Abstract
Clinacanthus nutans Lindau (C. nutans) is a traditional herbal medicine widely used in Asian countries for treating a number of remedies including snake and insect bites, skin rashes, viral infections, and cancer. However, the underlying molecular mechanisms for its action and whether C. nutans can offer protection on stroke damage in brain remain largely unknown. In the present study, we demonstrated protective effects of C. nutans extract to ameliorate neuronal apoptotic death in the oxygen-glucose deprivation model and to reduce infarction and mitigate functional deficits in the middle cerebral artery occlusion model, either administered before or after hypoxic/ischemic insult. Using pharmacological antagonist and siRNA knockdown approaches, we demonstrated ability for C. nutans extract to protect neurons and ameliorate ischemic injury through promoting the anti-apoptotic activity of peroxisome proliferator-activated receptor-gamma (PPAR-γ), a stress-induced transcription factor. Reporter and chromatin immunoprecipitation promoter analysis further revealed C. nutans extract to selectively increase CCAAT/enhancer binding protein (C/EBP)β binding to specific C/EBP binding site (-332~-325) on the PPAR-γ promoter to augment its transcription. In summary, we report a novel transcriptional activation involving C/EBPβ upregulation of PPAR-γ expression to suppress ischemic neuronal apoptosis and brain infarct. Recognition of C. nutans to enhance the C/EBPβ → PPAR-γ neuroprotective signaling pathway paves a new way for future drug development for prevention and treatment of ischemic stroke and other neurodegenerative diseases.
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Abbreviations
- ACO:
-
Acyl-CoA oxidase
- C. nutans :
-
Clinacanthus nutans Lindau
- CN:
-
80% ethanol leaf extract of C. nutans
- CNS:
-
Central nervous system
- C/EBP:
-
CCAAT/enhancer-binding protein
- ChIP:
-
Chromatin immunoprecipitation
- DMSO:
-
Dimethyl sulfoxide
- β-Gal:
-
β-Galactosidase
- icv:
-
Intracerebroventricular
- i.p.:
-
Intraperitoneal
- MCA:
-
Middle cerebral artery
- MRI:
-
Magnetic resonance imaging
- OGD:
-
Oxygen-glucose deprivation
- PNs:
-
Primary cortical neurons
- PPAR-γ:
-
Peroxisome proliferator-activated receptor-gamma
- PPRE:
-
PPAR response element
- tPA:
-
Tissue-type plasminogen activator
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Acknowledgements
We thank the Taiwan Mouse Clinic (TMC; http://tmc.sinica.edu.tw/index.html; MRI: Yu-Ying Tung) for technical support. All authors have read and agreed to the manuscript as written.
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This work was supported by grants from the Minister of Science and Technology and Academia Sinica of Taiwan to T.N. Lin.
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Wu, JS., Kao, MH., Tsai, HD. et al. Clinacanthus nutans Mitigates Neuronal Apoptosis and Ischemic Brain Damage Through Augmenting the C/EBPβ-Driven PPAR-γ Transcription. Mol Neurobiol 55, 5425–5438 (2018). https://doi.org/10.1007/s12035-017-0776-z
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DOI: https://doi.org/10.1007/s12035-017-0776-z