Traditional Chinese medicines derived natural inhibitors of ferroptosis on ischemic stroke

Abstract

Ischemic stroke (IS) is a globally prevalent cerebrovascular disorder resulting from cerebral vessel occlusion, leading to significant morbidity and mortality. The intricate pathological mechanisms underlying IS complicate the development of effective therapeutic interventions. Ferroptosis, a form of programmed cell death (PCD) characterized by iron overload and accumulation of lipid peroxidation products, has been increasingly recognized as a key contributor to IS pathology. Traditional Chinese medicines (TCMs) have long been utilized in the management of IS, prompting extensive research into their potential as sources of natural ferroptosis inhibitors. This review investigates the critical role of ferroptosis in IS and provides a comprehensive analysis of current research on natural ferroptosis inhibitors identified in TCMs, aiming to lay a theoretical groundwork for the development of innovative anti-IS therapies.

Keywords

Ischemic stroke / Traditional Chinese medicines / Natural inhibitors / Ferroptosis

References

[1] Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics-2023 update: a report from the American Heart Association[J]. Circulation, 2023, 147(8): e93-e621.

[2] Feigin VL, Brainin M, Norrving B, et al. World Stroke Organization (WSO): global stroke fact sheet 2022[J]. Int J Stroke, 2022, 17(1): 18-29.

[3] Mathias K, Machado RS, Stork S, et al. Blood-brain barrier permeability in the ischemic stroke: an update[J]. Microvasc Res, 2023, 151: 104621.

[4] Renú A, Blasco J, Millán M, et al. The chemical optimization of cerebral embolectomy trial: study protocol[J]. Int J Stroke, 2021, 16(1): 110-116.

[5] Liu A, Hu J, Yeh TS, et al. Neuroprotective strategies for stroke by natural products: advances and perspectives[J]. Curr Neuropharmacol, 2023, 21(11): 2283-2309.

[6] Barnes EC, Kumar R, Davis RA. The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery[J]. Nat Prod Rep, 2016, 33(3): 372-381.

[7] Khanam A, Ahmad S, Husain A, et al. Glycation and antioxidants: hand in the glove of antiglycation and natural antioxidants[J]. Curr Protein Pept Sci, 2020, 21(9): 899-915.

[8] Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072.

[9] Ryan SK, Ugalde CL, Rolland AS, et al. Therapeutic inhibition of ferroptosis in neurodegenerative disease[J]. Trends Pharmacol Sci, 2023, 44(10): 674-688.

[10] Zille M, Karuppagounder SS, Chen Y, et al. Neuronal death after hemorrhagic strokein vitro and in vivo shares features of ferroptosis and necroptosis[J]. Stroke, 2017, 48(4): 1033-1043.

[11] Chen G, Li C, Zhang L, et al. Hydroxysafflor yellow A and anhydrosafflor yellow B alleviate ferroptosis and parthanatos in PC12 cells injured by OGD/R[J]. Free Radic Biol Med, 2022, 179: 1-10.

[12] Zhang Y, Lu X, Tai B, et al. Ferroptosis and its multifaceted roles in cerebral stroke[J]. Front Cell Neurosci, 2021, 15: 615372.

[13] Katsarou A, Pantopoulos K. Basics and principles of cellular and systemic iron homeostasis[J]. Mol Aspects Med, 2020, 75: 100866.

[14] Kawabata H. Transferrin and transferrin receptors update[J]. Free Radic Biol Med, 2019, 133: 46-54.

[15] Xie Y, Hou W, Song X, et al. Ferroptosis: process and function[J]. Cell Death Differ, 2016, 23(3): 369-379.

[16] Chung WS, Allen NJ, Eroglu C. Astrocytes control synapse formation, function, and elimination[J]. Cold Spring Harb Perspect Biol, 2015, 7(9): a020370.

[17] Liebner S, Dijkhuizen RM, Reiss Y, et al. Functional morphology of the blood-brain barrier in health and disease[J]. Acta Neuropathol, 2018, 135(3): 311-336.

[18] Wu Q, Wei C, Guo S, et al. Acute iron overload aggravates blood-brain barrier disruption and hemorrhagic transformation after transient focal ischemia in rats with hyperglycemia[J]. IBRO Neurosci Rep, 2022, 13: 87-95.

