Daphnetin Improves Neuropathic Pain by Inhibiting the Expression of Chemokines and Inflammatory Factors in the Spinal Cord and Interfering with Glial Cell Polarization

Zhang, Tian-Rui; Liang, Wulin; Zhang, Mingqian; Cui, Shuang; Huang, Xiyan; Ou, Wen; Huang, Rikang; Gao, Jiahui; Jia, Zhanhong; Zhang, Shuofeng

doi:10.3390/ph16020243

Cited by 6 publications

(4 citation statements)

References 59 publications

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“…It was shown that intrathecal CX3CL1 administration evokes strong mechanical and thermal hypersensitivity [45]. It was also shown that the mRNA level of this chemokine is elevated in the spinal cords of animals with neuropathy evoked by TNF-α injection [74]. Additionally, its upregulation is observed in the oxaliplatin model of neuropathic pain [46].…”

Section: Cx3c Chemokine In Neuropathic Painmentioning

confidence: 99%

“…CXCR5 is a selective target of CXCL13; however, under physiological conditions in the CNS, it is expressed at a very low level [40]. Nevertheless, CXCL13 mRNA and/or protein levels increase in the spinal cord and/or DRGs in SNL- [40,68,72], CCI- [75], SpNI- [73], DB- [71], and TNFα-induced [74] neuropathic pain models. The intrathecal injection of CXCL13 induces pain hypersensitivity and astrocyte activation via CXCR5 [40].…”

Section: Chemokines In Neuropathic Painmentioning

confidence: 99%

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Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

Pawlik

Mika

2023

Molecules

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Neuropathic pain is a debilitating condition that affects millions of people worldwide. Numerous studies indicate that this type of pain is a chronic condition with a complex mechanism that tends to worsen over time, leading to a significant deterioration in patients’ quality of life and issues like depression, disability, and disturbed sleep. Presently used analgesics are not effective enough in neuropathy treatment and may cause many side effects due to the high doses needed. In recent years, many researchers have pointed to the important role of chemokines not only in the development and maintenance of neuropathy but also in the effectiveness of analgesic drugs. Currently, approximately 50 chemokines are known to act through 20 different seven-transmembrane G-protein-coupled receptors located on the surface of neuronal, glial, and immune cells. Data from recent years clearly indicate that more chemokines than initially thought (CCL1/2/3/5/7/8/9/11, CXCL3/9/10/12/13/14/17; XCL1, CX3CL1) have pronociceptive properties; therefore, blocking their action by using neutralizing antibodies, inhibiting their synthesis, or blocking their receptors brings neuropathic pain relief. Several of them (CCL1/2/3/7/9/XCL1) have been shown to be able to reduce opioid drug effectiveness in neuropathy, and neutralizing antibodies against them can restore morphine and/or buprenorphine analgesia. The latest research provides irrefutable evidence that chemokine receptors are promising targets for pharmacotherapy; chemokine receptor antagonists can relieve pain of different etiologies, and most of them are able to enhance opioid analgesia, for example, the blockade of CCR1 (J113863), CCR2 (RS504393), CCR3 (SB328437), CCR4 (C021), CCR5 (maraviroc/AZD5672/TAK-220), CXCR2 (NVPCXCR220/SB225002), CXCR3 (NBI-74330/AMG487), CXCR4 (AMD3100/AMD3465), and XCR1 (vMIP-II). Recent research has shown that multitarget antagonists of chemokine receptors, such as CCR2/5 (cenicriviroc), CXCR1/2 (reparixin), and CCR2/CCR5/CCR8 (RAP-103), are also very effective painkillers. A multidirectional strategy based on the modulation of neuronal–glial–immune interactions by changing the activity of the chemokine family can significantly improve the quality of life of patients suffering from neuropathic pain. However, members of the chemokine family are still underestimated pharmacological targets for pain treatment. In this article, we review the literature and provide new insights into the role of chemokines and their receptors in neuropathic pain.

