<em>Para</em>‑hydroxybenzaldehyde against transient focal cerebral ischemia in rats via mitochondrial preservation

Xiao,Tian; Yang,Liping; Chen,Pu; Duan,Xiaohua

doi:10.3892/etm.2022.11652

Para‑hydroxybenzaldehyde against transient focal cerebral ischemia in rats via mitochondrial preservation

Authors:
- Tian Xiao
- Liping Yang
- Pu Chen
- Xiaohua Duan
View Affiliations

Affiliations: Yunnan Key Laboratory of Dai and Yi Medicines, Yunnan University of Chinese Medicine, Kunming, Yunnan 650500, P.R. China
Published online on: October 11, 2022 https://doi.org/10.3892/etm.2022.11652
Article Number: 716
Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Gastrodia elata (GE) Blume has been widely used for thousands of years to treat various central and peripheral nervous disorders. P‑hydroxybenzaldehyde (PHBA) is a chemical component of GE. However, its role and mechanism in transient focal cerebral ischemia remain unclear. The present study aimed to investigate the protective effect of PHBA on middle cerebral artery occlusion (MCAO) rats. A total of 56 Sprague‑Dawley male rats were randomly divided into control, model, PHBA‑high dose (PHBA‑H) and PHBA‑low dose (PHBA‑L) groups. The MCAO injury model was replicated in all rats except for the control group. In the control group, only the right common carotid artery was isolated without embolization. After treatment with PHBA, the protective effects (neurological deficit score, cerebral index, weight and cerebral infarct) were analyzed. Western blotting was performed to estimate the protein levels of Bcl‑2, Bax and Caspase‑3. Apoptotic cells were detected using hematoxylin‑eosin staining and TUNEL immunofluorescence assay. Mitochondrial oxidative stress indicators, including reactive oxygen species (ROS), malondialdehyde (MDA) and total superoxide dismutase (T‑SOD), while dysfunction indicators, including mitochondrial permeability transition pore (MPTP), ATP and cytochrome C oxidase, were measured using commercial kits. The ultrastructure of mitochondria was observed under an electron microscope. Once the model was successful established, the rats in the MCAO group suffered neurological damage (P<0.001), increased cerebral index (P<0.001), decreased body weight (P<0.001) and had severe cerebral infarction (P<0.001). Moreover, the number of apoptotic cells and the levels of ROS (P<0.001) and MDA (P<0.05) in mitochondria and the protein levels of Bax (P<0.001) and cleaved caspase‑3 (P<0.001) were increased. The activities of T‑SOD (P<0.001) and cytochrome C oxidase (P<0.001) in the mitochondria, ATP content (P<0.05) and Bcl‑2 protein level (P<0.001) decreased, MPTP was stimulated to open and mitochondrial structures were damaged (P<0.001). PHBA treatment resulted in a decrease of the neurological deficit score (PHBA‑H 24 h, P<0.001; PHBA‑H 6 h and PHBA‑L 24 h, P<0.01; PHBA‑L 6 h, P<0.05), apoptotic cell number (P<0.001), mitochondrial ROS (P<0.001) and MPTP opening (P<0.001), Bax (P<0.01, P<0.001) and cleaved caspase‑3 protein expression (P<0.001) in rats. And the expression of Bcl‑2 protein (P<0.001) was increased. In addition, the cerebral index (P<0.05), weight loss (P<0.05), infarction rate (P<0.01) and MDA content (P<0.001) were decrease in the PHBA‑H group. The level of ATP (P<0.05) and cytochrome C oxidase (P<0.05) and T‑SOD activity (P<0.05) of PHBA‑H group rats increased, but no significant difference was observed in the PHBA‑L group. Overall, PHBA had a protective effect on transient focal cerebral ischemia in normal rats, regulated the expression of Bcl‑2, Bax and cleaved caspase‑3 proteins and improved the oxidative stress and dysfunction of mitochondria.

View Figures

View References

1	Wisen WP, Evans WR, Sure VN, Sperling JA, Sakamuri SS, Mostany R and Katakam PV: Nitric oxide synthase inhibitor is an effective therapy for ischemia-reperfusion injury in mice. FASEB J. 36 (Suppl 1)(R5443)2022.