[19] Liu C, Tian Q, Wang J, et al. Blocking P2RX7 attenuates ferroptosis in endothelium and reduces HG-induced hemorrhagic transformation after MCAO by inhibiting ERK1/2 and P53 Signaling pathways[J]. Mol Neurobiol, 2023, 60(2): 460-479.

[20] Kim HW, Shin JA, Kim HJ, et al. Enhanced repair processes and iron uptake by ischemic preconditioning in the brain during the recovery phase after ischemic stroke[J]. Brain Res, 2021, 1750: 147172.

[21] Zheng H, Guo X, Kang S, et al. Cdh5-mediated Fpn1 deletion exerts neuroprotective effects during the acute phase and inhibitory effects during the recovery phase of ischemic stroke[J]. Cell Death Dis, 2023, 14(2): 161.

[22] Xin S, Schick JA. PUFAs dictate the balance of power in ferroptosis[J]. Cell Calcium, 2023, 110: 102703.

[23] Stockwell B. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications[J]. Cell, 2022, 185(14): 2401-2421.

[24] Hassannia B, Vandenabeele P, Vanden BT. Targeting ferroptosis to iron out cancer[J]. Cancer Cell, 2019, 35(6): 830-849.

[25] Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition[J]. Nat Chem Biol, 2017, 13(1): 91-98.

[26] Kagan VE, Mao G, Qu F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis[J]. Nat Chem Biol, 2017, 13(1): 81-90.

[27] Wu H, Liu H, Zuo F, et al. Adenoviruses-mediated RNA interference targeting cytosolic phospholipase A2α attenuates focal ischemic brain damage in mice[J]. Mol Med Rep, 2018, 17(4): 5601-5610.

[28] Chen J, Yang L, Geng L, et al. Inhibition of Acyl-CoA synthetase long-chain family member 4 facilitates neurological recovery after stroke by regulation ferroptosis[J]. Front Cell Neurosci, 2021, 15: 632354.

[29] Cui Y, Zhang Y, Zhao X, et al. ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation[J]. Brain Behav Immun, 2021, 93: 312-321.

[30] Tuo QZ, Liu Y, Xiang Z, et al. Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion[J]. Signal Transduct Target Ther, 2022, 7(1): 59.

[31] Yigitkanli K, Zheng Y, Pekcec A, et al. Increased 12/15-lipoxygenase leads to widespread brain injury following global cerebral ischemia[J]. Transl Stroke Res, 2017, 8(2): 194-202.

[32] Chen X, Yu C, Kang R, et al. Cellular degradation systems in ferroptosis[J]. Cell Death Differ, 2021, 28(4): 1135-1148.

[33] Rochette L, Dogon G, Rigal E, et al. Lipid peroxidation and iron metabolism: two corner stones in the homeostasis control of ferroptosis[J]. Int J Mol Sci, 2022, 24(1): 449.

[34] Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4[J]. Free Radic Biol Med, 2020, 152: 175-185.

[35] Tian HY, Huang BY, Nie HF, et al. The interplay between mitochondrial dysfunction and ferroptosis during ischemia-associated central nervous system diseases[J]. Brain Sci, 2023, 13(10): 1367.

[36] Xu S, Yang J, Wan H, et al. Combination of Radix Astragali and safflower promotes angiogenesis in rats with ischemic stroke via silencing PTGS2[J]. Int J Mol Sci, 2023, 24(3): 2126.

[37] Deng M, Chen H, Long J, et al. Calycosin: a review of its pharmacological effects and application prospects[J]. Expert Rev Anti Infect Ther, 2021, 19(7): 911-925.

[38] Liu H, Zhao Z, Yan M, et al. Calycosin decreases cerebral ischemia/reperfusion injury by suppressing ACSL4-dependent ferroptosis[J]. Arch Biochem Biophys, 2023, 734: 109488.

[39] Pang DR, Su XQ, Zhu ZX, et al. Flavonoid dimers from the total phenolic extract of Chinese dragon’s blood, the red resin of Dracaena cochinchinensis[J]. Fitoterapia, 2016, 115: 135-141.

[40] Sun J, Chen X, Wang Y, et al. Neuroprotective effects of Longxue Tongluo Capsule on ischemic stroke rats revealed by LC-MS/MS-based metabolomics approach[J]. Chin Herb Med, 2023, 15(3): 430-438.

