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Andrographolide Attenuates Blood–Brain Barrier Disruption, Neuronal Apoptosis, and Oxidative Stress Through Activation of Nrf2/HO-1 Signaling Pathway in Subarachnoid Hemorrhage

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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

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Funding

This study was supported by grants from the National Natural Science Foundation of China (81971870 to M.C.L.).

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Author notes

  1. Pian Gong and Wei Zhang both authors, contributed equally to this study.

Authors and Affiliations

  1. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China

    Pian Gong, Wei Zhang, Changlin Zou, Shoumeng Han, Qi Tian, Jianfeng Wang, Peibang He, Yujia Guo & Mingchang Li

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  1. Pian Gong
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  2. Wei Zhang
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  3. Changlin Zou
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Contributions

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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Correspondence to Mingchang Li.

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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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