Amelioration of Neuropathic Pain and Attenuation of Neuroinflammation Responses by Tetrahydropalmatine Through the p38MAPK/NF-κB/iNOS Signaling Pathways in Animal and Cellular Models

Hu, Cheng; He, Menglin; Chen, Meijuan; Xu, Qian; Li, Sha; Cui, Yaomei; Qiu, Xizi; Tian, Weiqian

doi:10.1007/s10753-021-01593-x

Cited by 12 publications

(5 citation statements)

References 31 publications

(33 reference statements)

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“…Similar to previous reports [ 32 , 33 ], we used LPS to establish the in vitro neuropathic pain condition, and compared the effect of LPS on astrocytes with the effect of H 2 O 2 , a widely used inducer of cell senescence [ 34 ]. In the astrocyte cultures, the proportion of cells that robustly expressed SA β-Gal was increased after treatment with either LPS ( P Veh versus LPS = 0.005) or H 2 O 2 ( P Veh versus H2O2 = 0.003), when compared with the control (Con) cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Astrocyte senescence-like response related to peripheral nerve injury-induced neuropathic pain

Cheng

Deng

et al. 2023

Cell Mol Biol Lett

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Background Peripheral nerve damage causes neuroinflammation, which plays a critical role in establishing and maintaining neuropathic pain (NeP). The mechanisms contributing to neuroinflammation remain poorly elucidated, and pharmacological strategies for NeP are limited. Thus, in this study, we planned to explore the possible link between astrocyte senescence and NeP disorders following chronic sciatic nerve injury. Methods An NeP animal model was established by inducing chronic constrictive injury (CCI) to the sciatic nerve in adult rats. A senolytic drug combination of dasatinib and quercetin was gavaged daily from the first postoperative day until the end of the study. Paw mechanical withdrawal threshold (PMWT) and paw thermal withdrawal latency (PTWL) were evaluated to assess behaviors in response to pain in the experimental rats. Senescence-associated β-galactosidase staining, western blot analysis, and immunofluorescence were applied to examine the levels of proinflammatory factors and severity of the senescence-like response in the spinal cord. Lipopolysaccharide (LPS) was administered to induce senescence of spinal astrocytes in primary cultures in vitro, to explore the potential impacts of senescence on the secretion of proinflammatory factors. Furthermore, single-cell RNA sequencing (scRNA-seq) was conducted to identify senescence-related molecular responses in spinal astrocytes under neuropathic pain. Results Following sciatic nerve CCI, rats exhibited reduced PMWT and PTWL, increased levels of spinal proinflammatory factors, and an enhanced degree of senescence in spinal astrocytes. Treatment with dasatinib and quercetin effectively attenuated spinal neuroinflammation and mitigated the hypersensitivities of the rats subjected to sciatic nerve CCI. Mechanistically, the dasatinib-quercetin combination reversed senescence in LPS-stimulated primary cultured astrocytes and decreased the levels of proinflammatory factors. The scRNA-seq data revealed four potential senescence-related genes in the spinal astrocyte population, and the expression of clusterin (CLU) protein was validated via in vitro experiments. Conclusion The findings indicate the potential role of astrocyte senescence in neuroinflammation following peripheral nerve injury, and suggest that targeting CLU activation in astrocytes might provide a novel therapeutic strategy to treat NeP. Graphical abstract

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Section: Resultsmentioning

confidence: 99%

Astrocyte senescence-like response related to peripheral nerve injury-induced neuropathic pain

Cheng

Deng

et al. 2023

Cell Mol Biol Lett

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“…23 NF-κB, a crucial proinflammatory mediator regulator, is essential for neuropathic pain following peripheral nerve injury. 24,25 Previous research has indicated the specific regulatory role of PTP1B in NF-κB activation in various diseases. [26][27][28] Several studies have shown that ER stress contributes to neuroinflammation via the regulation of NF-κB.…”

Section: Discussionmentioning

confidence: 99%

“…NF‐κB, a crucial proinflammatory mediator regulator, is essential for neuropathic pain following peripheral nerve injury 24,25 . Previous research has indicated the specific regulatory role of PTP1B in NF‐κB activation in various diseases 26–28 .…”

Section: Discussionmentioning

confidence: 99%

Protein tyrosine phosphatase 1B contributes to neuropathic pain by aggravating NF‐κB and glial cells activation‐mediated neuroinflammation via promoting endoplasmic reticulum stress

