated autophagy

“…AMPK/mTOR-mediated autophagy has been reported to be involved in diabetes complications ( 52 ). Previous studies have revealed that AS-IV prevented podocyte injury by activating AMPK-mediated autophagy in diabetic nephropathy and promoted functional recovery after acute spinal cord injury by activating mTOR-mediated autophagy ( 53 , 54 ). To identify the underlying mechanism of autophagy in diabetic liver injury in T2DM, the present study focused on the AMPK/mTOR pathway.…”

Rea regulates microglial polarization and attenuates neuronal apoptosis via inhibition of the NF‐κB and MAPK signalings for spinal cord injury repair

“…SCI triggers microglia/macrophage activation and polarization to the M1 phenotype, resulting in inflammatory damage that impairs tissue repair and aggravates neurological symptoms 31 . Thus, re‐polarizing the activated microglia/macrophage to the anti‐inflammatory M2 phenotype can significantly improve recovery after SCI 9 . The number and distribution of the M1 macrophages was determined by immunostaining with CD68 and GFAP.…”

“…31 Thus, re-polarizing the activated microglia/macrophage to the anti-inflammatory M2 phenotype can significantly improve recovery after SCI. 9 The number and distribution of the M1 macrophages was determined by immunostaining with CD68 and GFAP. As shown in Figure 6A…”

“…Apart from the mechanical and structural damage caused by physical trauma, 3,4 SCI is also accompanied by pathological changes like inflammation, apoptosis, ischaemia and local oedema, which are collectively known as secondary injury 5‐8 . Microglial polarization is a key mechanism of the secondary inflammatory injury following SCI and an effective therapeutic target since regulation of microglial polarization can mitigate inflammation and reversing secondary inflammatory injury 9,10 . Neuroinflammation is driven by the activated M1 microglia, leading to neuronal apoptosis and damage to the central nervous system 11,12 .…”

Sanqi Oral Solution Ameliorates Renal Ischemia/Reperfusion Injury via Reducing Apoptosis and Enhancing Autophagy: Involvement of ERK/mTOR Pathways

“…Calycosin, one of the major components in Astragalus membranaceus, has been verified to inhibit oxidative stress-induced cardiomyocyte apoptosis via activating estrogen receptor-α/β ( Liu B. et al., 2016 ). Another active component Astragaloside IV can not only suppress apoptosis in mammary epithelial cells ( Wang F. et al., 2019 ) or cerebral I/R Injury ( Zhang et al., 2019 ), but also enhance autophagy via mTORC1 signalling ( Lin et al., 2020 ) or SIRT-NF-κB p65 axis ( Wang X. et al., 2019 ), and can reduce complement membranous attack complex induced podocyte injury through decreasing ERK expression ( Zheng et al., 2012 ). Ginsenoside Rg1, the main component in Panax notoginseng, was capable of protecting pheochromocytoma (PC12) cells against dopamine-induced apoptosis ( Chen et al., 2001 ).…”