2	Chen G, Shan X, Li L, Dong L, Huang G and Tao H: circHIPK3 regulates apoptosis and mitochondrial dysfunction induced by ischemic stroke in mice by sponging miR-148b-3p via CDK5R1/SIRT1. Exp Neurol. 355(114115)2022.PubMed/NCBI View Article : Google Scholar
3	Huang Y, Ye Z, Ma T, Li H, Zhao Y, Chen W, Wang Y, Yan X, Gao Y and Li Z: Carbon monoxide (CO) modulates hydrogen peroxide (H₂O₂)-mediated cellular dysfunction by targeting mitochondria in rabbit lens epithelial cells. Exp Eye Res. 169:68–78. 2018.PubMed/NCBI View Article : Google Scholar
4	Guan R, Zou W, Dai X, Yu X, Liu H, Chen Q and Teng W: Mitophagy, a potential therapeutic target for stroke. J Biomed Sci. 25(87)2018.PubMed/NCBI View Article : Google Scholar
5	Duan C, Kuang L, Hong C, Xiang X, Liu J, Li Q, Peng X, Zhou Y, Wang H, Liu L and Li T: Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2. Cell Death Dis. 12(1050)2021.PubMed/NCBI View Article : Google Scholar
6	Carinci M, Vezzani B, Patergnani S, Ludewig P, Lessmann K, Magnus T, Casetta I, Pugliatti M, Pinton P and Giorgi C: Different roles of mitochondria in cell death and inflammation: Focusing on mitochondrial quality control in ischemic stroke and reperfusion. Biomedicines. 9(169)2021.PubMed/NCBI View Article : Google Scholar
7	Lee HK, Jang JY, Yoo HS and Seong YH: Neuroprotective effect of 1,3-dipalmitoyl-2-oleoylglycerol derived from rice bran oil against cerebral ischemia-reperfusion injury in rats. Nutrients. 14(1380)2022.PubMed/NCBI View Article : Google Scholar
8	Pasala PK, Abbas Shaik R, Rudrapal M, Khan J, Alaidarous MA, Jagdish Khairnar S, Bendale AR, Naphade VD, Kumar Sahoo R, Zothantluanga JH and Walode SG: Cerebroprotective effect of Aloe Emodin: In silico and in vivo studies. Saudi J Biol Sci. 29:998–1005. 2022.PubMed/NCBI View Article : Google Scholar
9	Uzdensky AB: Apoptosis regulation in the penumbra after ischemic stroke: Expression of pro- and antiapoptotic proteins. Apoptosis. 24:687–702. 2019.PubMed/NCBI View Article : Google Scholar
10	Yan H, Huang W, Rao J and Yuan J: miR-21 regulates ischemic neuronal injury via the p53/Bcl-2/Bax signaling pathway. Aging (Albany NY). 13:22242–22255. 2021.PubMed/NCBI View Article : Google Scholar
11	Yang M, He Y, Deng S, Xiao L, Tian M, Xin Y, Lu C, Zhao F and Gong Y: Mitochondrial quality control: A pathophysiological mechanism and therapeutic target for stroke. Front Mol Neurosci. 14(786099)2022.PubMed/NCBI View Article : Google Scholar
12	Hu Q, Zuo T, Deng L, Chen S, Yu W, Liu S, Liu J, Wang X, Fan X and Dong Z: β-Caryophyllene suppresses ferroptosis induced by cerebral ischemia reperfusion via activation of the NRF2/HO-1 signaling pathway in MCAO/R rats. Phytomedicine. 102(154112)2022.PubMed/NCBI View Article : Google Scholar
13	Zhan HD, Zhou HY, Sui YP, Du XL, Wang WH, Dai L, Sui F, Huo HR and Jiang TL: The rhizome of Gastrodia elata blume-an ethnopharmacological review. J Ethnopharmacol. 189:361–385. 2016.PubMed/NCBI View Article : Google Scholar
14	Wang T, Chen H, Xia S, Chen X, Sun H and Xu Z: Ameliorative effect of parishin C against cerebral ischemia-induced brain tissue injury by reducing oxidative stress and inflammatory responses in rat model. Neuropsychiatr Dis Treat. 17:1811–1823. 2021.PubMed/NCBI View Article : Google Scholar
15	Zhang ZL, Gao YG, Zang P, Gu PP, Zhao Y, He ZM and Zhu HY: Research progress on mechanism of gastrodin and p-hydroxybenzyl alcohol on central nervous system. Zhongguo Zhong Yao Za Zhi. 45:312–320. 2020.PubMed/NCBI View Article : Google Scholar : (In Chinese).
