Nod樣受體蛋白3及其抑制藥物在癲癇中的研究進展_Journal of Epilepsy

Authors：

孫素娟 ^1,2 ,  劉學伍 ^1,2

1. ;
2. ;

Corresponding?author：

劉學伍, Email: snlxw1966@163.com

Keywords：

癲癇; 炎癥; Nod樣受體蛋白3; 藥物

DOI：

10.7507/2096-0247.202204011

Video：

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癲癇病因復雜多樣，多數癲癇患者病因不清，近年來越來越多的證據表明炎癥在癲癇中發揮了重要作用。Nod樣受體蛋白3（Nod-like receptor protein 3，NLRP3）炎癥小體是目前研究最為深入的炎癥體，抑制NLRP3炎癥體具有潛在的抗癲癇作用，NLRP3炎癥體作用機制及其各種抑制藥物仍在探索之中，繼續深入研究NLRP3炎癥體與癲癇的關系，有利于進一步明確癲癇病因，推動抗癲癇發作藥物開發的進步。本文對目前已知的NLRP3及其抑制藥物在癲癇中的研究進展進行綜述，為預防和治療癲癇提供新的思路和靶點。

Citation： 孫素娟, 劉學伍. Nod樣受體蛋白3及其抑制藥物在癲癇中的研究進展. Journal of Epilepsy, 2022, 8(4): 326-330. doi: 10.7507/2096-0247.202204011 Copy

