Abstract
Andrographolide (Andro), a diterpene of the labdane family extracted from the Asian plant Andrographis paniculata, is neuroprotective against stroke and Alzheimer’s disease. However, whether Andro protected the brain against subarachnoid hemorrhage (SAH) was still unknown. Thus, we explored whether Andro attenuated blood–brain barrier (BBB) disruption and neuronal apoptosis and inhibited oxidative stress to protect the brain against SAH both in vitro and in vivo and detected underlying mechanisms of Andro’s neuroprotective effects in the present study. Oxyhemoglobin (OxyHb)-treated neuronal PC12 cells were used as an in vitro model. An in vivo model was established using Sprague–Dawley rats. Moreover, we used an inhibitor of heme oxygenase-1 (HO-1) (ZnPPIX) in vitro and in vivo experiments to evaluate whether the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) cascade acted as one protective molecular mechanism of Andro against SAH. Our results revealed that, in vitro, Andro increased cell viability, inhibited apoptosis, and activated Nrf2/HO-1 cascade of neuronal PC12 cells treated with OxyHb. In vivo, Andro attenuated the neurological dysfunction, neuronal apoptosis, BBB disruption, brain edema, and oxidative stress and activated the Nrf2/HO-1 pathway. ZnPPIX reversed the effects of Andro in vitro and in vivo. Our research suggested that Andro alleviated BBB disruption, neuronal apoptosis, and oxidative stress in SAH, possibly via the Nrf2/HO-1 signaling pathway.
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Abbreviations
- SAH:
-
Subarachnoid Hemorrhage
- BBB:
-
Blood-Brain Barrier
- Nrf2:
-
Nuclear factor E2-related factor 2
- HO-1:
-
Heme oxygenase-1
- I/R:
-
Ischemia/reperfusion
- PBS:
-
Phosphate-buffered saline
- Andro:
-
Andrographolide
- OxyHb:
-
Oxyhemoglobin
- DMSO:
-
Dimethyl sulfoxide
References
Alfieri A, Srivastava S, Siow RC, Modo M, Fraser PA, Mann GE (2011) Targeting the Nrf2-Keap1 antioxidant defence pathway for neurovascular protection in stroke. J Physiol 589:4125–4136
Alfieri A, Srivastava S, Siow RCM, Cash D, Modo M, Duchen MR et al (2013) Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke. Free Radic Biol Med 65:1012–1022
Amin N, Du X, Chen S, Ren Q, Hussien AB, Botchway BOA et al (2021) Therapeutic impact of thymoquninone to alleviate ischemic brain injury via Nrf2/HO-1 pathway. Expert Opin Ther Targets 25:597–612
Chen Y, Chen J, Sun X, Shi X, Wang L, Huang L et al (2018) Evaluation of the neuroprotective effect of EGCG: a potential mechanism of mitochondrial dysfunction and mitochondrial dynamics after subarachnoid hemorrhage. Food Funct 9:6349–6359
Chern CM, Liou KT, Wang YH, Liao JF, Yen JC, Shen YC (2011) Andrographolide inhibits PI3K/AKT-dependent NOX2 and iNOS expression protecting mice against hypoxia/ischemia-induced oxidative brain injury. Planta Med 77:1669–1679
Coon JT, Ernst E (2004) Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med 70:293–298
de Rooij NK, Rinkel GJ, Dankbaar JW, Frijns CJ (2013) Delayed cerebral ischemia after subarachnoid hemorrhage: a systematic review of clinical, laboratory, and radiological predictors. Stroke 44:43–54
Garcia JH, Wagner S, Liu KF, Hu XJ (1995) Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats: statistical validation. Stroke 26:627–34; discussion 35
Gong P, Zhang Z, Zou C, Tian Q, Chen X, Hong M et al (2019a) Hippo/YAP signaling pathway mitigates blood-brain barrier disruption after cerebral ischemia/reperfusion injury. Behav Brain Res 356:8–17
Gong P, Zhang Z, Zou Y, Tian Q, Han S, Xu Z et al (2019b) Tetramethylpyrazine attenuates blood-brain barrier disruption in ischemia/reperfusion injury through the JAK/STAT signaling pathway. Eur J Pharmacol 854:289–297
Jiang C, Zuo F, Wang Y, Wan J, Yang Z, Lu H et al (2016) Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice. Neurobiol Aging 42:13–24
Jin S, Wang X, Xiang X, Wu Y, Hu J, Li Y, et al (2021) Inhibition of GPR17 with cangrelor improves cognitive impairment and synaptic deficits induced by Abeta1–42 through Nrf2/HO-1 and NF-kappaB signaling pathway in mice. Int Immunopharmacol 101:108335
Kaplan L, Chow BW, Gu C (2020) Neuronal regulation of the blood-brain barrier and neurovascular coupling. Nat Rev Neurosci 21:416–432
Kaspar JW, Niture SK, Jaiswal AK (2009) Nrf 2:INrf2 (Keap1) signaling in oxidative stress. Free Radical Biol Med 47:1304–1309