[41] Liu Y, Mi Y, Wang Y, et al. Loureirin C inhibits ferroptosis after cerebral ischemia reperfusion through regulation of the Nrf2 pathway in mice[J]. Phytomedicine, 2023, 113: 154729.

[42] Ouyang Z, Zhao M, Tang J, et al. In vivo pharmacokinetic comparisons of ferulic acid and puerarin after oral administration of monomer, medicinal substance aqueous extract and Nao-De-Sheng to rats[J]. Pharmacogn Mag, 2012, 8(32): 256-262.

[43] Hu ZY, Yang ZB, Zhang R, et al. The protective effect of vitexin compound B-1 on rat cerebral I/R injury through a mechanism involving modulation of miR-92b/NOX4 pathway[J]. CNS Neurol Disord Drug Targets, 2023, 22(1): 137-147.

[44] He M, Min JW, Kong WL, et al. A review on the pharmacological effects of vitexin and isovitexin[J]. Fitoterapia, 2016, 115: 74-85.

[45] Guo L, Shi L. Vitexin improves cerebral ischemia-reperfusion injury by attenuating oxidative injury and ferroptosis via Keap1/Nrf2/HO-1signaling[J]. Neurochem Res, 2023, 48(3): 980-995.

[46] Zhang Q, Fu X, Wang J, et al. Treatment effects of ischemic stroke by berberine, baicalin, and jasminoidin from Huang-Lian-Jie-Du-Decoction (HLJDD) explored by an integrated metabolomics approach[J]. Oxid Med Cell Longev, 2017, 2017: 9848594.

[47] Zhu H, Wang Z, Xing Y, et al. Baicalin reduces the permeability of the blood-brain barrier during hypoxia in vitro by increasing the expression of tight junction proteins in brain microvascular endothelial cells[J]. J Ethnopharmacol, 2012, 141(2): 714-720.

[48] Li M, Meng Z, Yu S, et al. Baicalein ameliorates cerebral ischemia-reperfusion injury by inhibiting ferroptosis via regulating GPX4/ACSL4/ACSL3 axis[J]. Chem Biol Interact, 2022, 366: 110137.

[49] Zhang J, Chen Y, Luo H, et al. Recent update on the pharmacological effects and mechanisms of dihydromyricetin[J]. Front Pharmacol, 2018, 9: 1204.

[50] Xie J, Zhang T, Li P, et al. Dihydromyricetin attenuates cerebral ischemia reperfusion injury by inhibiting SPHK1/mTOR signaling and targeting ferroptosis[J]. Drug Des Devel Ther, 2022, 16: 3071-3085.

[51] Zhang F, Yan Y, Zhang LM, et al. Pharmacological activities and therapeutic potential of galangin, a promising natural flavone, in age-related diseases[J]. Phytomedicine, 2023, 120: 155061.

[52] Guan X, Li Z, Zhu S, et al. Galangin attenuated cerebral ischemia-reperfusion injury by inhibition of ferroptosis through activating the SLC7A11/GPX4 axis in gerbils[J]. Life Sci, 2021, 264: 118660.

[53] Yu L, Wan H, Jin W, et al. Protective effects of effective ingredients of Danshen (Radix Salviae Miltiorrhizae) and Honghua (Flos Carthami) compatibility after rat hippocampal neurons induced by hypoxia injury[J]. J Tradit Chin Med, 2018, 38(5): 685-697.

[54] Guo H, Zhu L, Tang P, et al. Carthamin yellow improves cerebral ischemia-reperfusion injury by attenuating inflammation and ferroptosis in rats[J]. Int J Mol Med, 2021, 47(4): 52.

[55] Wang J, Mao J, Wang R, et al. Kaempferol protects against cerebral ischemia reperfusion injury through intervening oxidative and inflammatory stress induced apoptosis[J]. Front Pharmacol, 2020, 11: 424.

[56] Yuan Y, Zhai Y, Chen J, et al. Kaempferol ameliorates oxygen-glucose deprivation/reoxygenation-induced neuronal ferroptosis by activating Nrf2/SLC7A11/GPX4 axis[J]. Biomolecules, 2021, 11(7): 932.