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Section: Cx3c Chemokine In Neuropathic Painmentioning

confidence: 99%

Section: Chemokines In Neuropathic Painmentioning

confidence: 99%

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

Pawlik

Mika

2023

Molecules

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“…In the neuropathic pain rats, daphnetin was demonstrated to suppress the expression of pro-inflammatory factors IL-1β, IL-6, and TNF-α, exerting neuroprotective effects. Meanwhile, daphnetin suppressed the activation of microglia, astrocytes, and neurons, thus reducing the nociceptive sensitization in neuropathic pain rats ( Zhang et al, 2023 ). In addition, in an experimental autoimmune encephalomyelitis (EAE) mice model, daphnetin (2 and 8 mg/kg) treatment significantly decreased lymphocyte infiltration and demyelination, which was attributed to reduction in pro-inflammatory factors, including TNF-α and IL-17 and an increase in anti-inflammatory factors, such as IL-4 and IL-10 ( Soltanmohammadi et al, 2022 ).…”

Section: Effects Of Daphnetin On Inflammatory Factorsmentioning

confidence: 99%

The molecular effects underlying the pharmacological activities of daphnetin

Wei,

et al. 2024

Front. Pharmacol.

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As an increasingly well-known derivative of coumarin, daphnetin (7,8-dithydroxycoumarin) has demonstrated various pharmacological activities, including anti-inflammation, anti-cancer, anti-autoimmune diseases, antibacterial, organ protection, and neuroprotection properties. Various studies have been conducted to explore the action mechanisms and synthetic methods of daphnetin, given its therapeutic potential in clinical. Despite these initial insights, the precise mechanisms underlying the pharmacological activities of daphnetin remain largely unknown. In order to address this knowledge gap, we explore the molecular effects from the perspectives of signaling pathways, NOD-like receptor protein 3 (NLRP3) inflammasome and inflammatory factors; and try to find out how these mechanisms can be utilized to inform new combined therapeutic strategies.

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“…We used intrathecal injection for the administration of DAP to further clarify the effects of DAP in ameliorating NP at the spinal cord level and the mechanism of action. Our previous study found that DAP could inhibit the activation of spinal microglia in the TNF-α-induced NP rat model, which has profound implications for this study [ 14 ]. Therefore, during this study, we aimed to determine whether DAP can treat CCI-induced NP through spinal cord administration and explore the effects of DAP on the P2X 4 /P38 pathway of microglia under central sensitization conditions.…”

Section: Introductionmentioning

confidence: 99%

Daphnetin Ameliorates Neuropathic Pain via Regulation of Microglial Responses and Glycerophospholipid Metabolism in the Spinal Cord

Liang,

Zhang,

Zhang

et al. 2024

Pharmaceuticals

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Neuropathic pain (NP) is a common type of chronic pain caused by a lesion or disease of the somatosensory nervous system. This condition imposes a considerable economic burden on society and patients. Daphnetin (DAP) is a natural product isolated from a Chinese medicinal herb with various pharmacological activities, such as anti-inflammatory and analgesic properties. However, the underlying mechanisms of these effects are not fully understood. In the present study, we aimed to investigate DAP’s anti-inflammatory and analgesic effects and explore the underlying mechanisms of action. The NP model was established as chronic constrictive injury (CCI) of the sciatic nerve, and pain sensitivity was evaluated by measuring the mechanical withdrawal threshold (MWT) and thermal withdrawal threshold (TWT). The activation of microglia in the spinal dorsal horn was measured via immunofluorescence staining. Protein levels were measured using a western blot assay. Using a mass-spectrometry proteomics platform and an LC-MS/MS-based metabolomics platform, proteins and metabolites in spinal cord tissues were extracted and analyzed. DAP treatment ameliorated the MWT and TWT in CCI rats. The expression of IL-1β, IL-6, and TNF-α was inhibited by DAP treatment in the spinal cords of CCI rats. Moreover, the activation of microglia was suppressed after DAP treatment. The elevation in the levels of P2X4, IRF8, IRF5, BDNF, and p-P38/P38 in the spinal cord caused by CCI was inhibited by DAP. Proteomics and metabolomics results indicated that DAP ameliorated the imbalance of glycerophospholipid metabolism in the spinal cords of CCI rats. DAP can potentially ameliorate NP by regulating microglial responses and glycerophospholipid metabolism in the CCI model. This study provides a pharmacological justification for using DAP in the management of NP.

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Daphnetin Improves Neuropathic Pain by Inhibiting the Expression of Chemokines and Inflammatory Factors in the Spinal Cord and Interfering with Glial Cell Polarization

Cited by 6 publications

References 59 publications

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

The molecular effects underlying the pharmacological activities of daphnetin

Daphnetin Ameliorates Neuropathic Pain via Regulation of Microglial Responses and Glycerophospholipid Metabolism in the Spinal Cord

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