Research progress of translocator protein 18kDa in neuroinflammation induced by epilepsy_Journal of Epilepsy

Authors：

LIU Hongli ^1,2 , LIANG Bianbian ^1,2 , CHENG Xiaojing ² , ZHANG Tianli ² ,  ZHANG Xiaodong ² , GUO Jinkun ³

1. The Graduate School of Changzhi Medical College, Changzhi 046013, China;
2. Department of Neurology, Taiyuan Hospital of Peking University First Hospital, Taiyuan 030009, China;
3. Hunan University of Chinese Medicine, Changsha 410007, China;

Corresponding author：

ZHANG Xiaodong, Email: m13111062085@163.com

Keywords：

Epilepsy; Translocator protein 18kDa; Neuroinflammation; Gliocyte

DOI：

10.7507/2096-0247.202407004

Video：

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Currently, approximately one-third of epilepsy patients exhibit resistance to anti-seizure medications (Anti-seizure medications, ASMs), which can only alleviate symptoms, but cannot completely cure the condition. Consequently, the development of new ASMs from an understanding of epilepsy pathogenesis has emerged as an urgent social issue. The role of neuroinflammation in various neurological diseases has garnered significant attention as a popular research topic both domestically and internationally. Numerous studies have corroborated the involvement of neuroinflammation in the onset and progression of epilepsy. The biological target, Translocator protein 18 kDa (TSPO), is considered as a marker of neuroinflammation and is intricately involved in the entire neuroinflammatory response. Investigating the function of TSPO in epilepsy neuroinflammation can potentially uncover new treatment targets. At present, the exact mechanism of TSPO in epilepsy neuroinflammation remains unclear, thus necessitating a comprehensive summary and overview. This article reviewed the advancements made in TSPO research within the realm of neuroinflammation and its role in epileptic neuroinflammation, aiming to contribute novel insights for the identification of related targets and pathways for epilepsy treatment.

Citation： LIU Hongli, LIANG Bianbian, CHENG Xiaojing, ZHANG Tianli, ZHANG Xiaodong, GUO Jinkun. Research progress of translocator protein 18kDa in neuroinflammation induced by epilepsy. Journal of Epilepsy, 2024, 10(5): 435-439. doi: 10.7507/2096-0247.202407004 Copy