16	Yang F, Li G, Lin B and Zhang K: Gastrodin suppresses pyroptosis and exerts neuroprotective effect in traumatic brain injury model by inhibiting NLRP3 inflammasome signaling pathway. J Integr Neurosci. 21(72)2022.PubMed/NCBI View Article : Google Scholar
17	Liu Y, Lu YY, Huang L, Shi L, Zheng ZY, Chen JN, Qu Y, Xiao HT, Luo HR and Wu GS: Para-hydroxybenzyl alcohol delays the progression of neurodegenerative diseases in models of caenorhabditis elegans through activating multiple cellular protective pathways. Oxid Med Cell Longev. 2022(8986287)2022.PubMed/NCBI View Article : Google Scholar
18	Gong X, Cheng J, Zhang K, Wang Y, Li S and Luo Y: Transcriptome sequencing reveals Gastrodia elata Blume could increase the cell viability of eNPCs under hypoxic condition by improving DNA damage repair ability. J Ethnopharmacol. 282(114646)2022.PubMed/NCBI View Article : Google Scholar
19	Duan X, Wang W, Liu X, Yan H, Dai R and Lin Q: Neuroprotective effect of ethyl acetate extract from Gastrodia elata against transient focal cerebral ischemia in rats induced by middle cerebral artery occlusion. J Tradit Chin Med. 35:671–678. 2015.PubMed/NCBI View Article : Google Scholar
20	Jiang G, Hu Y, Liu L, Cai J, Peng C and Li Q: Gastrodin protects against MPP(+)-induced oxidative stress by up regulates heme oxygenase-1 expression through p38 MAPK/Nrf2 pathway in human dopaminergic cells. Neurochem Int. 75:79–88. 2014.PubMed/NCBI View Article : Google Scholar
21	Luo L, Kim SW, Lee HK, Kim ID, Lee H and Lee JK: Anti-Zn²⁺-toxicity of 4-hydroxybenzyl alcohol in astrocytes and neurons contribute to a robust neuroprotective effects in the postischemic brain. Cell Mol Neurobiol. 38:615–626. 2018.PubMed/NCBI View Article : Google Scholar
22	Li X, Xiang B, Shen T, Xiao C, Dai R, He F and Lin Q: Anti-neuroinflammatory effect of 3,4-dihydroxybenzaldehyde in ischemic stroke. Int Immunopharmacol. 82(106353)2020.PubMed/NCBI View Article : Google Scholar : (Epub ahead of print).