1.	Devinsky O, Vezzani A, O'Brien TJ, et al. Epilepsy. Nat Rev Dis Primers, 2018, 4: 18024.
2.	Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol, 2019, 15(8): 459-472.
3.	Wu C, Zhang G, Chen L, et al. The role of nlrp3 and il-1beta in refractory epilepsy brain injury. Front Neurol, 2019, 10: 1418.
4.	Alyu F, Dikmen M. Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms. Acta Neuropsychiatr, 2017, 29(1): 1-16.
5.	Mohseni-Moghaddam P, Roghani M, Khaleghzadeh-Ahangar H, et al. A literature overview on epilepsy and inflammasome activation. Brain Res Bull, 2021, 172: 229-235.
6.	Mangan MSJ, Olhava EJ, Roush WR, et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov., 2018, 17(8): 588-606.
7.	Grebe A, Hoss F, Latz E. NLRP3 Inflammasome and the IL-1 pathway in atherosclerosis. Circ Res, 2018, 122(12): 1722-1740.
8.	Bauernfeind FG, Horvath G, Stutz A, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol, 2009, 183(2): 787-791.
9.	Zeng QZ, Yang F, Li CG, et al. Paclitaxel enhances the innate immunity by promoting nlrp3 inflammasome activation in macrophages. Front Immunol, 2019, 10: 72.
10.	Cristina de BTE, Leandro MVE, Boni RDB, et al. NLRP3 and NLRP1 inflammasomes are up-regulated in patients with mesial temporal lobe epilepsy and may contribute to overexpression of caspase-1 and IL-beta in sclerotic hippocampi. Brain Res, 2021, 1752: 147230.
11.	Shen K, Mao Q, Yin X, et al. NLRP3 Inflammasome activation leads to epileptic neuronal apoptosis. Curr Neurovasc Res, 2018, 15(4): 276-281.
12.	Zhang H, Yu S, Xia L, et al. NLRP3 inflammasome activation enhances ADK expression to accelerate epilepsy in mice. Neurochem Res, 2022, 47(3): 713-722.
13.	Wang Z, Zhou L, An D, et al. TRPV4-induced inflammatory response is involved in neuronal death in pilocarpine model of temporal lobe epilepsy in mice. Cell Death Dis, 2019, 10(6): 386.
14.	Malko P, Syed Mortadza SA, McWilliam J, et al. TRPM2 channel in microglia as a new player in neuroinflammation associated with a spectrum of central nervous system pathologies. Front Pharmacol, 2019, 10: 239.
15.	Hu H, Zhu T, Gong L, et al. Transient receptor potential melastatin 2 contributes to neuroinflammation and negatively regulates cognitive outcomes in a pilocarpine-induced mouse model of epilepsy. Int Immunopharmacol, 2020, 87: 106824.
16.	Yue J, He J, Wei Y, et al. Decreased expression of Rev-Erbalpha in the epileptic foci of temporal lobe epilepsy and activation of Rev-Erbalpha have anti-inflammatory and neuroprotective effects in the pilocarpine model. J Neuroinflammation, 2020, 17(1): 43.
17.	Jiang Q, Tang G, Zhong XM, et al. Role of Stat3 in NLRP3/caspase-1-mediated hippocampal neuronal pyroptosis in epileptic mice. Synapse, 2021, 75(12): e22221.
18.	Yue J, Wei YJ, Yang XL, et al. NLRP3 inflammasome and endoplasmic reticulum stress in the epileptogenic zone in temporal lobe epilepsy: molecular insights into their interdependence. Neuropathol Appl Neurobiol, 2020, 46(7): 770-785.