1.	Huang Y, Li Y, Pan H, et al. Global, regional, and national burden of neurological disorders in 204 countries and territories worldwide. J Glob Health, 2023, 13: 04160.
2.	Ding D, Zhou D, Sander JW, et al. Epilepsy in China: major progress in the past two decades. Lancet Neurol, 2021, 20(4): 316-326.
3.	Thijs RD, Surges R, O'Brien TJ, et al. Epilepsy in adults. Lancet, 2019, 393(10172): 689-701.
4.	Pong AW, Xu KJ, Klein P. Recent advances in pharmacotherapy for epilepsy. Curr Opin Neurol, 2023, 36(2): 77-85.
5.	Paudel YN, Shaikh MF, Shah S, et al. Role of inflammation in epilepsy and neurobehavioral comorbidities: implication for therapy. Eur J Pharmacol, 2018, 837: 145-155.
6.	Soltani Khaboushan A, Yazdanpanah N, Rezaei N. Neuroinflammation and proinflammatory cytokines in epileptogenesis. Mol Neurobiol, 2022, 59(3): 1724-1743.
7.	Zimmer LA, Ennis M, Shipley MT. Soman-induced seizures rapidly activate astrocytes and microglia in discrete brain regions. J Comp Neurol, 1997, 378(4): 482-492.
8.	Saraste M, Matilainen M, Vuorimaa A, et al. Association of serum neurofilament light with microglial activation in multiple sclerosis. J Neurol Neurosurg Psychiatry, 2023, 94(9): 698-706.
9.	Qin L, Xiao L, Zhu H, et al. Translocator protein (18 kDa) positron emission tomography imaging as a biomarker of neuroinflammation in epilepsy. Neurol Sci, 2024, Online ahead of print.
10.	Costa B, Cavallini C, Da Pozzo E, et al. The anxiolytic etifoxine binds to TSPO Ro5-4864 binding site with long residence time showing a high neurosteroidogenic activity. ACS Chem Neurosci, 2017, 8(7): 1448-1454.
11.	Rupprecht R, Papadopoulos V, Rammes G, et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov, 2010, 9(12): 971-988.
12.	García-García L, Shiha AA, Fernández de la Rosa R, et al. Metyrapone prevents brain damage induced by status epilepticus in the rat lithium-pilocarpine model. Neuropharmacology, 2017, 123: 261-273.
13.	Batarseh A, Papadopoulos V. Regulation of translocator protein 18 kDa (TSPO) expression in health and disease states. Mol Cell Endocrinol, 2010, 327(1-2): 1-12.
14.	Gatliff J, East D, Crosby J, et al. TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control. Autophagy, 2014, 10(12): 2279-2296.
15.	Bader S, Wolf L, Milenkovic VM, et al. Differential effects of TSPO ligands on mitochondrial function in mouse microglia cells. Psychoneuroendocrinology, 2019, 106: 65-76.
16.	Gavish M, Veenman L. Regulation of mitochondrial, cellular, and organismal functions by TSPO. Adv Pharmacol, 2018, 82: 103-136.
17.	Chung JY, Chen H, Midzak A, et al. Drug ligand-induced activation of translocator protein (TSPO) stimulates steroid production by aged brown Norway rat Leydig cells. Endocrinology, 2013, 154(6): 2156-2165.
18.	Weidner LD, Kannan P, Mitsios N, et al. The expression of inflammatory markers and their potential influence on efflux transporters in drug-resistant mesial temporal lobe epilepsy tissue. Epilepsia, 2018, 59(8): 1507-1517.
19.	Notter T, Schalbetter SM, Clifton NE, et al. Neuronal activity increases translocator protein (TSPO) levels. Mol Psychiatry, 2021, 26(6): 2025-2037.
20.	Barron AM, Higuchi M, Hattori S, et al. Regulation of anxiety and depression by mitochondrial translocator protein-mediated steroidogenesis: the role of neurons. Mol Neurobiol, 2021, 58(2): 550-563.
21.	Rupprecht R, Wetzel CH, Dorostkar M, et al. Translocator protein (18kDa) TSPO: a new diagnostic or therapeutic target for stress-related disorders? Mol Psychiatry, 2022, 27(7): 2918-2926.
22.	Dupont AC, Largeau B, Santiago Ribeiro MJ, et al. Translocator protein-18 kDa (TSPO) positron emission tomography (PET) imaging and its clinical impact in neurodegenerative diseases. Int J Mol Sci, 2017, 18(4): 18040785.
23.	Betlazar C, Middleton RJ, Banati R, et al. The Translocator protein (TSPO) in mitochondrial bioenergetics and immune processes. Cells, 2020, 9(2): 9020512.