[57] Shi B, Liu J, Zhang Q, et al. Effect of co-administration of Acori Tatarinowii Rhizoma volatile oil on pharmacokinetic fate of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat[J]. J Sep Sci, 2020, 43(12): 2349-2362.

[58] Chen W, Xu B, Xiao A, et al. TRPM7 inhibitor carvacrol protects brain from neonatal hypoxic-ischemic injury[J]. Mol Brain, 2015, 8: 11.

[59] Li Z, Hua C, Pan X, et al. Carvacrol exerts neuroprotective effects via suppression of the inflammatory response in middle cerebral artery occlusion rats[J]. Inflammation, 2016, 39(4): 1566-1572.

[60] Ahmad S, Nabi R, Alvi SS, et al. Carvacrol protects against carbonyl osmolyte-induced structural modifications and aggregation to serum albumin: insights from physicochemical and molecular interaction studies[J]. Int J Biol Macromol, 2022, 213: 663-674.

[61] Guan X, Li X, Yang X, et al. The neuroprotective effects of carvacrol on ischemia/reperfusion-induced hippocampal neuronal impairment by ferroptosis mitigation[J]. Life Sci, 2019, 235: 116795.

[62] Kadri S, El AM, Limam F, et al. Preventive and curative effects of grape seed powder on stroke using in vitro and in vivo models of cerebral ischemia/reperfusion[J]. Biomed Pharmacother, 2020, 125: 109990.

[63] Yu P, Wang L, Tang F, et al. Resveratrol-mediated neurorestoration after cerebral ischemic injury-sonic hedgehog signaling pathway[J]. Life Sci, 2021, 280: 119715.

[64] Zhu H, Huang J, Chen Y, et al. Resveratrol pretreatment protects neurons from oxygen-glucose deprivation/reoxygenation and ischemic injury through inhibiting ferroptosis[J]. Biosci Biotechnol Biochem, 2022, 86(6): 704-716.

[65] Cao Z, Chen L, Liu Y, et al. Oxysophoridine rescues spinal cord injury via anti-inflammatory, anti-oxidative stress and anti-apoptosis effects[J]. Mol Med Rep, 2018, 17(2): 2523-2528.

[66] Zhao J, Ma M, Li L, et al. Oxysophoridine protects against cerebral ischemia/reperfusion injury via inhibition of TLR4/p38MAPK-mediated ferroptosis[J]. Mol Med Rep, 2023, 27(2): 44.

[67] Kim SH, Yook TH, Kim JU. Rehmanniae Radix, an effective treatment for patients with various inflammatory and metabolic diseases: results from a review of Korean publications[J]. J Pharmacopuncture, 2017, 20(2): 81-88.

[68] Sun M, Shen X, Ma Y. Rehmannioside A attenuates cognitive deficits in rats with vascular dementia (VD) through suppressing oxidative stress, inflammation and apoptosis[J]. Biomed Pharmacother, 2019, 120: 109492.

[69] Fu C, Wu Y, Liu S, et al. Rehmannioside A improves cognitive impairment and alleviates ferroptosis via activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway after ischemia[J]. J Ethnopharmacol, 2022, 289: 115021.

[70] Kishi C, Higashihara M, Takemoto Y, et al. Inhaled volatile β-caryophyllene is incorporated into the aortic wall and attenuates nicotine-induced aorta degeneration via a CB2 receptor-dependent pathway[J]. Biomed Pharmacother, 2022, 153: 113423.

[71] Hu Q, Zuo T, Deng L, et al. β-Caryophyllene suppresses ferroptosis induced by cerebral ischemia reperfusion via activation of the NRF2/HO-1 signaling pathway in MCAO/R rats[J]. Phytomedicine, 2022, 102: 154112.

[72] Xia D, Li W, Tang C, et al. Astragaloside IV, as a potential anticancer agent[J]. Front Pharmacol, 2023, 14: 1065505.

[73] Yao M, Zhang L, Wang L. Astragaloside IV: a promising natural neuroprotective agent for neurological disorders[J]. Biomed Pharmacother, 2023, 159: 114229.

[74] Wang L, Liu C, Wang L, et al. Astragaloside IV mitigates cerebral ischaemia-reperfusion injury via inhibition of P62/Keap1/Nrf2 pathway-mediated ferroptosis[J]. Eur J Pharmacol, 2023, 944: 175516.