Li M, Wang W, Mai H, Zhang X, Wang J, Gao Y et al (2016) Methazolamide improves neurological behavior by inhibition of neuron apoptosis in subarachnoid hemorrhage mice. Sci Rep 6:35055
Link TE, Murakami K, Beem-Miller M, Tranmer BI, Wellman GC (2008) Oxyhemoglobin-induced expression of R-type Ca2+ channels in cerebral arteries. Stroke 39:2122–2128
Macdonald RL (2014) Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 10:44–58
Niture SK, Khatri R, Jaiswal AK (2014) Regulation of Nrf2-an update. Free Radical Biol Med 66:36–44
Ostrowski RP, Colohan AR, Zhang JH (2006) Molecular mechanisms of early brain injury after subarachnoid hemorrhage. Neurol Res 28:399–414
Otsuka S, Setoyama K, Takada S, Nakanishi K, Terashi T, Norimatsu K et al (2021) Preconditioning exercise in rats attenuates early brain injury resulting from subarachnoid hemorrhage by reducing oxidative stress, inflammation, and neuronal apoptosis. Mol Neurobiol 58:5602–5617
Sugawara T, Ayer R, Jadhav V, Zhang JH (2008) A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods 167:327–334
Taylor WF, Yanez M, Moghadam SE, Moridi Farimani M, Soroury S, Ebrahimi SN, et al (2019) 7-epi-clusianone, a multi-targeting natural product with potential chemotherapeutic, immune-modulating, and anti-angiogenic properties. Molecules 24
Tran QTN, Tan WSD, Wong WSF, Chai CLL (2020) Polypharmacology of andrographolide: beyond one molecule one target. Nat Prod Rep
Wang KC, Yeh YT, Nguyen P, Limqueco E, Lopez J, Thorossian S et al (2016a) Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis. Proc Natl Acad Sci USA 113:11525–11530
Wang W, Li M, Wang Y, Li Q, Deng G, Wan J et al (2016b) GSK-3beta inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/beta-catenin signaling pathway after acute ischemic stroke in rats. Mol Neurobiol 53:7028–7036
Wang Z, Ma C, Meng CJ, Zhu GQ, Sun XB, Huo L et al (2012) Melatonin activates the Nrf2-ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model. J Pineal Res 53:129–137
Wong SK, Chin KY, Ima-Nirwana S (2021) A review on the molecular basis underlying the protective effects of Andrographis paniculata and andrographolide against myocardial injury. Drug Des Dev Ther 15:4615–4632
Xie S, Deng W, Chen J, Wu QQ, Li H, Wang J et al (2020) Andrographolide protects against adverse cardiac remodeling after myocardial infarction through enhancing Nrf2 signaling pathway. Int J Biol Sci 16:12–26
Yang T, Sun Y, Mao L, Zhang M, Li Q, Zhang L et al (2018a) Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation. Redox Biol 17:323–337
Yang Y, Dong B, Lu J, Wang G, Yu Y (2018b) Hemopexin reduces blood-brain barrier injury and protects synaptic plasticity in cerebral ischemic rats by promoting EPCs through the HO-1 pathway. Brain Res 1699:177–185
Zhang L, Wang X, Lu X, Ma Y, Xin X, Xu X et al (2020) Tetramethylpyrazine enhanced the therapeutic effects of human umbilical cord mesenchymal stem cells in experimental autoimmune encephalomyelitis mice through Nrf2/HO-1 signaling pathway. Stem Cell Res Ther 11:186
Zhang R, Xu M, Wang Y, Xie F, Zhang G, Qin X (2017) Nrf2-a promising therapeutic target for defensing against oxidative stress in stroke. Mol Neurobiol 54:6006–6017
Zhang T, Wu P, Budbazar E, Zhu Q, Sun C, Mo J et al (2019) Mitophagy reduces oxidative stress via Keap1 (kelch-like epichlorohydrin-associated protein 1)/Nrf2 (nuclear factor-E2-related factor 2)/PHB2 (prohibitin 2) pathway after subarachnoid hemorrhage in rats. Stroke 50:978–988
Zou Y, Gong P, Zhao W, Zhang J, Wu X, Xin C et al (2019) Quantitative iTRAQ-based proteomic analysis of piperine protected cerebral ischemia/reperfusion injury in rat brain. Neurochem Int 124:51–61
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This study was supported by grants from the National Natural Science Foundation of China (81971870 to M.C.L.).
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PG and ML designed the research; PG and WZ conducted the research; CZ, SH, QT, and JW analyzed the data; PH and YG made the figures; PG and ML drafted the manuscript; PG and ML contributed to the writing of the manuscript.
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Gong, P., Zhang, W., Zou, C. et al. Andrographolide Attenuates Blood–Brain Barrier Disruption, Neuronal Apoptosis, and Oxidative Stress Through Activation of Nrf2/HO-1 Signaling Pathway in Subarachnoid Hemorrhage. Neurotox Res 40, 508–519 (2022). https://doi.org/10.1007/s12640-022-00486-7
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DOI: https://doi.org/10.1007/s12640-022-00486-7