Hyperoside Attenuate Inflammation in HT22 Cells Via Upregulating SIRT1 To Activities Wnt/β-Catenin And Sonic Hedgehog Pathways Part 3

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4. Discussion

Neuroinflammation is associated with the pathology of many neurological complications, including hearing loss, AD, PD, neuropathic pain, cognitive impairment, and cerebral ischemic injury [2,16-24]. Identification of effective inflammatory protective candidate agents is one of the hot spots in the treatment of neurological complications [25]. Effective medical treatment reduces neuroinflammation or prevents neurodegeneration. Hyperoside has been reported to treat neuroinflammation in neurological complications [12], However, in recent years, there has been little research on the mechanism by which hyperoside alleviates neuroinflammation. In the present study, we explored the anti-inflammatory effects of hyperoside on LPS-induced HT22 neuroinflammation in mouse neuronal cells. We demonstrated that hyperoside attenuated apoptosis, inflammation, and oxidative stress and simultaneously restored the levels of neurotrophic factor proteins BDNF, TrkB, and NGF in HT22 cells induced by LPS.In addition, we provide evidence that STRI1 is highly expressed under the action of hyperoside and activates Wnt/β-catenin and sonic hedgehog pathways. In our study, hyperoside significantly inhibited the LPS-induced apoptosis, inflammation, and oxidative stress production by increased STRI and activating the Wnt/β-catenin and sonic hedgehog pathways.

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Neurons are the basic structural and functional units of the nervous system [26]. Changes in the structure and function of neurons in the brain will cause nerve damage [27]. HT22 cells are a kind of mouse hippocampal neuronal cells, which are widely used as an in vitro neuronal model associated with neuroinflammation and nerve injury in studies to identify effective inflammatory protective candidate agents [28]. Previous studies have shown that systemic administration of LPS triggers nerve injury and neuroinflammation and in the brain, which induces neurodegeneration in mice [29, 30]. In the present study, we used HT22 cells as a neuronal cell model to examine the protective effect of hyperoside on LPS-activated neuroinflammation. We found that LPS inhibited HT22 activity, pro-moted the level of proinflammatory cytokines (TNF-α, -1β, L-6, and IL-8)and apoptosis proteins Bax and xaspase-3, and activated oxidative stress. However, pretreatment with hyperoside significantly protected HT22 cells from LPS-induced cell growth inhibition by inhibiting apoptosis; down-regulating TNF-α,IL-1β,IL-6, IL-8, Bax, and caspase-3 levels; and inhibiting oxidative stress. These results are consistent with previous studies on hyperoside as antioxidants, anti-inflammatory agents, and antiapoptotic agents.

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Regulation that protects neuronal survival is essential in the pathological process of alleviating neurological complications caused by neuroinflammation [2, 31]. In the development of neuronal, BDNF, as an important nerve growth factor, plays

an important role in the growth, survival, and differentiation of neurons [32].BDNF enhances neuronal survival and protects synaptic function by binding to tropomyosin receptor kinase B(TrkB)[33,34]. Simultaneously, BDNF promotes neuronal outward growth and recombination of dendritic spines, thereby improving neuronal connectivity [35]. NGF is a nerve cell growth regulator with dual biological functions of neuron nutrition and neurite outgrowth promotion. It has been proven to protect neurons by promoting nerve fiber regeneration [36, 37]. Previous studies have shown that LPS-induced inflammation is the main cause of neuronal death in the hippocampus. In this study, we found that the expression levels of BDNF, TrkB, and NGF in HT22 cells induced by LPS were significantly reduced and hyperoside treatment significantly restores the expression levels of BDNF, TrkB, and NGF.

SIRT1 is the main regulator of neurogenesis and plays a neuroprotective role in neurological diseases [38]. Previous studies showed that activation of SIRT1 reversed nerve dam-age in different neurological diseases by augmenting hippo-campal neurogenesis [39]. Simultaneously, previous reports also demonstrated that activation of SIRT1 reduces the level of oxidative stress and the extent of inflammation [40]. In addition, crucially, Li et al. found that hyperoside enhances SIRTl protein expression in a mechanism that protects ECV-304 cells from tertbutyl hydrogen peroxide-induced damage [41]. Thus, we speculate that hyperoside alleviating neuroinflammation may be related to the level of SIRT1. In this study, we found that hyperoside significantly increased the expression of SIRT1 in cells, while the SIRT1 inhibitor NAM effect attenuated the alleviating effect of hyperoside on neuroinflammation induced by LPS. Wnt/β-catenin and sonic hedgehog pathways are confirmed to be regulated by SIRTl; SIRT1-mediated deacetylation in the process of c-myc degradation, which affected the stability of c-myc and increased the transcriptional activity of β-catenin, activates Wnt signaling through β-catenin [42]; simultaneously, SIRT1 agonist SRT1720 activated the sonic hedgehog signal-ing [43]. In addition, we have also observed that Wnt/β-catenin and sonic hedgehog signaling pathways are inhibited in neuroinflammation [44, 45]. Simultaneously, Wnt/β-catenin and sonic hedgehog signaling pathways are involved in the development of neuroinflammation-mediated hearing loss and other neurological diseases [46-55]. In this study, we found that hyperoside activates the expression of Wntl, β-catenin, Shh, and patch by upregulating SIRT1.

In summary, the present study showed that hyperoside alleviated apoptosis, inflammation, oxidative stress, and reduction of a neurotrophic factors in the LPS-induced HT22 cells. We further found that hyperoside alleviated nerve damage by upregulating SIRT1 to activate Wnt/β-catenin and sonic hedgehog signaling pathways. In conclusion, based on our findings, the therapeutic effect of hyperoside on neuroinflammation is further clarified, providing a possible treatment basis for its clinical application for neuroinflammation.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors' Contributions

THW and JGX designed the experiments.JH and LZ wrote the article.JH, LZ, JC, TBC, BL, NDZ, and XQW performed experiments and analyzed data. All the authors read and approved the final manuscript. Jin Huang and Liang Zhou contributed equally to this work

This article is extracted from Hindawi Neural Plasticity Volume 2021, Article ID 8706400, 10 pages https://doi.org/10.1155/2021/8706400