Iranian Journal of Basic Medical Sciences

Iranian Journal of Basic Medical Sciences

Sappanone A suppresses CHOP expression and exerts neuroprotective effects in epilepsy

Articles in Press

Document Type : Original Article

Authors
Jie Fu
Jinglun Li
Xiu Chen
Department of Neurology, the Affiliated Hospital of Southwest Medical University. Taiping Street, Jiangyang District, Luzhou, 646000, China
10.22038/ijbms.2026.95426.20696
Abstract
Objective(s): Sappanone A (SA) is a compound derived from Caesalpinia sappan L that exhibits multiple biological effects, including anti-apoptotic, anti-inflammatory, and anti-oxidant activities. Because oxidative stress, cell apoptosis, and neuroinflammation are associated with the pathophysiology of epilepsy, we conducted this study to explore the role of SA in epilepsy.
Materials and Methods: We used SA to treat pentylenetetrazole (PTZ)-induced mice as well as HT22 hippocampal cells exposed to Mg²⁺-free solution. Seizure behavior in the mice was recorded. Nissl staining, TUNEL assay, and flow cytometry were used to evaluate neuronal damage and apoptosis. Moreover, we employed biochemical tests to assess inflammation and oxidative stress levels, and conducted quantitative reverse transcription polymerase chain reaction and western blot to detect CHOP expression.
Results: Pretreatments with SA (25 and 50 mg/kg) significantly prolonged seizure latency and reduced seizure duration in PTZ-induced epileptic mice (all P<0.001), whereas 10 mg/kg had no significant effects. At effective doses, SA also alleviated neuronal damage, reduced inflammation, and attenuated oxidative stress (all P<0.05). Furthermore, SA suppressed CHOP expression, and CHOP overexpression partially reversed SA’s protective effects (P<0.05).
Conclusion: Our findings suggest that SA pretreatment exerts neuroprotective effects against epilepsy, potentially through suppression of CHOP expression. However, the causal relationship between CHOP suppression and SA-mediated neuroprotection in epilepsy warrants further investigation.
Keywords
Apoptosis
CHOP
Epilepsy
Inflammation
Oxidative stress
Sappanone A
Subjects
1. Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol 2019; 15: 459-472.
2. Thijs RD, Surges R, O’Brien TJ, Sander JW. Epilepsy in adults. Lancet 2019; 393: 689-701.
3. Asadi-Pooya AA, Brigo F, Lattanzi S, Blumcke I. Adult epilepsy. Lancet 2023; 402: 412-424.
4. Keezer MR, Sisodiya SM, Sander JW. Comorbidities of epilepsy: Current concepts and future perspectives. Lancet Neurol 2016; 15: 106-115.
5. Jackson CF, Makin SM, Marson AG, Kerr M. Non-pharmacological interventions for people with epilepsy and intellectual disabilities. Cochrane Database Syst Rev 2015; 2015: CD005502.
6. Zhou Z, Wu Y, Hua W, Yan X, Li L, Zhu A, et al. Sappanone A ameliorates acetaminophen-induced acute liver injury in mice. Toxicology 2022; 480: 153336.
7. Fu J, Chen X, Li J, Peng L. Research advances of Sappanone A in inflammation-related diseases. Front Med (Lausanne) 2025; 12: 1569732.
8. Wang M, Chen Z, Yang L, Ding L. Sappanone A protects against inflammation, oxidative stress and apoptosis in cerebral ischemia-reperfusion injury by alleviating endoplasmic reticulum stress. Inflammation 2021; 44: 934-945.
9. Ren L, Chen Y, Xia J, Song X, Tao L, Li J, et al. Sappanone A promotes motor function recovery in spinal cord injury mice by inhibiting microglial M1 polarization via activation of the Keap1/Nrf2 pathway. FASEB J  2025; 39: e71298.
10. Ko DK, Brandizzi F. Dynamics of ER stress-induced gene regulation in plants. Nat Rev Genet 2024; 25: 513-525.
11. Shen W, Poliquin S, Macdonald RL, Dong M, Kang JQ. Endoplasmic reticulum stress increases inflammatory cytokines in an epilepsy mouse model Gabrg2(+/Q390X) knockin: A link between genetic and acquired epilepsy? Epilepsia 2020; 61: 2301-2312.  
12. Fu J, Tao T, Li Z, Chen Y, Li J, Peng L. The roles of ER stress in epilepsy: Molecular mechanisms and therapeutic implications. Biomed Pharmacother 2020; 131: 110658.
13. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol 2010; 8: e1000412.
14. Fu J, Peng L, Wang W, He H, Zeng S, Chen TC, et al. Sodium valproate reduces neuronal apoptosis in acute pentylenetetrzole-induced seizures via inhibiting ER stress. Neurochem Res 2019; 44: 2517-2526.
15. Liu X, Yu D, Wang T. Sappanone A attenuates allergic airway inflammation in ovalbumin-induced asthma. Int Arch Allergy Immunol 2016; 170: 180-186. 
16. Racine RJ. Modification of seizure activity by electrical stimulation. II. motor seizure. Electroencephalogr Clin Neurophysiol 1972; 32: 281-294.
17. Geronzi U, Lotti F, Grosso S. Oxidative stress in epilepsy. Expert Rev Neurother  2018; 18: 427-434.
18. Kamali AN, Zian Z, Bautista JM, Hamedifar H, Hossein-Khannazer N, Hosseinzadeh R, et al. The potential role of pro-inflammatory and anti-inflammatory cytokines in epilepsy pathogenesis. Endocr Metab Immune Disord Drug Targets 2021; 21: 1760-1774.