19.	Xiang T, Luo X, Ye L, et al. Klotho alleviates NLRP3 inflammasome-mediated neuroinflammation in a temporal lobe epilepsy rat model by activating the Nrf2 signaling pathway. Epilepsy Behav, 2022, 128: 108509.
20.	Wang L, Ding J, Zhu C, et al. Semaglutide attenuates seizure severity and ameliorates cognitive dysfunction by blocking the NLR family pyrin domain containing 3 inflammasome in pentylenetetrazolekindled mice. Int J Mol Med, 2021, 48(6): 219.
21.	Sakthivel KM, Guruvayoorappan C. Amentoflavone inhibits iNOS, COX-2 expression and modulates cytokine profile, NF-kappaB signal transduction pathways in rats with ulcerative colitis. Int Immunopharmacol, 2013, 17(3): 907-916.
22.	Rong S, Wan D, Fan Y, et al. Amentoflavone Affects Epileptogenesis and Exerts Neuroprotective Effects by Inhibiting NLRP3 Inflammasome. Front Pharmacol, 2019, 10: 856.
23.	Sun Y, Ma J, Li D, et al. Interleukin-10 inhibits interleukin-1beta production and inflammasome activation of microglia in epileptic seizures. J Neuroinflammation, 2019, 16(1): 66.
24.	Liu R, Wu S, Guo C, et al. Ibuprofen exerts antiepileptic and neuroprotective effects in the rat model of pentylenetetrazol-induced epilepsy via the cox-2/nlrp3/il-18 pathway. Neurochem Res, 2020, 45(10): 2516-2526.
25.	Xia S, Yang P, Li F, et al. Chaihu-Longgu-Muli Decoction exerts an antiepileptic effect in rats by improving pyroptosis in hippocampal neurons. J Ethnopharmacol, 2021, 270: 113794.
26.	Li X, Lin J, Hua Y, et al. Agmatine alleviates epileptic seizures and hippocampal neuronal damage by inhibiting gasdermin d-mediated pyroptosis. Front Pharmacol, 2021, 12: 627557.
27.	He Q, Jiang L, Man S, et al. Curcumin reduces neuronal loss and inhibits the nlrp3 inflammasome activation in an epileptic rat model. Curr Neurovasc Res, 2018, 15(3): 186-192.
28.	Dai J, Jiang C, Chen H, et al. Rapamycin attenuates high glucose-induced inflammation through modulation of mtor/nf-kappab pathways in macrophages. Front Pharmacol, 2019, 10: 1292.
29.	Aghaie F, Moradifar F, Hosseini A. Rapamycin attenuates depression and anxiety-like behaviors through modulation of the NLRP3 pathway in pentylenetetrazole-kindled male Wistar rats. Fundam Clin Pharmacol, 2021, 35(6): 1045-1054.
30.	Wang ZF, Wang J, Zhang HY, et al. Huperzine A exhibits anti-inflammatory and neuroprotective effects in a rat model of transient focal cerebral ischemia. J Neurochem, 2008, 106(4): 1594-1603.
31.	Mohseni-Moghaddam P, Sadr SS, Roghani M, et al. Huperzine A ameliorates cognitive dysfunction and neuroinflammation in kainic acid-induced epileptic rats by antioxidant activity and NLRP3/caspase-1 pathway inhibition. Clin Exp Pharmacol Physiol, 2019, 46(4): 360-372.
32.	Shen K, Jiang W, Zhang C, et al. Molecular mechanism of a specific NLRP3 inhibitor to alleviate seizure severity induced by pentylenetetrazole. Curr Mol Pharmacol, 2021, 14(4): 579-586.
33.	Kursun O, Yemisci M, van den Maagdenberg A, et al. Migraine and neuroinflammation: the inflammasome perspective. J Headache Pain, 2021, 22(1): 55.
34.	DeSena AD, Do T, Schulert GS. Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade. J Neuroinflammation, 2018, 15(1): 38.