23	Kim HJ, Hwang IK and Won MH: Vanillin, 4-hydroxybenzyl aldehyde and 4-hydroxybenzyl alcohol prevent hippocampal CA1 cell death following global ischemia. Brain Res. 1181:130–141. 2007.PubMed/NCBI View Article : Google Scholar
24	Wu J, Wu B, Tang C and Zhao J: Analytical techniques and pharmacokinetics of Gastrodia elata blume and its constituents. Molecules. 22(1137)2017.PubMed/NCBI View Article : Google Scholar
25	Liu CS, Liang X, Wei XH, Chen FL, Tang QF and Tan XM: Comparative pharmacokinetics of major bioactive components from Puerariae radix-gastrodiae rhizome extracts and their intestinal absorption in rats. J Chromatogr B Analyt Technol Biomed Life Sci. 1105:38–46. 2019.PubMed/NCBI View Article : Google Scholar
26	Loh YC, Oo CW, Tew WY, Wen X, Wei X and Yam MF: The predominance of endothelium-derived relaxing factors and beta-adrenergic receptor pathways in strong vasorelaxation induced by 4-hydroxybenzaldehyde in the rat aorta. Biomed Pharmacother. 150(112905)2022.PubMed/NCBI View Article : Google Scholar
27	Lee JY, Jang YW, Kang HS, Moon H, Sim SS and Kim CJ: Anti-inflammatory action of phenolic compounds from Gastrodia elata root. Arch Pharm Res. 29:849–858. 2006.PubMed/NCBI View Article : Google Scholar
28	Ha JH, Lee DU, Lee JT, Kim JS, Yong CS, Kim JA, Ha JS and Huh K: 4-Hydroxybenzaldehyde from Gastrodia elata B1. is active in the antioxidation and GABAergic neuromodulation of the rat brain. J Ethnopharmacol. 73:329–333. 2000.PubMed/NCBI View Article : Google Scholar
29	Feng J, Sun H, Xu Y, Yang Q and He F: Gastrointestinal absorption characteristics of p-hydroxybenzaldehyde, a constituent of Gastrodia elata. Pharmacology and Clinics of Chinese Materia Medica. 37:23–28. 2021.
30	Zhu YP, Li X, Du Y, Zhang L, Ran L and Zhou NN: Protective effect and mechanism of p-hydroxybenzaldehyde on blood-brain barrier. Zhongguo Zhong Yao Za Zhi. 43:1021–1027. 2018.PubMed/NCBI View Article : Google Scholar : (In Chinese).
31	Ha JH, Shin SM, Lee SK, Kim JS, Shin US, Huh K, Kim JA, Yong CS, Lee NJ and Lee DU: In vitro effects of hydroxybenzaldehydes from Gastrodia elata and their analogues on GABAergic neurotransmission, and a structure-activity correlation. Planta Med. 67:877–880. 2001.PubMed/NCBI View Article : Google Scholar
32	Gorsky A, Monsour M, Nguyen H, Castelli V, Lee JY and Borlongan CV: Metabolic switching of cultured mesenchymal stem cells creates super mitochondria in rescuing ischemic neurons. Neuromolecular Med: Jul 20, 2022 (Epub ahead of print).
33	Brenza TM, Ghaisas S, Ramirez JEV, Harischandra D, Anantharam V, Kalyanaraman B, Kanthasamy AG and Narasimhan B: Neuronal protection against oxidative insult by polyanhydride nanoparticle-based mitochondria-targeted antioxidant therapy. Nanomedicine. 13:809–820. 2017.PubMed/NCBI View Article : Google Scholar
34	Buchke S, Sharma M, Bora A, Relekar M, Bhanu P and Kumar J: Mitochondria-targeted, nanoparticle-based drug-delivery systems: Therapeutics for mitochondrial disorders. Life (Basel). 12(657)2022.PubMed/NCBI View Article : Google Scholar
35	Li N, Qin S, Xie L, Qin T, Yang Y, Fang W and Chen MH: Elevated serum potassium concentration alleviates cerebral ischemia-reperfusion injury via mitochondrial preservation. Cell Physiol Biochem. 48:1664–1674. 2018.PubMed/NCBI View Article : Google Scholar
36	Zhang M, Yang JK and Ma J: Regulation of the long noncoding RNA XIST on the inflammatory polarization of microglia in cerebral infarction. Exp Ther Med. 22(924)2021.PubMed/NCBI View Article : Google Scholar
37	Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL and Bartkowski H: Rat middle cerebral artery occlusion: Evaluation of the model and development of a neurologic examination. Stroke. 17:472–476. 1986.PubMed/NCBI View Article : Google Scholar
