Advances in the p38 Mitogen-activated protein kinase signalling pathway in epilepsy_Journal of Epilepsy

Authors：

YANG Can ¹ , LI Xuebin ¹ , KONG Qingxia ² ,  LI Qiubo ³

1. Clinical Medical College of Jining Medical University, Jining 272000, China;
2. Department of Neurology, Affiliated Hospital of Jining Medical University, Jining 272000, China;
3. Department of Paediatrics, Affiliated Hospital of Jining Medical University, Jining 272000, China;

Corresponding author：

LI Qiubo, Email: Lqb0072@126.com

Keywords：

p38; Mitogen-activated protein kinase; Epilepsy; Inflammation; Apoptosis

DOI：

10.7507/2096-0247.202302001

Video：

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Epilepsy is a disorder of the brain in which sudden abnormal discharges of neurons cause transient dysfunction and is a common disorder of the nervous system. Although most patients experience remission of symptoms with medication, about 20 ~ 30% of patients still have poor outcomes with medication and progress to refractory epilepsy. The etiology of epilepsy is complex and the exact pathogenesis is not yet clear. Current research has explored the pathophysiological mechanisms underlying epileptogenesis, thus providing a basis for identifying potential therapeutic targets for epilepsy and advancing the precision treatment of epilepsy. p38 Mitogen-activated protein kinase (MAPK) signalling pathway is a conserved class of kinases involved in many physiological/pathological processes by regulating intracellular gene expression levels, cell division, differentiation and apoptosis in response to various extracellular stimuli in order to mediate intracellular signalling cascades. The p38 MAPK signalling pathway is one of the subfamilies of MAPK that mediates inflammatory responses, apoptosis, tissue edema and other biological processes involved in the development of central nervous system diseases. The p38 MAPK signalling pathway is now reviewed for its involvement in the development of epilepsy through unused pathways, in order to identify new potential targets for epilepsy treatment and provide clinical precision.

Citation： YANG Can, LI Xuebin, KONG Qingxia, LI Qiubo. Advances in the p38 Mitogen-activated protein kinase signalling pathway in epilepsy. Journal of Epilepsy, 2023, 9(3): 243-247. doi: 10.7507/2096-0247.202302001 Copy