1. Devinsky O, Vezzani A, O'Brien TJ, et al. Epilepsy. Nat Rev Dis Primers, 2018, 4: 18024.
2. Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol, 2019, 15(8): 459-472.
3. Wu C, Zhang G, Chen L, et al. The role of nlrp3 and il-1beta in refractory epilepsy brain injury. Front Neurol, 2019, 10: 1418.
4. Alyu F, Dikmen M. Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms. Acta Neuropsychiatr, 2017, 29(1): 1-16.
5. Mohseni-Moghaddam P, Roghani M, Khaleghzadeh-Ahangar H, et al. A literature overview on epilepsy and inflammasome activation. Brain Res Bull, 2021, 172: 229-235.
6. Mangan MSJ, Olhava EJ, Roush WR, et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov., 2018, 17(8): 588-606.
7. Grebe A, Hoss F, Latz E. NLRP3 Inflammasome and the IL-1 pathway in atherosclerosis. Circ Res, 2018, 122(12): 1722-1740.
8. Bauernfeind FG, Horvath G, Stutz A, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol, 2009, 183(2): 787-791.
9. Zeng QZ, Yang F, Li CG, et al. Paclitaxel enhances the innate immunity by promoting nlrp3 inflammasome activation in macrophages. Front Immunol, 2019, 10: 72.
10. Cristina de BTE, Leandro MVE, Boni RDB, et al. NLRP3 and NLRP1 inflammasomes are up-regulated in patients with mesial temporal lobe epilepsy and may contribute to overexpression of caspase-1 and IL-beta in sclerotic hippocampi. Brain Res, 2021, 1752: 147230.
11. Shen K, Mao Q, Yin X, et al. NLRP3 Inflammasome activation leads to epileptic neuronal apoptosis. Curr Neurovasc Res, 2018, 15(4): 276-281.
12. Zhang H, Yu S, Xia L, et al. NLRP3 inflammasome activation enhances ADK expression to accelerate epilepsy in mice. Neurochem Res, 2022, 47(3): 713-722.
13. Wang Z, Zhou L, An D, et al. TRPV4-induced inflammatory response is involved in neuronal death in pilocarpine model of temporal lobe epilepsy in mice. Cell Death Dis, 2019, 10(6): 386.
14. Malko P, Syed Mortadza SA, McWilliam J, et al. TRPM2 channel in microglia as a new player in neuroinflammation associated with a spectrum of central nervous system pathologies. Front Pharmacol, 2019, 10: 239.
15. Hu H, Zhu T, Gong L, et al. Transient receptor potential melastatin 2 contributes to neuroinflammation and negatively regulates cognitive outcomes in a pilocarpine-induced mouse model of epilepsy. Int Immunopharmacol, 2020, 87: 106824.
16. Yue J, He J, Wei Y, et al. Decreased expression of Rev-Erbalpha in the epileptic foci of temporal lobe epilepsy and activation of Rev-Erbalpha have anti-inflammatory and neuroprotective effects in the pilocarpine model. J Neuroinflammation, 2020, 17(1): 43.
17. Jiang Q, Tang G, Zhong XM, et al. Role of Stat3 in NLRP3/caspase-1-mediated hippocampal neuronal pyroptosis in epileptic mice. Synapse, 2021, 75(12): e22221.
18. Yue J, Wei YJ, Yang XL, et al. NLRP3 inflammasome and endoplasmic reticulum stress in the epileptogenic zone in temporal lobe epilepsy: molecular insights into their interdependence. Neuropathol Appl Neurobiol, 2020, 46(7): 770-785.
19. Xiang T, Luo X, Ye L, et al. Klotho alleviates NLRP3 inflammasome-mediated neuroinflammation in a temporal lobe epilepsy rat model by activating the Nrf2 signaling pathway. Epilepsy Behav, 2022, 128: 108509.
20. Wang L, Ding J, Zhu C, et al. Semaglutide attenuates seizure severity and ameliorates cognitive dysfunction by blocking the NLR family pyrin domain containing 3 inflammasome in pentylenetetrazolekindled mice. Int J Mol Med, 2021, 48(6): 219.
21. Sakthivel KM, Guruvayoorappan C. Amentoflavone inhibits iNOS, COX-2 expression and modulates cytokine profile, NF-kappaB signal transduction pathways in rats with ulcerative colitis. Int Immunopharmacol, 2013, 17(3): 907-916.
22. Rong S, Wan D, Fan Y, et al. Amentoflavone Affects Epileptogenesis and Exerts Neuroprotective Effects by Inhibiting NLRP3 Inflammasome. Front Pharmacol, 2019, 10: 856.
23. Sun Y, Ma J, Li D, et al. Interleukin-10 inhibits interleukin-1beta production and inflammasome activation of microglia in epileptic seizures. J Neuroinflammation, 2019, 16(1): 66.
24. Liu R, Wu S, Guo C, et al. Ibuprofen exerts antiepileptic and neuroprotective effects in the rat model of pentylenetetrazol-induced epilepsy via the cox-2/nlrp3/il-18 pathway. Neurochem Res, 2020, 45(10): 2516-2526.
25. Xia S, Yang P, Li F, et al. Chaihu-Longgu-Muli Decoction exerts an antiepileptic effect in rats by improving pyroptosis in hippocampal neurons. J Ethnopharmacol, 2021, 270: 113794.
26. Li X, Lin J, Hua Y, et al. Agmatine alleviates epileptic seizures and hippocampal neuronal damage by inhibiting gasdermin d-mediated pyroptosis. Front Pharmacol, 2021, 12: 627557.
27. He Q, Jiang L, Man S, et al. Curcumin reduces neuronal loss and inhibits the nlrp3 inflammasome activation in an epileptic rat model. Curr Neurovasc Res, 2018, 15(3): 186-192.
28. Dai J, Jiang C, Chen H, et al. Rapamycin attenuates high glucose-induced inflammation through modulation of mtor/nf-kappab pathways in macrophages. Front Pharmacol, 2019, 10: 1292.
29. Aghaie F, Moradifar F, Hosseini A. Rapamycin attenuates depression and anxiety-like behaviors through modulation of the NLRP3 pathway in pentylenetetrazole-kindled male Wistar rats. Fundam Clin Pharmacol, 2021, 35(6): 1045-1054.
30. Wang ZF, Wang J, Zhang HY, et al. Huperzine A exhibits anti-inflammatory and neuroprotective effects in a rat model of transient focal cerebral ischemia. J Neurochem, 2008, 106(4): 1594-1603.
31. Mohseni-Moghaddam P, Sadr SS, Roghani M, et al. Huperzine A ameliorates cognitive dysfunction and neuroinflammation in kainic acid-induced epileptic rats by antioxidant activity and NLRP3/caspase-1 pathway inhibition. Clin Exp Pharmacol Physiol, 2019, 46(4): 360-372.
32. Shen K, Jiang W, Zhang C, et al. Molecular mechanism of a specific NLRP3 inhibitor to alleviate seizure severity induced by pentylenetetrazole. Curr Mol Pharmacol, 2021, 14(4): 579-586.
33. Kursun O, Yemisci M, van den Maagdenberg A, et al. Migraine and neuroinflammation: the inflammasome perspective. J Headache Pain, 2021, 22(1): 55.
34. DeSena AD, Do T, Schulert GS. Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade. J Neuroinflammation, 2018, 15(1): 38.

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