38	Tian J, Yao H, Liu Y, Wang X, Wu J, Wang J, Yu D, Xie Y, Gao J, Zhu Y and Yang C: Extracellular vesicles from bone marrow stromal cells reduce the impact of stroke on glial cell activation and blood brain-barrier permeability via a putative miR-124/PRX1 signalling pathway. Eur J Neurosci. 56:3786–3805. 2022.PubMed/NCBI View Article : Google Scholar
39	Lee J, Kang CG, Park CR, Hong IK and Kim DY: The neuroprotective effects of pregabalin after cerebral ischemia by occlusion of the middle cerebral artery in rats. Exp Ther Med. 21(165)2021.PubMed/NCBI View Article : Google Scholar
40	Yu SS, Zhao J, Zheng WP and Zhao Y: Neuroprotective effect of 4-hydroxybenzyl alcohol against transient focal cerebral ischemia via anti-apoptosis in rats. Brain Res. 1308:167–175. 2010.PubMed/NCBI View Article : Google Scholar
41	Cui L, Zhang X, Yang R, Liu L, Wang L, Li M and Du W: Baicalein is neuroprotective in rat MCAO model: Role of 12/15-lipoxygenase, mitogen-activated protein kinase and cytosolic phospholipase A2. Pharmacol Biochem Behav. 96:469–475. 2010.PubMed/NCBI View Article : Google Scholar
42	Jang JH, Son Y, Kang SS, Bae CS, Kim JC, Kim SH, Shin T and Moon C: Neuropharmacological potential of Gastrodia elata blume and its components. Evid Based Complement Alternat Med. 2015(309261)2015.PubMed/NCBI View Article : Google Scholar
43	Liu Y, Gao J, Peng M, Meng H, Ma H, Cai P, Xu Y, Zhao Q and Si G: A review on central nervous system effects of gastrodin. Front Pharmacol. 9(24)2018.PubMed/NCBI View Article : Google Scholar
44	Xiang B, Xiao C, Shen T and Li X: Anti-inflammatory effects of anisalcohol on lipopolysaccharide-stimulated BV2 microglia via selective modulation of microglia polarization and down-regulation of NF-κB p65 and JNK activation. Mol Immunol. 95:39–46. 2018.PubMed/NCBI View Article : Google Scholar
45	Shi A, Xiang J, He F, Zhu Y, Zhu G, Lin Y and Zhou N: The phenolic components of Gastrodia elata improve prognosis in rats after cerebral ischemia/reperfusion by enhancing the endogenous antioxidant mechanisms. Oxid Med Cell Longev. 2018(7642158)2018.PubMed/NCBI View Article : Google Scholar
46	Li L, Wan G, Han B and Zhang Z: Echinacoside alleviated LPS-induced cell apoptosis and inflammation in rat intestine epithelial cells by inhibiting the mTOR/STAT3 pathway. Biomed Pharmacother. 104:622–628. 2018.PubMed/NCBI View Article : Google Scholar
47	Liu B, Li F, Shi J, Yang D, Deng Y and Gong Q: Gastrodin ameliorates subacute phase cerebral ischemia-reperfusion injury by inhibiting inflammation and apoptosis in rats. Mol Med Rep. 14:4144–4152. 2016.PubMed/NCBI View Article : Google Scholar
48	Mi Y, Mao Y, Cheng H, Ke G, Liu M, Fang C and Wang Q: Studies of blood-brain barrier permeability of gastrodigenin in vitro and in vivo. Fitoterapia. 140(104447)2020.PubMed/NCBI View Article : Google Scholar
49	Wang S, Nan Y, Zhu W, Yang T, Tong Y and Fan Y: Gastrodin improves the neurological score in MCAO rats by inhibiting inflammation and apoptosis, promoting revascularization. Int J Clin Exp Pathol. 11:5343–5350. 2018.PubMed/NCBI
50	Ning L, Sun H, Feng J, Yang Q, Zhou Y and He F: Tissue distribution of p-hydroxybenzaldehyde metabolite 4-HBA in rats. J Shanghai Univ Tradit Chin Med. 35:65–70. 2021.
51	Kim HS, Choi JA, Kim BY, Ferrer L, Choi J, Wendisch VF and Lee JH: Engineered corynebacterium glutamicum as the platform for the production of aromatic aldehydes. Front Bioeng Biotechnol. 10(880277)2022.PubMed/NCBI View Article : Google Scholar
52	Duan XH, Li ZL, Yang DS, Zhang FL, Lin Q and Dai R: Study on the chemical constituents of Gastrodia elata. Zhong Yao Cai. 36:1608–1611. 2013.PubMed/NCBI(In Chinese).