Jiao,

Zhang,

Zhang

et al. 2024

CNS Neurosci Ther

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BackgroundNeuropathic pain is a prevalent and highly debilitating condition that impacts millions of individuals globally. Neuroinflammation is considered a key factor in the development of neuropathic pain. Accumulating evidence suggests that protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in regulating neuroinflammation. Nevertheless, the specific involvement of PTP1B in neuropathic pain remains largely unknown. This study aims to examine the impact of PTP1B on neuropathic pain and unravel the underlying molecular mechanisms implicated.MethodsIn the current study, we evaluated the paw withdrawal threshold (PWT) of male rats following spared nerve injury (SNI) to assess the presence of neuropathic pain. To elucidate the underlying mechanisms, western blotting, immunofluorescence, and electron microscopy techniques were employed.ResultsOur results showed that SNI significantly elevated PTP1B levels, which was accompanied by an increase in the expression of endoplasmic reticulum (ER) stress markers (BIP, p‐PERK, p‐IRE1α, and ATF6) and phosphorylated NF‐κB in the spinal dorsal horn. SNI‐induced mechanical allodynia was impaired by the treatment of intrathecal injection of PTP1B siRNA or PTP1B‐IN‐1, a specific inhibitor of PTP1B. Moreover, the intrathecal administration of PTP1B‐IN‐1 effectively suppressed the expression of ER stress markers (BIP, p‐PERK/p‐eIF2α, p‐IRE1α, and ATF6), leading to the inhibition of NF‐κB, microglia, and astrocytes activation, as well as a decrease in pro‐inflammatory cytokines, including TNF‐α, IL‐6, and IL‐1β. However, these effects were reversed by intrathecal administration of tunicamycin (Tm, an inducer of ER stress). Additionally, intrathecal administration of Tm in healthy rats resulted in the development of mechanical allodynia and the activation of NF‐κB‐mediated neuroinflammatory signaling.ConclusionsThe upregulation of PTP1B induced by SNI facilitates the activation of NF‐κB and glial cells via ER stress in the spinal dorsal horn. This, in turn, leads to an increase in the production of pro‐inflammatory cytokines, thereby contributing to the development and maintenance of neuropathic pain. Therefore, targeting PTP1B could be a promising therapeutic strategy for the treatment of neuropathic pain.

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“…The metabolites of NO can generate nitroso salts, leading to oxidative reduction metabolic disorders [167]. iNOS has been detected in nerve damage caused by various factors and is closely associated with neuroinflammation and neuropathic pain [168]. The expression of iNOS has also been found in diverse central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, ischemic brain injury, and traumatic brain injury [169][170][171][172].…”

Section: Inos/no•mentioning

confidence: 99%

The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders

Xu,

Jia,

et al. 2024

Antioxidants

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Central neurological disorders are significant contributors to morbidity, mortality, and long-term disability globally in modern society. These encompass neurodegenerative diseases, ischemic brain diseases, traumatic brain injury, epilepsy, depression, and more. The involved pathogenesis is notably intricate and diverse. Ferroptosis and neuroinflammation play pivotal roles in elucidating the causes of cognitive impairment stemming from these diseases. Given the concurrent occurrence of ferroptosis and neuroinflammation due to metabolic shifts such as iron and ROS, as well as their critical roles in central nervous disorders, the investigation into the co-regulatory mechanism of ferroptosis and neuroinflammation has emerged as a prominent area of research. This paper delves into the mechanisms of ferroptosis and neuroinflammation in central nervous disorders, along with their interrelationship. It specifically emphasizes the core molecules within the shared pathways governing ferroptosis and neuroinflammation, including SIRT1, Nrf2, NF-κB, Cox-2, iNOS/NO·, and how different immune cells and structures contribute to cognitive dysfunction through these mechanisms. Researchers’ findings suggest that ferroptosis and neuroinflammation mutually promote each other and may represent key factors in the progression of central neurological disorders. A deeper comprehension of the common pathway between cellular ferroptosis and neuroinflammation holds promise for improving symptoms and prognosis related to central neurological disorders.

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Amelioration of Neuropathic Pain and Attenuation of Neuroinflammation Responses by Tetrahydropalmatine Through the p38MAPK/NF-κB/iNOS Signaling Pathways in Animal and Cellular Models

Cited by 12 publications

References 31 publications

Astrocyte senescence-like response related to peripheral nerve injury-induced neuropathic pain

Astrocyte senescence-like response related to peripheral nerve injury-induced neuropathic pain

Protein tyrosine phosphatase 1B contributes to neuropathic pain by aggravating NF‐κB and glial cells activation‐mediated neuroinflammation via promoting endoplasmic reticulum stress

The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders

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