24.	Garland EF, Dennett O, Lau LC, et al. The mitochondrial protein TSPO in Alzheimer's disease: relation to the severity of AD pathology and the neuroinflammatory environment. J Neuroinflammation, 2023, 20(1): 186-201.
25.	Conti E, Grana D, Angiulli F, et al. TSPO modulates oligomeric amyloid-β-induced monocyte chemotaxis: relevance for neuroinflammation in Alzheimer's disease. J Alzheimers Dis, 2023, 95(2): 549-559.
26.	Airas L, Yong VW. Microglia in multiple sclerosis - pathogenesis and imaging. Curr Opin Neurol, 2022, 35(3): 299-306.
27.	Dimitrova-Shumkovska J, Krstanoski L, Veenman L. Diagnostic and therapeutic potential of TSPO studies regarding neurodegenerative diseases, psychiatric disorders, alcohol use disorders, traumatic brain injury, and stroke: an update. Cells, 2020, 9(4): 9040870.
28.	Gallus M, Roll W, Dik A, et al. Translational imaging of TSPO reveals pronounced innate inflammation in human and murine CD8 T cell-mediated limbic encephalitis. Sci Adv, 2023, 9(23): 7595.
29.	Dickstein LP, Liow JS, Austermuehle A, et al. Neuroinflammation in neocortical epilepsy measured by PET imaging of translocator protein. Epilepsia, 2019, 60(6): 1248-1254.
30.	Nutma E, Ceyzériat K, Amor S, et al. Cellular sources of TSPO expression in healthy and diseased brain. Eur J Nucl Med Mol Imaging, 2021, 49(1): 146-163.
31.	Nozaki K, Ito H, Ohgidani M, et al. Antidepressant effect of the translocator protein antagonist ONO-2952 on mouse behaviors under chronic social defeat stress. Neuropharmacology, 2020, 162: 107835.
32.	Nguyen DL, Wimberley C, Truillet C, et al. Longitudinal positron emission tomography imaging of glial cell activation in a mouse model of mesial temporal lobe epilepsy: Toward identification of optimal treatment windows. Epilepsia, 2018, 59(6): 1234-1244.
33.	Bascuñana P, Gendron T, Sander K, et al. Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers. Epilepsia, 2019, 60(11): 2325-2333.
34.	Bertoglio D, Amhaoul H, Goossens J, et al. TSPO PET upregulation predicts epileptic phenotype at disease onset independently from chronic TSPO expression in a rat model of temporal lobe epilepsy. Neuroimage Clin, 2021, 31: 102701.
35.	Dedeurwaerdere S, Callaghan PD, Pham T, et al. PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy. EJNMMI Res, 2012, 2(1): 1-13.
36.	Kaneko KI, Irie S, Mawatari A, et al. [(18)F]DPA-714 PET imaging for the quantitative evaluation of early spatiotemporal changes of neuroinflammation in rat brain following status epilepticus. Eur J Nucl Med Mol Imaging, 2022, 49(7): 2265-2275.
37.	Gershen LD, Zanotti-Fregonara P, Dustin IH, et al. Neuroinflammation in temporal lobe epilepsy measured using positron emission tomographic imaging of translocator protein. JAMA Neurol, 2015, 72(8): 882-888.
38.	Maroso M, Balosso S, Ravizza T, et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med, 2010, 16(4): 413-419.
39.	Ravizza T, Vezzani A. Status epilepticus induces time-dependent neuronal and astrocytic expression of interleukin-1 receptor type I in the rat limbic system. Neuroscience, 2006, 137(1): 301-308.
40.	Aronica E, Ravizza T, Zurolo E, et al. Astrocyte immune responses in epilepsy. Glia, 2012, 60(8): 1258-1268.
41.	Zhou D, Ji L, Chen Y. TSPO Modulates IL-4-induced microglia/macrophage M2 polarization via PPAR-γ pathway. J Mol Neurosci, 2020, 70(4): 542-549.
42.	Abraham J, Fox PD, Condello C, et al. Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol Dis, 2012, 46(2): 425-430.
43.	Wolf BJ, Brackhan M, Bascuñana P, et al. TSPO PET identifies different anti-inflammatory minocycline treatment response in two rodent models of epileptogenesis. Neurotherapeutics, 2020, 17(3): 1228-1238.
44.	Bloms-Funke P, Bankstahl M, Bankstahl J, et al. The novel dual-mechanism Kv7 potassium channel/TSPO receptor activator GRT-X is more effective than the Kv7 channel opener retigabine in the 6-Hz refractory seizure mouse model. Neuropharmacology, 2022, 203: 108884.