53	Lemmerman LR, Harris HN, Balch MHH, Rincon-Benavides MA, Higuita-Castro N, Arnold DW and Gallego-Perez D: Transient middle cerebral artery occlusion with an intraluminal suture enables reproducible induction of ischemic stroke in mice. Bio Protoc. 12(e4305)2022.PubMed/NCBI View Article : Google Scholar
54	Yuan Y, Xia F, Gao R, Chen Y, Zhang Y, Cheng Z, Zhao H and Xu L: Kaempferol mediated AMPK/mTOR signal pathway has a protective effect on cerebral ischemic-reperfusion injury in rats by inducing autophagy. Neurochem Res. 47:2187–2197. 2022.PubMed/NCBI View Article : Google Scholar
55	Zhu A, Lin Y, Hu X, Lin Z, Lin Y, Xie Q, Ni S, Cheng H, Lu Q, Lai S, et al: Treadmill exercise decreases cerebral edema in rats with local cerebral infarction by modulating AQP4 polar expression through the caveolin-1/TRPV4 signaling pathway. Brain Res Bull. 188:155–168. 2022.PubMed/NCBI View Article : Google Scholar
56	Jin M, Kim KM, Lim C, Cho S and Kim YK: Neuroprotective effects of Korean White ginseng and Red ginseng in an ischemic stroke mouse model. J Ginseng Res. 46:275–282. 2022.PubMed/NCBI View Article : Google Scholar
57	Qi S, Zhang X, Fu Z, Pi A, Shi F, Fan Y, Zhang J, Xiao T, Shang D, Lin M, et al: (±)-5-bromo-2-(5-fluoro-1-hydroxyamyl) benzoate protects against oxidative stress injury in PC12 cells exposed to H₂O₂ through activation of Nrf2 pathway. Front Pharmacol. 13(943111)2022.PubMed/NCBI View Article : Google Scholar
58	Song ZL, Bai F, Zhang B and Fang J: Synthesis of Dithiolethiones and Identification of Potential Neuroprotective Agents via Activation of Nrf2-Driven Antioxidant Enzymes. J Agric Food Chem. 68:2214–2231. 2020.PubMed/NCBI View Article : Google Scholar
59	Huang SS, Su HH, Chien SY, Chung HY, Luo ST, Chu YT, Wang YH, MacDonald IJ, Lee HH and Chen YH: Activation of peripheral TRPM8 mitigates ischemic stroke by topically applied menthol. J Neuroinflammation. 19(192)2022.PubMed/NCBI View Article : Google Scholar
60	Wu J, Jin Z, Yang X and Yan LJ: Post-ischemic administration of 5-methoxyindole-2-carboxylic acid at the onset of reperfusion affords neuroprotection against stroke injury by preserving mitochondrial function and attenuating oxidative stress. Biochem Biophys Res Commun. 497:444–450. 2018.PubMed/NCBI View Article : Google Scholar
61	Narne P, Pandey V and Phanithi PB: Interplay between mitochondrial metabolism and oxidative stress in ischemic stroke: An epigenetic connection. Mol Cell Neurosci. 82:176–194. 2017.PubMed/NCBI View Article : Google Scholar
62	Li Y, Zhang X, Ma A and Kang Y: Rational application of β-hydroxybutyrate attenuates ischemic stroke by suppressing oxidative stress and mitochondrial-dependent apoptosis via activation of the Erk/CREB/eNOS pathway. ACS Chem Neurosci. 12:1219–1227. 2021.PubMed/NCBI View Article : Google Scholar
63	Kaushik P, Ali M, Salman M, Tabassum H and Parvez S: Harnessing the mitochondrial integrity for neuroprotection: Therapeutic role of piperine against experimental ischemic stroke. Neurochem Int. 149(105138)2021.PubMed/NCBI View Article : Google Scholar
64	Morkuniene R, Rekuviene E and Kopustinskiene DM: Rotenone decreases ischemia-induced injury by inhibiting mitochondrial permeability transition: A study in brain. Methods Mol Biol. 2497:63–72. 2022.PubMed/NCBI View Article : Google Scholar
65	Huang P, Wu SP, Wang N, Seto S and Chang D: Hydroxysafflor yellow A alleviates cerebral ischemia reperfusion injury by suppressing apoptosis via mitochondrial permeability transition pore. Phytomedicine. 85(153532)2021.PubMed/NCBI View Article : Google Scholar