19. Zhang K, Yang Z, Yang Z, Du L, Zhou Y, Fu S, et al. Targeting microglial GLP1R in epilepsy: A novel approach to modulate neuroinflammation and neuronal apoptosis. Eur J Pharmacol 2024; 981: 176903.
20. Unal O, Erzurumlu Y, Asci H, Gunduru Acar B, Bedir M, Ozmen O. Nebivolol protects the liver against lipopolysaccharide-induced oxidative stress, inflammation, and endoplasmic reticulum-related apoptosis through Chop and Bip/GRP78 signaling. Naunyn Schmiedebergs Arch Pharmacol 2024; 397: 5899-5907. 
21. Wang Z, Chen Z, Wang X, Hu Y, Kong J, Lai J, et al. Sappanone a prevents diabetic kidney disease by inhibiting kidney inflammation and fibrosis via the NF-kappaB signaling pathway. Front Pharmacol 2022; 13: 953004. 
22. Zhang Z, Zhang N, Li M, Ma X, Qiu Y. Sappanone a alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis via activating the SIRT1/Nrf2 signaling pathway. Naunyn Schmiedebergs Arch Pharmacol 2024; 397: 8759-8770.
23. Shi X, Tao G, Ji L, Tian G. Sappanone A protects against myocardial ischemia reperfusion injury by modulation of Nrf2. Drug Des Devel Ther 2013; 14: 61-71. 
24. Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation. Exp Neurol 2013; 244: 11-21. 
25. Vezzani A, Lang B, Aronica E. Immunity and Inflammation in Epilepsy. Cold Spring Harb Perspect Med 2015; 6: a022699.
26. Paudel YN, Shaikh MF, Shah S, Kumari Y, Othman I. Role of inflammation in epilepsy and neurobehavioral comorbidities: Implication for therapy. Eur J Pharmacol 2018; 837: 145-155.
27. Liao LX, Song XM, Wang LC, Lv HN, Chen JF, Liu D, et al. Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy. Proc Natl Acad Sci U S A 2017; 114: E5986-E5994.
28. Sorriento D, De Luca N, Trimarco B, Iaccarino G. The antioxidant therapy: New insights in the treatment of hypertension. Front Physiol 2018; 9: 258. 
29. Aguiar CC, Almeida AB, Araújo PV, de Abreu RN, Chaves EM, do Vale OC, et al. Oxidative stress and epilepsy: Literature review. Oxid Med Cell Longev 2012; 2012: 795259.
30. Tsai HL, Chang CN, Chang SJ. The effects of pilocarpine-induced status epilepticus on oxidative stress/damage in developing animals. Brain Dev 2010; 32: 25-31.
31. Moldogazieva NT, Zavadskiy SP, Astakhov DV, Terentiev AA. Lipid peroxidation: Reactive carbonyl species, protein/DNA adducts, and signaling switches in oxidative stress and cancer. Biochem Biophys Res Commun 2023; 687: 149167.
32. Alvi AM, Al Kury LT, Alattar A, Ullah I, Muhammad AJ, Alshaman R, et al. Carveol attenuates seizure severity and neuroinflammation in pentylenetetrazole-kindled epileptic rats by regulating the Nrf2 signaling pathway. Oxid Med Cell Longev 2021; 2021: 9966663.
33. Sudha K, Rao AV, Rao A. Oxidative stress and antioxidants in epilepsy. Clin Chim Acta 2001; 303: 19-24. 
34. Nkwingwa BK, Wado EK, Foyet HS, Bouvourne P, Jugha VT, Mambou AHMY, et al. Ameliorative effects of Albizia adianthifolia aqueous extract against pentylenetetrazole-induced epilepsy and associated memory loss in mice: Role of GABAergic, antioxidant defense and anti-inflammatory systems. Biomed Pharmacother 2023; 165: 115093. 
35. Yang N, Guan QW, Chen FH, Xia QX, Yin XX, Zhou HH, et al. Antioxidants targeting mitochondrial oxidative stress: Promising neuroprotectants for epilepsy. Oxid Med Cell Longev 2020; 2020: 6687185. 
36. Shi X, Tao G, Ji L, Tian G. Sappanone A alleviates hypoxia/reoxygenation-induced cardiomyocytes injury through inhibition of mitochondrial apoptosis and activation of PI3K-Akt-Gsk-3beta pathway. Biosci Rep 2020; 40: BSR20192442.
37. Dong H, Dong B, Zhang N, Liu S, Zhao H. microRNA-182 negatively influences the neuroprotective effect of apelin against neuronal injury in epilepsy. Neuropsychiatr Dis Treat 2020; 16: 327-338.
38. Méndez-Armenta M, Nava-Ruíz C, Juárez-Rebollar D, Rodríguez-Martínez E, Gómez PY. Oxidative stress associated with neuronal apoptosis in experimental models of epilepsy. Oxid Med Cell Longev 2014; 2014: 293689.
39. Shi S, Feng X, Cao Z, Wang L, Sun M, Zhao Z, et al. Screening, analysis, and validation of endoplasmic reticulum stress-related DEGs in epilepsy. Cell Mol Neurobiol 2025; 45: 51.
40. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 2004; 11:381-389. 
41. Yingjiao Li, Cui Wang, Yajun Lian, Haifeng Zhang, Xianghe Meng, Mengyan Yu, et al. Role of the mitochondrial calcium uniporter in Mg2+-free-induced epileptic hippocampal neuronal apoptosis. Int J Neurosci 2020; 130: 1024-1032.
42. Nanchang Xie, Yingjiao Li, Cui Wang, Yajun Lian, Haifeng Zhang, Yujuan Li, et al. FAM134B attenuates seizure-induced apoptosis and endoplasmic reticulum stress in hippocampal neurons by promoting autophagy. Cell Mol Neurobiol 2020; 40: 1297-1305. 
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 22 September 2026