1. Huang Y, Li Y, Pan H, et al. Global, regional, and national burden of neurological disorders in 204 countries and territories worldwide. J Glob Health, 2023, 13: 04160.
2. Ding D, Zhou D, Sander JW, et al. Epilepsy in China: major progress in the past two decades. Lancet Neurol, 2021, 20(4): 316-326.
3. Thijs RD, Surges R, O'Brien TJ, et al. Epilepsy in adults. Lancet, 2019, 393(10172): 689-701.
4. Pong AW, Xu KJ, Klein P. Recent advances in pharmacotherapy for epilepsy. Curr Opin Neurol, 2023, 36(2): 77-85.
5. Paudel YN, Shaikh MF, Shah S, et al. Role of inflammation in epilepsy and neurobehavioral comorbidities: implication for therapy. Eur J Pharmacol, 2018, 837: 145-155.
6. Soltani Khaboushan A, Yazdanpanah N, Rezaei N. Neuroinflammation and proinflammatory cytokines in epileptogenesis. Mol Neurobiol, 2022, 59(3): 1724-1743.
7. Zimmer LA, Ennis M, Shipley MT. Soman-induced seizures rapidly activate astrocytes and microglia in discrete brain regions. J Comp Neurol, 1997, 378(4): 482-492.
8. Saraste M, Matilainen M, Vuorimaa A, et al. Association of serum neurofilament light with microglial activation in multiple sclerosis. J Neurol Neurosurg Psychiatry, 2023, 94(9): 698-706.
9. Qin L, Xiao L, Zhu H, et al. Translocator protein (18 kDa) positron emission tomography imaging as a biomarker of neuroinflammation in epilepsy. Neurol Sci, 2024, Online ahead of print.
10. Costa B, Cavallini C, Da Pozzo E, et al. The anxiolytic etifoxine binds to TSPO Ro5-4864 binding site with long residence time showing a high neurosteroidogenic activity. ACS Chem Neurosci, 2017, 8(7): 1448-1454.
11. Rupprecht R, Papadopoulos V, Rammes G, et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov, 2010, 9(12): 971-988.
12. García-García L, Shiha AA, Fernández de la Rosa R, et al. Metyrapone prevents brain damage induced by status epilepticus in the rat lithium-pilocarpine model. Neuropharmacology, 2017, 123: 261-273.
13. Batarseh A, Papadopoulos V. Regulation of translocator protein 18 kDa (TSPO) expression in health and disease states. Mol Cell Endocrinol, 2010, 327(1-2): 1-12.
14. Gatliff J, East D, Crosby J, et al. TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control. Autophagy, 2014, 10(12): 2279-2296.
15. Bader S, Wolf L, Milenkovic VM, et al. Differential effects of TSPO ligands on mitochondrial function in mouse microglia cells. Psychoneuroendocrinology, 2019, 106: 65-76.
16. Gavish M, Veenman L. Regulation of mitochondrial, cellular, and organismal functions by TSPO. Adv Pharmacol, 2018, 82: 103-136.
17. Chung JY, Chen H, Midzak A, et al. Drug ligand-induced activation of translocator protein (TSPO) stimulates steroid production by aged brown Norway rat Leydig cells. Endocrinology, 2013, 154(6): 2156-2165.
18. Weidner LD, Kannan P, Mitsios N, et al. The expression of inflammatory markers and their potential influence on efflux transporters in drug-resistant mesial temporal lobe epilepsy tissue. Epilepsia, 2018, 59(8): 1507-1517.
19. Notter T, Schalbetter SM, Clifton NE, et al. Neuronal activity increases translocator protein (TSPO) levels. Mol Psychiatry, 2021, 26(6): 2025-2037.
20. Barron AM, Higuchi M, Hattori S, et al. Regulation of anxiety and depression by mitochondrial translocator protein-mediated steroidogenesis: the role of neurons. Mol Neurobiol, 2021, 58(2): 550-563.
21. Rupprecht R, Wetzel CH, Dorostkar M, et al. Translocator protein (18kDa) TSPO: a new diagnostic or therapeutic target for stress-related disorders? Mol Psychiatry, 2022, 27(7): 2918-2926.
22. Dupont AC, Largeau B, Santiago Ribeiro MJ, et al. Translocator protein-18 kDa (TSPO) positron emission tomography (PET) imaging and its clinical impact in neurodegenerative diseases. Int J Mol Sci, 2017, 18(4): 18040785.
23. Betlazar C, Middleton RJ, Banati R, et al. The Translocator protein (TSPO) in mitochondrial bioenergetics and immune processes. Cells, 2020, 9(2): 9020512.