1.	Wen X, Jiao L, Tan H. MAPK/ERK pathway as a central regulator in vertebrate organ regeneration. Int J Mol Sci, 2022, 23(3): 1464.
2.	Martinez-Limon A, Joaquin M, Caballero M, et al. The p38 pathway: from biology to cancer therapy. Int J Mol Sci, 2020, 21(6): 1913.
3.	张奎明, 崔应麟, 葛鸾蝶, 等. p38 MAPK信号通路对缺血性脑卒中作用的研究进展. 医学综述, 2021, 27(9): 1691-1695.
4.	Hou K, Xiao ZC, Dai HL. p38 MAPK endogenous inhibition improves neurological deficits in global cerebral ischemia/reperfusion mice. Neural Plast, 2022, 10: 3300327.
5.	Li H, Luo XB, Xu Y, et al. A brief ischemic postconditioning protects against amyloid-beta peptide neurotoxicity by downregulating MLK3-MKK3/6-P38MAPK signal in rat hippocampus. J Alzheimers Dis, 2019, 71(2): 671-684.
6.	张富慧, 郝静峰, 张自艳, 等. 菊苣酸调控p38 MAPK/NF-κB/NLRP3信号通路对缺血性脑卒中大鼠神经元凋亡及炎症反应的影响. 中风与神经疾病杂志, 2022, 39(8): 694-698.
7.	Lin H, Dixon S G, Hu W, et al. p38 MAPK is a major regulator of amyloid beta-induced IL-6 expression in human microglia. Mol Neurobiol, 2022, 59(9): 5284-5298.
8.	郭鸿儒, 陈燕惠. 炎症免疫与癫痫. 癫痫杂志, 2021, 7(5): 426-430.
9.	Kim J E, Park H, Choi S H, et al. Roscovitine attenuates microglia activation and monocyte infiltration via p38 mapk inhibition in the rat frontoparietal cortex following status epilepticus. Cells, 2019, 8(7): 746.
10.	Yu T, Huo L, Lei J, et al. Modulation of microglia M2 polarization and alleviation of hippocampal neuron injury by MiR-106b-5p/RGMa in a mouse model of status epilepticus. Inflammation, 2022, 45(6): 2223-2242.
11.	Plastira I, Bernhart E, Joshi L, et al. MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia. J Neuroinflammation, 2020, 17(1): 127.
12.	Liu Q, Zhang Y, Liu S, et al. Correction to: cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca(2+)-dependent PKC/p38MAPK/NF-kappaB pathway. J Neuroinflammation, 2022, 19(1): 14.
13.	Kim J E, Park H, Lee J E, et al. CDDO-me inhibits microglial activation and monocyte infiltration by abrogating NF kappaB- and p38 MAPK-mediated signaling pathways following status epilepticus. Cells, 2020, 9(5): 1123.
14.	Lu W, Wu Z, Zhang C, et al. Jujuboside a exhibits an antiepileptogenic effect in the rat model via protection against traumatic epilepsy-induced oxidative stress and inflammatory responses. Evid Based Complement Alternat Med, 2022, 12: 7792791.
15.	Kim JE, Park H, Lee JE, et al. Blockade of 67-kDa laminin receptor facilitates AQP4 down-regulation and BBB disruption via ERK1/2-and p38 MAPK-mediated PI3K/AKT activations. Cells, 2020, 9(7): 1670.
16.	Kim JE, Park H, Jeong MJ, Kang TC. Epigallocatechin-3-gallate and PEDF 335 peptide, 67LR activators, attenuate vasogenic edema, and astroglial degeneration following status epilepticus. Antioxidants (Basel), 2020, 9(9): 854.
17.	Tower J. Programmed cell death in aging. Ageing Res Rev, 2015, 23（Pt A）: 90-100.
18.	Erekat NS. Apoptosis and its therapeutic implications in neurodegenerative diseases. Clin Anat, 2022, 35(1): 65-78.
19.	Sun X, Kong L, Zhou L. Protective effect of fructus corni polysaccharide on hippocampal tissues and its relevant mechanism in epileptic rats induced by lithium chloride-pilocarpine. Exp Ther Med, 2018, 16(1): 445-451.
20.	Huang Q, Liu X, Wu Y, et al. P38 MAPK pathway mediates cognitive damage in pentylenetetrazole-induced epilepsy via apoptosis cascade. Epilepsy Res, 2017, 133: 89-92.
21.	Wang L, Song LF, Chen XY, et al. MiR-181b inhibits P38/JNK signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid-induced epilepsy via targeting TLR4. CNS Neurosci Ther, 2019, 25(1): 112-122.
22.	Pang W, Lu S, Zheng R, et al. Investigation into antiepileptic effect of ganoderic acid a and its mechanism in seizure rats induced by pentylenetetrazole. Biomed Res Int, 2022, 12: 5940372.
23.	Huang R, Zhu Y, Lin L, et al. Solid lipid nanoparticles enhanced the neuroprotective role of curcumin against epilepsy through activation of Bcl-2 family and P38 MAPK pathways. ACS Chem Neurosci, 2020, 11(13): 1985-1995.
24.	Chen Q, Lu H, Duan C, et al. PDCD4 simultaneously promotes microglia activation via PDCD4-MAPK-NF-κB positive loop and facilitates neuron apoptosis during neuroinflammation. Inflammation. 2022, 45（1）: 234-252.
25.	Yang Z, Wang J, Yu C, et al. Inhibition of p38 MAPK signaling regulates the expression of eaat2 in the brains of epileptic rats. Front Neurol, 2018, 9: 925.
26.	Yang X, Zhang H, Wu J, et al. Humanin attenuates NMDA-induced excitotoxicity by inhibiting ROS-dependent JNK/p38 MAPK pathway. Int J Mol Sci. 2018, 19（10）: 2982.
27.	Boison D. Adenosine dysfunction in epilepsy. Glia, 2012, 60(8): 1234-1243.
28.	Zhou X, Chen Q, Huang H, et al. Inhibition of p38 MAPK regulates epileptic severity by decreasing expression levels of A1R and ENT1. Mol Med Rep, 2020, 22(6): 5348-5357.

