Liquiritin Ameliorates Painful Diabetic Neuropathy in SD Rats by Inhibiting NLRP3-MMP-9-mediated Reversal of Aquaporin-4 Polarity in the Glymphatic System

Overview

Journal Front Pharmacol

Date 2024 Sep 19

PMID 39295943

Authors

Shuai-Ying Jia

Wen-Qin Yin

Wen-Mei Xu

Jiang Li

Wei Yan

Jing-Yan Lin

Affiliations

Soon will be listed here.

Abstract

Background: Despite advancements in diabetes treatment, the management of Painful Diabetic Neuropathy (PDN) remains challenging. Our previous research indicated a significant correlation between the expression and distribution of Aquaporin-4 (AQP4) in the spinal glymphatic system and PDN. However, the potential role and mechanism of liquiritin in PDN treatment remain uncertain.

Methods: This study established a rat model of PDN using a combination of low-dose Streptozotocin (STZ) and a high-fat, high-sugar diet. Rats were treated with liquiritin and MCC950 (an NLRP3 inhibitor). We monitored fasting blood glucose, body weight, and mechanical allodynia periodically. The glymphatic system's clearance function was evaluated using Magnetic Resonance Imaging (MRI), and changes in proteins including NLRP3, MMP-9, and AQP4 were detected through immunofluorescence and Western blot techniques.

Results: The rats with painful diabetic neuropathy (PDN) demonstrated several physiological changes, including heightened mechanical allodynia, compromised clearance function within the spinal glymphatic system, altered distribution of AQP4, increased count of activated astrocytes, elevated expression levels of NLRP3 and MMP-9, and decreased expression of AQP4. However, following treatment with liquiritin and MCC950, these rats exhibited notable improvements.

Conclusion: Liquiritin may promote the restoration of AQP4 polarity by inhibiting NLRP3 and MMP-9, thereby enhancing the clearance functions of the spinal cord glymphatic system in PDN rats, alleviating the progression of PDN.

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References

Dai J, Lin W, Zheng M, Liu Q, He B, Luo C . Alterations in AQP4 expression and polarization in the course of motor neuron degeneration in SOD1G93A mice. Mol Med Rep. 2017; 16(2):1739-1746. PMC: 5562093. DOI: 10.3892/mmr.2017.6786. View

Tokhi A, Ahmed Z, Arif M, Ur Rehman N, Sheibani V, Sewell R . Effects of 1-methyl-1, 2, 3, 4-tetrahydroisoquinoline on a diabetic neuropathic pain model. Front Pharmacol. 2023; 14:1128496. PMC: 10073420. DOI: 10.3389/fphar.2023.1128496. View

Deng J, Zhao F, Yu X, Zhao Y, Li D, Shi H . Expression of aquaporin 4 and breakdown of the blood-brain barrier after hypoglycemia-induced brain edema in rats. PLoS One. 2014; 9(9):e107022. PMC: 4180270. DOI: 10.1371/journal.pone.0107022. View

Paschou S, Papanas N . Type 2 Diabetes Mellitus and Menopausal Hormone Therapy: An Update. Diabetes Ther. 2019; 10(6):2313-2320. PMC: 6848654. DOI: 10.1007/s13300-019-00695-y. View

Troili F, Cipollini V, Moci M, Morena E, Palotai M, Rinaldi V . Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System. Front Neuroanat. 2020; 14:17. PMC: 7177187. DOI: 10.3389/fnana.2020.00017. View

Peng L, Wen L, Shi Q, Gao F, Huang B, Meng J . Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial-mesenchymal transition and inflammation. Cell Death Dis. 2020; 11(11):978. PMC: 7666141. DOI: 10.1038/s41419-020-03178-2. View

Jessen N, Munk A, Lundgaard I, Nedergaard M . The Glymphatic System: A Beginner's Guide. Neurochem Res. 2015; 40(12):2583-99. PMC: 4636982. DOI: 10.1007/s11064-015-1581-6. View

Iliff J, Wang M, Zeppenfeld D, Venkataraman A, Plog B, Liao Y . Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci. 2013; 33(46):18190-9. PMC: 3866416. DOI: 10.1523/JNEUROSCI.1592-13.2013. View

Yamaguchi T, Miyamoto T, Shikata E, Yamaguchi I, Shimada K, Yagi K . Activation of the NLRP3/IL-1β/MMP-9 pathway and intracranial aneurysm rupture associated with the depletion of ERα and Sirt1 in oophorectomized rats. J Neurosurg. 2022; 138(1):191-198. DOI: 10.3171/2022.4.JNS212945. View

10.

Gundersen G, Vindedal G, Skare O, Nagelhus E . Evidence that pericytes regulate aquaporin-4 polarization in mouse cortical astrocytes. Brain Struct Funct. 2013; 219(6):2181-6. PMC: 4223569. DOI: 10.1007/s00429-013-0629-0. View

11.

Liu S, Lam M, Sial A, Hemley S, Bilston L, Stoodley M . Fluid outflow in the rat spinal cord: the role of perivascular and paravascular pathways. Fluids Barriers CNS. 2018; 15(1):13. PMC: 5924677. DOI: 10.1186/s12987-018-0098-1. View

12.

Islam M, Loots D . Experimental rodent models of type 2 diabetes: a review. Methods Find Exp Clin Pharmacol. 2009; 31(4):249-61. DOI: 10.1358/mf.2009.31.4.1362513. View

13.

Tesfaye S, Sloan G, Petrie J, White D, Bradburn M, Young T . Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT. Health Technol Assess. 2022; 26(39):1-100. PMC: 9589396. DOI: 10.3310/RXUO6757. View

14.

Zhang Q, Huang H, Qiu M, Wu Z, Xin Z, Cai X . Traditional Uses, Pharmacological Effects, and Molecular Mechanisms of Licorice in Potential Therapy of COVID-19. Front Pharmacol. 2021; 12:719758. PMC: 8661450. DOI: 10.3389/fphar.2021.719758. View

15.

Xian S, Ding R, Li M, Chen F . LncRNA NEAT1/miR-128-3p/AQP4 axis regulating spinal cord injury-induced neuropathic pain progression. J Neuroimmunol. 2020; 351:577457. DOI: 10.1016/j.jneuroim.2020.577457. View

16.

Zhang J, Zhan Z, Li X, Xing A, Jiang C, Chen Y . Intermittent Fasting Protects against Alzheimer's Disease Possible through Restoring Aquaporin-4 Polarity. Front Mol Neurosci. 2017; 10:395. PMC: 5712566. DOI: 10.3389/fnmol.2017.00395. View

17.

Seifert G, Schilling K, Steinhauser C . Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci. 2006; 7(3):194-206. DOI: 10.1038/nrn1870. View

18.

Furman B . Streptozotocin-Induced Diabetic Models in Mice and Rats. Curr Protoc. 2021; 1(4):e78. DOI: 10.1002/cpz1.78. View

19.

Ljubimov A, Burgeson R, Butkowski R, Couchman J, Zardi L, Ninomiya Y . Basement membrane abnormalities in human eyes with diabetic retinopathy. J Histochem Cytochem. 1996; 44(12):1469-79. DOI: 10.1177/44.12.8985139. View

20.

Meyers S, Tam R, Lee J, Kolind S, Vavasour I, Mackie E . Does hydration status affect MRI measures of brain volume or water content?. J Magn Reson Imaging. 2016; 44(2):296-304. DOI: 10.1002/jmri.25168. View