24. Garland EF, Dennett O, Lau LC, et al. The mitochondrial protein TSPO in Alzheimer's disease: relation to the severity of AD pathology and the neuroinflammatory environment. J Neuroinflammation, 2023, 20(1): 186-201.
25. Conti E, Grana D, Angiulli F, et al. TSPO modulates oligomeric amyloid-β-induced monocyte chemotaxis: relevance for neuroinflammation in Alzheimer's disease. J Alzheimers Dis, 2023, 95(2): 549-559.
26. Airas L, Yong VW. Microglia in multiple sclerosis - pathogenesis and imaging. Curr Opin Neurol, 2022, 35(3): 299-306.
27. Dimitrova-Shumkovska J, Krstanoski L, Veenman L. Diagnostic and therapeutic potential of TSPO studies regarding neurodegenerative diseases, psychiatric disorders, alcohol use disorders, traumatic brain injury, and stroke: an update. Cells, 2020, 9(4): 9040870.
28. Gallus M, Roll W, Dik A, et al. Translational imaging of TSPO reveals pronounced innate inflammation in human and murine CD8 T cell-mediated limbic encephalitis. Sci Adv, 2023, 9(23): 7595.
29. Dickstein LP, Liow JS, Austermuehle A, et al. Neuroinflammation in neocortical epilepsy measured by PET imaging of translocator protein. Epilepsia, 2019, 60(6): 1248-1254.
30. Nutma E, Ceyzériat K, Amor S, et al. Cellular sources of TSPO expression in healthy and diseased brain. Eur J Nucl Med Mol Imaging, 2021, 49(1): 146-163.
31. Nozaki K, Ito H, Ohgidani M, et al. Antidepressant effect of the translocator protein antagonist ONO-2952 on mouse behaviors under chronic social defeat stress. Neuropharmacology, 2020, 162: 107835.
32. Nguyen DL, Wimberley C, Truillet C, et al. Longitudinal positron emission tomography imaging of glial cell activation in a mouse model of mesial temporal lobe epilepsy: Toward identification of optimal treatment windows. Epilepsia, 2018, 59(6): 1234-1244.
33. Bascuñana P, Gendron T, Sander K, et al. Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers. Epilepsia, 2019, 60(11): 2325-2333.
34. Bertoglio D, Amhaoul H, Goossens J, et al. TSPO PET upregulation predicts epileptic phenotype at disease onset independently from chronic TSPO expression in a rat model of temporal lobe epilepsy. Neuroimage Clin, 2021, 31: 102701.
35. Dedeurwaerdere S, Callaghan PD, Pham T, et al. PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy. EJNMMI Res, 2012, 2(1): 1-13.
36. Kaneko KI, Irie S, Mawatari A, et al. [(18)F]DPA-714 PET imaging for the quantitative evaluation of early spatiotemporal changes of neuroinflammation in rat brain following status epilepticus. Eur J Nucl Med Mol Imaging, 2022, 49(7): 2265-2275.
37. Gershen LD, Zanotti-Fregonara P, Dustin IH, et al. Neuroinflammation in temporal lobe epilepsy measured using positron emission tomographic imaging of translocator protein. JAMA Neurol, 2015, 72(8): 882-888.
38. Maroso M, Balosso S, Ravizza T, et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med, 2010, 16(4): 413-419.
39. Ravizza T, Vezzani A. Status epilepticus induces time-dependent neuronal and astrocytic expression of interleukin-1 receptor type I in the rat limbic system. Neuroscience, 2006, 137(1): 301-308.
40. Aronica E, Ravizza T, Zurolo E, et al. Astrocyte immune responses in epilepsy. Glia, 2012, 60(8): 1258-1268.
41. Zhou D, Ji L, Chen Y. TSPO Modulates IL-4-induced microglia/macrophage M2 polarization via PPAR-γ pathway. J Mol Neurosci, 2020, 70(4): 542-549.
42. Abraham J, Fox PD, Condello C, et al. Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol Dis, 2012, 46(2): 425-430.
43. Wolf BJ, Brackhan M, Bascuñana P, et al. TSPO PET identifies different anti-inflammatory minocycline treatment response in two rodent models of epileptogenesis. Neurotherapeutics, 2020, 17(3): 1228-1238.
44. Bloms-Funke P, Bankstahl M, Bankstahl J, et al. The novel dual-mechanism Kv7 potassium channel/TSPO receptor activator GRT-X is more effective than the Kv7 channel opener retigabine in the 6-Hz refractory seizure mouse model. Neuropharmacology, 2022, 203: 108884.

Journal of Epilepsy

Research progress of translocator protein 18kDa in neuroinflammation induced by epilepsy

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