Gypenoside XVII protects against spinal cord injury in mice by regulating the microRNA‑21‑mediated PTEN/AKT/mTOR pathway

Abstract

Gypenoside XVII (GP-17), one of the dominant active components of Gynostemma pentaphyllum, has been studied extensively and found to have a variety of pharmacological effects, including neuroprotective properties. However, the neuroprotective effects of GP-17 against spinal cord injury (ScI), as well as its underlying mechanisms of action remain unknown. The present study aimed to investigate the effects of GP-17 on motor recovery and histopathological changes following ScI and to elucidate the mechanisms underlying its neuroprotective effects in a mouse model of ScI. Motor recovery was evaluated using the Basso, Beattie and Bresnahan (BBB) locomotor rating scale. Spinal cord edema was detected by the wet/dry weight method. H&E staining was performed to examine the effect of GP-17 on spinal cord damage. Inflammatory response production was assessed by ELISA. candidate miRNAs were identified following the integrated analysis of the Gene Expression Omnibus (GEO) dataset GSE67515. Western blot analysis was also performed to detect the expression levels of associated proteins. The results revealed that GP-17 treatment improved functional recovery, and suppressed neuronal apoptosis and the inflammatory response in the mouse model of SCI. Moreover, it was observed that miR-21 expression was downregulated following ScI, whereas it was upregulated following the administration of GP-17. The inhibition of miR-21 eliminated the protective effects of GP-17 on ScI-induced neuronal apoptosis and the inflammatory response. In addition, phosphatase and tensin homologue (PTEN), a key molecule in the activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, was identified as a target of miR-21, and PTEN expression was downregulated by GP-17 through miR-21. Furthermore, the PTEN/AKT/mTOR pathway was inactivated by ScI, whereas it was re-activated by GP-17 through the regulation of miR-21 in mice with SCI. On the whole, the findings of the present study suggest that GP-17 plays a protective role in ScI via regulating the miR-21/PTEN/AKT/mTOR pathway.

ThePI3K/AKTsignalling pathway in inflammation, cell death and glial scar formation after traumatic spinal cord injury: Mechanisms and therapeutic opportunities

“…Many miRNAs can affect the PI3K/AKT signalling pathway by regulating PTEN; these miRNAs include miR-29a-3p, 204 miR-29b-3p, 205 miR-212-3p, 206 miR-494 207 and miR-21. 208 Overexpression of these miRNAs after SCI inhibits PTEN expression through the PTEN/AKT signalling axis, thus decreasing apoptosis and inflammation; it also promotes the recovery of nerve function in SCI animals. Furthermore, miR-17 has been shown to promote the formation of glial scars and inhibit axon regeneration in the chronic phase of SCI by targeting PTEN to activate the PI3K/AKT pathway.…”

Quercetin Can Improve Spinal Cord Injury by Regulating the mTOR Signaling Pathway

“…The regulation of cell apoptosis is often accompanied by phosphorylation of the mTOR and changes in the expression of upstream and downstream factors ( Figure 3 ). SCI affects upstream factors to instigate a downregulation in the expressions, p-Akt and p-mTOR ( 97 ). In Sprague-Dawley rats with traumatic SCI, LC3, and Beclin1 expressions are decreased along with the accumulation of autophagy substrate (p62) and ubiquitinated proteins, subsequently leading to impaired autophagy activity.…”

“…But the inhibition of the miR-21 can diminish the protective effect of neuronal apoptosis and inflammation induced by SCI. Therefore, the activation of the mir-21/PTEN/Akt/mTOR pathway may suppress neuronal apoptosis and inflammation ( 97 ). The neuroprotective effect of the miR-92a-3p is positively correlated with the activation of the PTEN/Akt/mTOR pathway after SCI ( 99 ).…”

The Role of Tissue Geometry in Spinal Cord Regeneration

“…For example, the decline in the intrinsic growth potential of CNS neurons with maturity appears to play an important role in limiting regeneration [32]. Treatments that target intracellular pathways involved in axonal transport, such as the mechanistic target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN) and growth-associated protein 43 (GAP-43), offer potential therapeutic targets for enhancing axonal growth and functional recovery [33][34][35][36][37][38][39][40]. Similar evidence has been obtained for the use of neurotrophic factors, which can also contribute to greater regeneration and/or collateral sprouting [41][42][43][44].…”