66	Su F, Yang H, Guo A, Qu Z, Wu J and Wang Q: Mitochondrial BKCa mediates the protective effect of low-dose ethanol preconditioning on oxygen-glucose deprivation and reperfusion-induced neuronal apoptosis. Front Physiol. 12(719753)2021.PubMed/NCBI View Article : Google Scholar
67	Malko P and Jiang LH: TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions. Redox Biol. 37(101755)2020.PubMed/NCBI View Article : Google Scholar
68	Xu M, Ma Q, Fan C, Chen X, Zhang H and Tang M: Ginsenosides Rb1 and Rg1 protect primary cultured astrocytes against oxygen-glucose deprivation/reoxygenation-induced injury via improving mitochondrial function. Int J Mol Sci. 20(6086)2019.PubMed/NCBI View Article : Google Scholar
69	Pozdnyakov DI, Chernikov MV, Sarkisyan KK and Rybalko IE: Neuroprotective potential of pyrimidine-4-H1-OHa derivatives in experimental cerebral ischemia. Zh Nevrol Psikhiatr Im S S Korsakova. 121:63–68. 2021.PubMed/NCBI View Article : Google Scholar : (In Russian).
70	Morse PT, Goebel DJ, Wan J, Tuck S, Hakim L, Hüttemann CL, Malek MH, Lee I, Sanderson TH and Hüttemann M: Cytochrome c oxidase-modulatory near-infrared light penetration into the human brain: Implications for the noninvasive treatment of ischemia/reperfusion injury. IUBMB Life. 73:554–567. 2021.PubMed/NCBI View Article : Google Scholar
71	Ma Y, Zhao P, Zhu J, Yan C, Li L, Zhang H, Zhang M, Gao X and Fan X: Naoxintong protects primary neurons from oxygen-glucose deprivation/reoxygenation induced injury through PI3K-Akt signaling pathway. Evid Based Complement Alternat Med. 2016(5815946)2016.PubMed/NCBI View Article : Google Scholar
72	Zeng JW, Chen BY, Lv XF, Sun L, Zeng XL, Zheng HQ, Du YH, Wang GL, Ma MM and Guan YY: Transmembrane member 16A participates in hydrogen peroxide-induced apoptosis by facilitating mitochondria-dependent pathway in vascular smooth muscle cells. Br J Pharmacol. 175:3669–3684. 2018.PubMed/NCBI View Article : Google Scholar
73	He F, Wu Q, Xu B, Wang X, Wu J, Huang L and Cheng J: Suppression of Stim1 reduced intracellular calcium concentration and attenuated hypoxia/reoxygenation induced apoptosis in H9C2 cells. Biosci Rep. 37(BSR20171249)2017.PubMed/NCBI View Article : Google Scholar
74	Momenabadi S, Vafaei AA, Zahedi Khorasani M and Vakili A: Pre-ischemic oxytocin treatment alleviated neuronal injury via suppressing NF-κB, MMP-9, and apoptosis regulator proteins in a mice model of stroke. Cell J. 24:337–345. 2022.PubMed/NCBI View Article : Google Scholar
75	Huang LY, Song JX, Cai H, Wang PP, Yin QL, Zhang YD, Chen J, Li M, Song JJ, Wang YL, et al: Healthy serum-derived exosomes improve neurological outcomes and protect blood-brain barrier by inhibiting endothelial cell apoptosis and reversing autophagy-mediated tight junction protein reduction in rat stroke model. Front Cell Neurosci. 16(841544)2022.PubMed/NCBI View Article : Google Scholar
76	Cory S and Adams JM: The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002.PubMed/NCBI View Article : Google Scholar
77	Zhai Y, Liu B, Wu L, Zou M, Mei X and Mo X: Pachymic acid prevents neuronal cell damage induced by hypoxia/reoxygenation via miR-155/NRF2/HO-1 axis. Acta Neurobiol Exp (Wars). 82:197–206. 2022.PubMed/NCBI View Article : Google Scholar
78	Yan Y, Liu Y, Yang Y, Ding Y and Sun X: Carnosol suppresses microglia cell inflammation and apoptosis through PI3K/AKT/mTOR signaling pathway. Immunopharmacol Immunotoxicol. 1–11. 2022.PubMed/NCBI View Article : Google Scholar : (Epub ahead of print).
