Targeting Forkhead box O1-aquaporin 5 axis mitigates neuropathic pain in a CCI rat model through inhibiting astrocytic and microglial activation

Yu, Yijun; Wang, Meng; Yu, Xiao; Yan, Yi; Yu, Bo; Zhang, Dayin

doi:10.1080/21655979.2022.2053032

Cited by 6 publications

(5 citation 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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“…Aquaporins, mainly responsible for water transport and clearance, play an important role in the development of CNS diseases. Studies have shown that AQP1, AQP2, AQP4, AQP5, and AQP9 are directly or indirectly related to neuropathic pain, and among them, AQP4 is closely related to neuropathic pain [13][14][15][16][17]. The CNS is sensitive to changes in the surrounding environment and lacks traditional lymphatic pathways.…”

Section: Discussionmentioning

confidence: 99%

“…In a study of rats and mice, the expression of AQP5 was up-regulated after crushed sciatic nerve injury, and neuropathic pain is one of the main symptoms of sciatic nerve injury, suggesting that AQP5 may be related to neuropathic pain [40]. In addition, topical administration of gabapentin was found to alleviate neuropathic ocular pain by inducing AQP5 expression in the lacrimal gland, and resveratrol was found to mitigate neuropathic pain by inhibiting AQP5 activation caused by chronic contractile injury [16,135]. Moreover, studies have indicated that AQP5 colocalizes with AQP2 in the kidney, and AQP5 can also regulate AQP2 expression, which is associated with neuropathic pain [15,41,136].…”

Section: Aqp5mentioning

confidence: 99%

“…Studies have shown that several aquaporins are closely related to neuropathic pain, including aquaporin 1 (AQP1), aquaporin 2 (AQP2), aquaporin 4 (AQP4), aquaporin 5 (AQP5) and aquaporin 9 (AQP9) [13][14][15][16][17]. Since AQPs promote water and solute transport and are involved in the occurrence and development of many diseases, it is logical that AQPs are involved in the occurrence and development of neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

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Aquaporins and Neuropathic Pain

Wang¹,

Xu²,

Xu³

et al. 2023

Front. Biosci. (Landmark Ed)

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Neuropathic pain is a chronic secondary pain condition resulting from lesions or diseases of the peripheral or central nervous system (CNS). Neuropathic pain is closely related to edema, inflammation, increased neuronal excitability, and central sensitization caused by glutamate accumulation. Aquaporins (AQPs), mainly responsible for the transport and clearance of water and solute, play important roles in developing CNS diseases, especially neuropathic pain. This review focuses on the interaction of AQPs with neuropathic pain, and the potential of AQPs, especially aquaporins 4, as therapeutic targets.

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“… 19 Furthermore, the FoxO1–AQP5 axis alleviates chronic constriction injury (CCI)-induced neuropathic pain (NP) by modulating the ERK and p38 MAPK signaling pathways. 20 However, the effect and mechanism of AQP5 on the LG nerve remain unclear.…”

mentioning

confidence: 99%

Regulation of Axon Guidance by Slit2 and Netrin-1 Signaling in the Lacrimal Gland of Aqp5 Knockout Mice

Bai,

Di,

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose Dry eye disease (DED) is multifactorial and associated with nerve abnormalities. We explored an Aquaporin 5 (AQP5)-deficiency-induced JunB activation mechanism, which causes abnormal lacrimal gland (LG) nerve distribution through Slit2 upregulation and Netrin-1 repression. Methods Aqp5 knockout ( Aqp5 − / − ) and wild-type ( Aqp5 +/+ ) mice were studied. LGs were permeabilized and stained with neuronal class III β-tubulin, tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP). Whole-mount images were acquired through tissue clearing and 3D fluorescence imaging. Mouse primary trigeminal ganglion (TG) neurons were treated with LG extracts and Netrin-1/Slit2 neutralizing antibody. Transcription factor (TF) prediction and chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) experiments verified the JunB binding and regulatory effect on Netrin-1 and Slit2. Results Three-dimensional tissue and section immunofluorescence showed reduced LG nerves in Aqp5 − / − mice, with sympathetic and sensory nerves significantly decreased. Netrin-1 was reduced and Slit2 increased in Aqp5 − / − mice LGs. Aqp5 +/+ mice LG tissue extracts (TEs) promoted Aqp5 − / − TG neurons axon growth, but Netrin-1 neutralizing antibody (NAb) could inhibit that promotion. Aqp5 − / − mice LG TEs inhibited Aqp5 +/+ TG axon growth, but Slit2 NAb alleviated that inhibition. Furthermore, JunB, a Netrin-1 and Slit2 TF, could bind them and regulate their expression. SR11302, meanwhile, reversed the Netrin-1 and Slit2 shifts caused by AQP5 deficiency. Conclusions AQP5 deficiency causes LG nerve abnormalities. Persistent JunB activation, the common denominator for Netrin-1 suppression and Slit2 induction, was found in Aqp5 − / − mice LG epithelial cells. This affected sensory and sympathetic nerve fibers’ distribution in LGs. Our findings provide insights into preventing, reversing, and treating DED.

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Targeting Forkhead box O1-aquaporin 5 axis mitigates neuropathic pain in a CCI rat model through inhibiting astrocytic and microglial activation

Cited by 6 publications

References 53 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

Aquaporins and Neuropathic Pain

Regulation of Axon Guidance by Slit2 and Netrin-1 Signaling in the Lacrimal Gland of Aqp5 Knockout Mice

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