1. Wen X, Jiao L, Tan H. MAPK/ERK pathway as a central regulator in vertebrate organ regeneration. Int J Mol Sci, 2022, 23(3): 1464.
2. Martinez-Limon A, Joaquin M, Caballero M, et al. The p38 pathway: from biology to cancer therapy. Int J Mol Sci, 2020, 21(6): 1913.
3. 张奎明, 崔应麟, 葛鸾蝶, 等. p38 MAPK信号通路对缺血性脑卒中作用的研究进展. 医学综述, 2021, 27(9): 1691-1695.
4. Hou K, Xiao ZC, Dai HL. p38 MAPK endogenous inhibition improves neurological deficits in global cerebral ischemia/reperfusion mice. Neural Plast, 2022, 10: 3300327.
5. Li H, Luo XB, Xu Y, et al. A brief ischemic postconditioning protects against amyloid-beta peptide neurotoxicity by downregulating MLK3-MKK3/6-P38MAPK signal in rat hippocampus. J Alzheimers Dis, 2019, 71(2): 671-684.
6. 张富慧, 郝静峰, 张自艳, 等. 菊苣酸调控p38 MAPK/NF-κB/NLRP3信号通路对缺血性脑卒中大鼠神经元凋亡及炎症反应的影响. 中风与神经疾病杂志, 2022, 39(8): 694-698.
7. Lin H, Dixon S G, Hu W, et al. p38 MAPK is a major regulator of amyloid beta-induced IL-6 expression in human microglia. Mol Neurobiol, 2022, 59(9): 5284-5298.
8. 郭鸿儒, 陈燕惠. 炎症免疫与癫痫. 癫痫杂志, 2021, 7(5): 426-430.
9. Kim J E, Park H, Choi S H, et al. Roscovitine attenuates microglia activation and monocyte infiltration via p38 mapk inhibition in the rat frontoparietal cortex following status epilepticus. Cells, 2019, 8(7): 746.
10. Yu T, Huo L, Lei J, et al. Modulation of microglia M2 polarization and alleviation of hippocampal neuron injury by MiR-106b-5p/RGMa in a mouse model of status epilepticus. Inflammation, 2022, 45(6): 2223-2242.
11. Plastira I, Bernhart E, Joshi L, et al. MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia. J Neuroinflammation, 2020, 17(1): 127.
12. Liu Q, Zhang Y, Liu S, et al. Correction to: cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca(2+)-dependent PKC/p38MAPK/NF-kappaB pathway. J Neuroinflammation, 2022, 19(1): 14.
13. Kim J E, Park H, Lee J E, et al. CDDO-me inhibits microglial activation and monocyte infiltration by abrogating NF kappaB- and p38 MAPK-mediated signaling pathways following status epilepticus. Cells, 2020, 9(5): 1123.
14. Lu W, Wu Z, Zhang C, et al. Jujuboside a exhibits an antiepileptogenic effect in the rat model via protection against traumatic epilepsy-induced oxidative stress and inflammatory responses. Evid Based Complement Alternat Med, 2022, 12: 7792791.
15. Kim JE, Park H, Lee JE, et al. Blockade of 67-kDa laminin receptor facilitates AQP4 down-regulation and BBB disruption via ERK1/2-and p38 MAPK-mediated PI3K/AKT activations. Cells, 2020, 9(7): 1670.
16. Kim JE, Park H, Jeong MJ, Kang TC. Epigallocatechin-3-gallate and PEDF 335 peptide, 67LR activators, attenuate vasogenic edema, and astroglial degeneration following status epilepticus. Antioxidants (Basel), 2020, 9(9): 854.
17. Tower J. Programmed cell death in aging. Ageing Res Rev, 2015, 23（Pt A）: 90-100.
18. Erekat NS. Apoptosis and its therapeutic implications in neurodegenerative diseases. Clin Anat, 2022, 35(1): 65-78.
19. Sun X, Kong L, Zhou L. Protective effect of fructus corni polysaccharide on hippocampal tissues and its relevant mechanism in epileptic rats induced by lithium chloride-pilocarpine. Exp Ther Med, 2018, 16(1): 445-451.
20. Huang Q, Liu X, Wu Y, et al. P38 MAPK pathway mediates cognitive damage in pentylenetetrazole-induced epilepsy via apoptosis cascade. Epilepsy Res, 2017, 133: 89-92.
21. Wang L, Song LF, Chen XY, et al. MiR-181b inhibits P38/JNK signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid-induced epilepsy via targeting TLR4. CNS Neurosci Ther, 2019, 25(1): 112-122.
22. Pang W, Lu S, Zheng R, et al. Investigation into antiepileptic effect of ganoderic acid a and its mechanism in seizure rats induced by pentylenetetrazole. Biomed Res Int, 2022, 12: 5940372.
23. Huang R, Zhu Y, Lin L, et al. Solid lipid nanoparticles enhanced the neuroprotective role of curcumin against epilepsy through activation of Bcl-2 family and P38 MAPK pathways. ACS Chem Neurosci, 2020, 11(13): 1985-1995.
24. Chen Q, Lu H, Duan C, et al. PDCD4 simultaneously promotes microglia activation via PDCD4-MAPK-NF-κB positive loop and facilitates neuron apoptosis during neuroinflammation. Inflammation. 2022, 45（1）: 234-252.
25. Yang Z, Wang J, Yu C, et al. Inhibition of p38 MAPK signaling regulates the expression of eaat2 in the brains of epileptic rats. Front Neurol, 2018, 9: 925.
26. Yang X, Zhang H, Wu J, et al. Humanin attenuates NMDA-induced excitotoxicity by inhibiting ROS-dependent JNK/p38 MAPK pathway. Int J Mol Sci. 2018, 19（10）: 2982.
27. Boison D. Adenosine dysfunction in epilepsy. Glia, 2012, 60(8): 1234-1243.
28. Zhou X, Chen Q, Huang H, et al. Inhibition of p38 MAPK regulates epileptic severity by decreasing expression levels of A1R and ENT1. Mol Med Rep, 2020, 22(6): 5348-5357.

Journal of Epilepsy

Advances in the p38 Mitogen-activated protein kinase signalling pathway in epilepsy

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