[75] Pang HQ, Guo JX, Yang Y, et al. Elucidating the chemical interaction effects of herb pair Danshen-Chuanxiong and its anti-ischemic stroke activities evaluation[J]. J Ethnopharmacol, 2023, 318(Pt B): 117058.

[76] Wu C, Duan F, Yang R, et al. 15,16-Dihydrotanshinone I protects against ischemic stroke by inhibiting ferroptosis via the activation of nuclear factor erythroid 2-related factor 2[J]. Phytomedicine, 2023, 114: 154790.

[77] Li Q, Shen L, Liang P, et al. DL-3-n-Butylphthalide protects against memory deficits in vascular dementia rats by attenuating pyroptosis via TLR-4/NF-κB signaling pathway[J]. Neuropsychobiology, 2023, 82(3): 150-157.

[78] Xu S, Li X, Li Y, et al. Neuroprotective effect of DL-3-n-butylphthalide against ischemia-reperfusion injury is mediated by ferroptosis regulation the SLC7A11/GSH/GPX4 pathway and the attenuation of blood-brain barrier disruption[J]. Front Aging Neurosci, 2023, 15: 1028178.

[79] Sharifi-Razavi A, Karimi N, Jafarpour H. Evaluation of selenium supplementation in acute ischemic stroke outcome: an outcome assessor blind, randomized, placebo-controlled, feasibility study[J]. Neurol India, 2022, 70(1): 87-93.

[80] Tuo QZ, Masaldan S, Southon A, et al. Characterization of selenium compounds for anti-ferroptotic activity in neuronal cells and after cerebral ischemia-reperfusion injury[J]. Neurotherapeutics, 2021, 18(4): 2682-2691.

[81] Zhuo Z, Wang H, Zhang S, et al. Selenium supplementation provides potent neuroprotection following cerebral ischemia in mice[J]. J Cereb Blood Flow Metab, 2023, 43(7): 1060-1076.

[82] Han J, Zhang JZ, Zhong ZF, et al. Gualou Guizhi Decoction promotes neurological functional recovery and neurogenesis following focal cerebral ischemia/reperfusion[J]. Neural Regen Res, 2018, 13(8): 1408-1416.

[83] Gupta S, Gupta YK. Combination of Zizyphus jujuba and silymarin showed better neuroprotective effect as compared to single agent in MCAo-induced focal cerebral ischemia in rats[J]. J Ethnopharmacol, 2017, 197: 118-127.

[84] Kolnik S, Corry K, Hildahl K, et al. Vitamin E decreases cytotoxicity and mitigates inflammatory and oxidative stress responses in a ferret organotypic brain slice model of neonatal hypoxia-ischemia[J]. Dev Neurosci, 2022, 44(4-5): 233-245.

[85] Rink C, Christoforidis G, Khanna S, et al. Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis[J]. J Cereb Blood Flow Metab, 2011, 31(11): 2218-2230.

[86] Park HA, Kubicki N, Gnyawali S, et al. Natural vitamin E α-tocotrienol protects against ischemic stroke by induction of multidrug resistance-associated protein 1[J]. Stroke, 2011, 42(8): 2308-2314.

[87] Fan X, Shen W, Wang L, et al. Efficacy and safety of DL-3-n-butylphthalide in the treatment of poststroke cognitive impairment: a systematic review and meta-analysis[J]. Front Pharmacol, 2021, 12: 810297.

[88] Gao ZP, Zheng SZ, Kamei KI, et al. Recent progress in cancer therapy based on the combination of ferroptosis with photodynamic therapy[J]. Acta Mater Med, 2022, 1(4): 411-426.

[89] Dong X, Tu J, Pang B, et al. The “Top 50 High Impact Researches of Traditional Medicine” published in 2021 [J]. Acupunct Herbal Med, 2023, 3( 4): 232-243.

Funding

Natural Science Foundation of Ningxia Province(2022AAC02029)

Open Project of Ningxia Key Laboratory of Pharmaceuticals Creation and Generic Medicine Research(XZ2020010)

Key Research and Development Plan of Ningxia Hui Autonomous Region(2022BFH02012)