Patchouli Alcohol Improves the Integrity of the Blood-Spinal Cord Barrier by Inhibiting Endoplasmic Reticulum Stress Through the Akt/CHOP/Caspase-3 Pathway Following Spinal Cord Injury

Huang, Chongan; Zhang, Weiqi; Chu, Feifan; Qian, Haoliang; Qi, Fangzhou; Ye, Mengke; Zhou, Jianyi; Zhi, Lin; Dong, Chenlin; Wang, Xiangyang; Wang, Qingqing; Jin, Haiming

doi:10.3389/fcell.2021.693533

Cited by 6 publications

(3 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inflammatory cytokines, as direct mediators, affect the prognosis of spinal cord injury to different degrees ( Hu et al, 2016 ). One of the main pathological features of SCI is neuronal apoptosis ( Huang et al, 2021 ), a kind of energy-dependent programmed death, which can be divided into exogenous and endogenous pathways according to triggering mechanisms ( Ren et al, 2019 ). Apoptosis occurs within a few hours after primary SCI and reaches the peak within several days ( Beattie et al, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

Elucidating the Potential Mechanisms Underlying Distraction Spinal Cord Injury-Associated Neuroinflammation and Apoptosis

Han

Liang

Hai

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The incidence of distraction spinal cord injury (DSCI), which results from spinal cord ischemia due to vascular compromise and spinal cord tract disturbances, remains high. Furthermore, because no ideal animal model that mimics DSCI in clinical settings is available thus far, the related molecular mechanisms underlying DSCI remain unclear. Thus, this study aimed to establish a porcine model of DSCI and investigate the neuroinflammation and apoptosis mechanisms in these pigs. Before surgery, all pigs were randomly divided into three groups: sham group, osteotomy surgery only; the incomplete distraction spinal cord injury (IDSCI) and complete distraction spinal cord injury (CDSCI) group, osteotomy plus DSCI surgery with a motor-evoked potential (MEP) amplitude decreased by approximately 75% and 100%, respectively. After surgery, modified Tarlov scoring and MRC muscle strength scoring were used to evaluate neurologic function in each group. We observed the distracted spinal cord using MRI, and then all pigs were sacrificed. Inflammatory cytokine levels in the spinal cord and cerebrospinal fluid (CSF) were also analyzed. We used immunofluorescence staining to assess the neuronal and microglial structure and function and astrocyte hyperplasia in the central DSCI lesions (T15). Western blotting was used to determine the expression of apoptosis-related proteins. Results showed that the modified Tarlov scoring and muscle strength decreased significantly in the two DSCI groups. T2-MRI showed a relative enhancement at the center of the DSCI lesions. H&E and Lxol fast blue staining revealed that spinal cord distraction destroyed the normal structure of spinal cord tissues and nerve fiber tracts, exacerbating inflammatory cell infiltration, hyperemia, and edema. The IL-1β, IL-6, and TNF-α levels increased in the spinal cord and CSF following DSCI. Immunofluorescence staining results indicated the GFAP, Iba-1 expression increased following DSCI, whereas the NeuN expression reduced. Moreover, DSCI promoted the protein expression of P53, Bcl-2-associated X protein (Bax), and Caspase-3 in the spinal cord tissues, whereas it reduced the Bcl-2 expression. This study successfully established a porcine DSCI model that closely mimics DSCI in clinical settings, and clarified the mechanisms underlying DSCI-associated neuroinflammation and apoptosis; thus, our findings highlight potential DSCI-treatment strategies for further establishing suitable drug therapies.

show abstract

Section: Introductionmentioning

confidence: 99%

Elucidating the Potential Mechanisms Underlying Distraction Spinal Cord Injury-Associated Neuroinflammation and Apoptosis

Han

Liang

Hai

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…As previously reported, ER tress-associated apoptotic proteins, including CHOP, GRP78 and Caspase-12, are activated after SCI. 29 CHOP, which is a crucial pro-apoptotic factor during ER stress-induced apoptosis, may contribute to the activation of Caspase-12 and provide a potential link among the three unfolded protein response branches. 30 In addition, GRP78 expression is upregulated under ER tress.…”

Section: Discussionmentioning

confidence: 99%

Sitagliptin attenuates neuronal apoptosis via inhibiting the endoplasmic reticulum stress after acute spinal cord injury