79	Liu X, Zhu X, Chen M, Ge Q, Shen Y and Pan S: Resveratrol protects PC12 cells against OGD/R-induced apoptosis via the mitochondrial-mediated signaling pathway. Acta Biochim Biophys Sin (Shanghai). 48:342–353. 2016.PubMed/NCBI View Article : Google Scholar
80	Wang PC, Wang SX, Yan XL, He YY, Wang MC, Zheng HZ, Shi XG, Tan YH and Wang LS: Combination of paeoniflorin and calycosin-7-glucoside alleviates ischaemic stroke injury via the PI3K/AKT signalling pathway. Pharm Biol. 60:1469–1477. 2022.PubMed/NCBI View Article : Google Scholar
81	Khaksar S, Bigdeli M, Samiee A and Shirazi-Zand Z: Antioxidant and anti-apoptotic effects of cannabidiol in model of ischemic stroke in rats. Brain Res Bull. 180:118–130. 2022.PubMed/NCBI View Article : Google Scholar
82	Li Z, Xiao G, Wang H, He S and Zhu Y: A preparation of Ginkgo biloba L. leaves extract inhibits the apoptosis of hippocampal neurons in post-stroke mice via regulating the expression of Bax/Bcl-2 and caspase-3. J Ethnopharmacol. 280(114481)2021.PubMed/NCBI View Article : Google Scholar
83	Yang L, Tao Y, Luo L, Zhang Y, Wang X and Meng X: Dengzhan Xixin injection derived from a traditional Chinese herb Erigeron breviscapus ameliorates cerebral ischemia/reperfusion injury in rats via modulation of mitophagy and mitochondrial apoptosis. J Ethnopharmacol. 288(114988)2022.PubMed/NCBI View Article : Google Scholar
84	Nhu NT, Li Q, Liu Y, Xu J, Xiao SY and Lee SD: Effects of mdivi-1 on neural mitochondrial dysfunction and mitochondria-mediated apoptosis in ischemia-reperfusion injury after stroke: A systematic review of preclinical studies. Front Mol Neurosci. 14(778569)2021.PubMed/NCBI View Article : Google Scholar
85	Gan L, Liao S, Tong Y, Li W, Peng W and Deng S: Long noncoding RNA H19 mediates neural stem/progenitor cells proliferation, differentiation and apoptosis through the p53 signaling pathway after ischemic stroke. Biochem Biophys Res Commun. 597:8–15. 2022.PubMed/NCBI View Article : Google Scholar : (Epub ahead of print).
86	MacDougall G, Anderton RS, Mastaglia FL, Knuckey NW and Meloni BP: Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics. Neurobiol Dis. 121:17–33. 2019.PubMed/NCBI View Article : Google Scholar
87	Shefa U, Jeong NY, Song IO, Chung HJ, Kim D, Jung J and Huh Y: Mitophagy links oxidative stress conditions and neurodegenerative diseases. Neural Regen Res. 14:749–756. 2019.PubMed/NCBI View Article : Google Scholar
88	Awooda HA, Lutfi MF, Sharara GG and Saeed AM: Oxidative/nitrosative stress in rats subjected to focal cerebral ischemia/reperfusion. Int J Health Sci (Qassim). 9:17–24. 2015.PubMed/NCBI View Article : Google Scholar
89	Chen Y: Disturbed cerebral circulation and metabolism matters: A preface to the special issue ‘stroke and energy metabolism’: A preface to the special issue ‘stroke and energy metabolism’. J Neurochem. 160:10–12. 2022.PubMed/NCBI View Article : Google Scholar