Tang

Dai

et al. 2023

Hum Exp Toxicol

View full text Add to dashboard Cite

Regulation of endoplasmic reticulum stress (ER) stress-induced apoptosis and nerve regeneration is a hopeful way for acute spinal cord injury (SCI). Sitagliptin (Sita) is one of dipeptidyl peptidase-4 (DPP-4) inhibitor, which is beneficial neurons damaged diseases. However, its protective mechanisms of avoiding nerve injury remain unclear. In this study, we further investigated the mechanism of the anti-apoptotic and neuroprotective effects of Sita in promoting locomotor recovery from SCI. In vivo results showed that Sita treatment reduced neural apoptosis caused by SCI. Moreover, Sita effectively attenuated the ER tress and associated apoptosis in rats with SCI. A striking feature was the occurrence of nerve fiber regeneration at the lesion site, which eventually led to significant locomotion recovery. In vitro results showed that the PC12 cell injury model induced by Thapsigargin (TG) also showed similar neuroprotective effects. Overall, sitagliptin showed potent neuroprotective effects by targeting the ER stress-induced apoptosis both in vivo and vitro, thus facilitating the regeneration of the injured spinal cord.

show abstract

“…Activation of the PI3K/Akt pathway attenuates ER stress ( Hsu et al, 2017 ). Huang et al (2021) demonstrated that activation of the Akt pathway can alleviate ER stress, thereby alleviating BSCB disruption caused by ER stress ( Huang et al, 2021 ). It is possible that the protective effect of Akt pathway on BSCB is through regulating ER stress.…”

Section: Discussionmentioning

confidence: 99%

Experimental treatments to attenuate blood spinal cord barrier rupture in rats with traumatic spinal cord injury: A meta-analysis and systematic review

Deng

Sun

2022

Front. Pharmacol.

View full text Add to dashboard Cite

Background: Traumatic spinal cord injury (t-SCI) is a severe injury that has a devastating impact on neurological function. Blood spinal cord barrier (BSCB) destruction following SCI aggravates the primary injury, resulting in a secondary injury. A series of experimental treatments have been proven to alleviate BSCB destruction after t-SCI.Methods: From a screen of 1,189 papers, which were retrieved from Pubmed, Embase, and Web of science, we identified 28 papers which adhered to strict inclusion and exclusion criteria. Evans blue (EB) leakage on the first day post-SCI was selected as the primary result. Secondary outcomes included the expression of tight junction (TJ) proteins and adhesion junction (AJ) proteins in protein immunoblotting. In addition, we measured functional recovery using the Basso, Beattie, Besnahan (BBB) score and we analyzed the relevant mechanisms to explore the similarities between different studies.Result: The forest plot of Evans blue leakage (EB leakage) reduction rate: the pooled effect size of the 28 studies was 0.54, 95% CI: 0.47–0.61, p < 0.01. This indicates that measures to mitigate BSCB damage significantly improved in reducing overall EB leakage. In addition TJ proteins (Occludin, Claudin-5, and ZO-1), AJ proteins (P120 and β-catenin) were significantly upregulated after treatment in all publications. Moreover, BBB scores were significantly improved. Comprehensive studies have shown that in t-SCI, inhibition of matrix metalloproteinases (MMPs) is the most commonly used mechanism to mitigate BSCB damage, followed by endoplasmic reticulum (ER) stress and the Akt pathway. In addition, we found that bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos), which inhibit the TIMP2/MMP signaling pathway, may be the most effective way to alleviate BSCB injury.Conclusion: This study systematically analyzes the experimental treatments and their mechanisms for reducing BSCB injury in the early stage of t-SCI. BMSC-Exos, which inhibit MMP expression, are currently the most effective therapeutic modality for alleviating BSCB damage. In addition, the regulation of MMPs in particular as well as the Akt pathway and the ER stress pathway play important roles in alleviating BSCB injury.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022324794.

show abstract

Patchouli Alcohol Improves the Integrity of the Blood-Spinal Cord Barrier by Inhibiting Endoplasmic Reticulum Stress Through the Akt/CHOP/Caspase-3 Pathway Following Spinal Cord Injury

Cited by 6 publications

References 43 publications

Elucidating the Potential Mechanisms Underlying Distraction Spinal Cord Injury-Associated Neuroinflammation and Apoptosis

Elucidating the Potential Mechanisms Underlying Distraction Spinal Cord Injury-Associated Neuroinflammation and Apoptosis

Sitagliptin attenuates neuronal apoptosis via inhibiting the endoplasmic reticulum stress after acute spinal cord injury

Experimental treatments to attenuate blood spinal cord barrier rupture in rats with traumatic spinal cord injury: A meta-analysis and systematic review

Contact Info

Product

Resources

About