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Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia/reperfusion via MAPK-mTOR signaling pathway.
J Ethnopharmacol. 2013 Aug 26; 149(1):270-80.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Huang-Lian-Jie-Du-Decotion (HLJDD, Hwangryun-Hae-Dok-Decotion in Japan), an ancient antipyretic and detoxifying traditional Chinese medicine formula, was reported to have protective effect on ischemic stroke.

AIM OF THE RESEARCH

To investigate the therapeutic effect of HLJDD on ischemic stroke and explore its mode of action.

MATERIAL AND METHODS

A model of ischemic stroke in the rat was established after transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Rats were assigned randomly to groups of control, sham, transient ischemia/reperfusion (I/R), and three treatment groups by HLJDD at 2.5, 5.0, 10.0mg/kg. The neurological deficit, the cerebral infarct size, morphology abnormality, biochemical parameters were examined, and the levels of relevant proteins were determined by immunoblotting analysis to evaluate the protective effects of HLJDD on ischemic stroke and explore the underlying mechanism.

RESULTS

Compared with I/R group, HLJDD significantly ameliorated neurological deficit and histopathology changes, decreased infarct area, and restored the levels of biochemical indicators including nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), total superoxide dismutase (T-SOD), Cu/Zn-SOD, Mn-SOD and glutathione peroxidase (GSH-PX). HLJDD also notably elevated the levels of microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and other autophagy related genes (Atgs), promoted the activation of extracellular signal-regulated kinases (ERK), protein kinase B (Akt), 3-phosphoinositide-dependent kinase (PDK1), and inhibited the activation of mammalian target of rapamycin (mTOR), c-Jun N-terminal protein kinases (JNK), p38, phosphatase and tensin homolog (PTEN).

CONCLUSION

HLJDD showed neuroprotective effects on ischemic stroke, at least in part to the induced protective autophagy via the regulation of mitogen-activated protein kinase (MAPK) signals. This Akt-independent protective autophagy is favorable in the treatment of stroke, avoiding unfavorable side-effects associated with the inactivation of Akt. The efficacy of HLJDD on ischemic stroke and its safety warranted by its long-term clinical use in traditional Chinese medicine favored further study to develop HLJDD as an effective therapeutic agent to treat ischemic stroke.

Authors+Show Affiliations

State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23811213

Citation

Wang, Peng-Ran, et al. "Huang-Lian-Jie-Du-Decotion Induced Protective Autophagy Against the Injury of Cerebral Ischemia/reperfusion Via MAPK-mTOR Signaling Pathway." Journal of Ethnopharmacology, vol. 149, no. 1, 2013, pp. 270-80.
Wang PR, Wang JS, Zhang C, et al. Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia/reperfusion via MAPK-mTOR signaling pathway. J Ethnopharmacol. 2013;149(1):270-80.
Wang, P. R., Wang, J. S., Zhang, C., Song, X. F., Tian, N., & Kong, L. Y. (2013). Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia/reperfusion via MAPK-mTOR signaling pathway. Journal of Ethnopharmacology, 149(1), 270-80. https://doi.org/10.1016/j.jep.2013.06.035
Wang PR, et al. Huang-Lian-Jie-Du-Decotion Induced Protective Autophagy Against the Injury of Cerebral Ischemia/reperfusion Via MAPK-mTOR Signaling Pathway. J Ethnopharmacol. 2013 Aug 26;149(1):270-80. PubMed PMID: 23811213.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia/reperfusion via MAPK-mTOR signaling pathway. AU - Wang,Peng-Ran, AU - Wang,Jun-Song, AU - Zhang,Chao, AU - Song,Xing-Fang, AU - Tian,Na, AU - Kong,Ling-Yi, Y1 - 2013/06/28/ PY - 2012/09/27/received PY - 2013/05/18/revised PY - 2013/06/20/accepted PY - 2013/7/2/entrez PY - 2013/7/3/pubmed PY - 2014/3/29/medline KW - (β-Nicotinamide adenine dinucleotide, reduced disodium salt, trihydrate) KW - 2,3,5-triphenyltetrazolium chloride KW - 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium KW - 3-phosphoinositide-dependent kinase KW - 5,5′-Dithiobis-(2-nitrobenzoic acid) KW - ANOVA KW - Akt KW - Atg KW - Autophagy KW - Autophagy related genes KW - BCA KW - BSA KW - Bicinchoninic acid KW - CCA KW - CMC-Na KW - DTNB KW - ECA KW - ECL KW - ERK KW - Fetal Bovine Serum Albumin KW - Fig. KW - Figure KW - GSH KW - GSH-PX KW - GSSG KW - HE KW - HLJDD KW - Huang-Lian-Jie-Du-Decotion KW - Huanglian-Jie-Du-Decotion KW - I/R KW - ICA KW - IPC KW - JNK KW - LC3 KW - LCBF KW - LDF KW - MAPK KW - MCA KW - MCAO KW - MDA KW - Middle cerebral artery occlusion (MCAO) KW - Mitogen-activated protein kinase (MAPK) KW - NADH KW - NO KW - PAPTOR KW - PDK1 KW - PI3K KW - PIP(2) KW - PIP(3) KW - PTEN KW - Protein kinase B (Akt) KW - RICTOR KW - ROS KW - S.D. KW - S6K KW - SDS-PAGE KW - Stroke KW - T-SOD KW - TBS-T KW - TTC KW - WST-1 KW - c-Jun N-terminal protein kinases KW - carboxymethyl cellulose sodium salt KW - common carotid artery KW - enhanced chemiluminescence KW - external carotid artery KW - extracellular signal-regulated kinases KW - glutathione KW - glutathione disulfide KW - glutathione peroxidase KW - hematoxylin–eosin KW - i.g. KW - internal carotid artery KW - intragastric administration KW - ischemia/reperfusion KW - ischemic preconditioning KW - laser Doppler flow meter KW - local cortical blood flow KW - mLST8 KW - mLST8 and mammalian stress-activated protein kinase interacting protein KW - mSIN1 KW - mTOR KW - mTOR complex1 KW - mTORC1 KW - malondialdehyde KW - mammalian lethal with Sec13 protein 8 KW - mammalian target of rapamycin KW - microtubule-associated protein1 light chain 3 KW - middle cerebral artery KW - middle cerebral artery occlusion KW - mitogen-activated protein kinase KW - nitric oxide KW - one-way analysis of variance KW - p70 ribosomal S6 kinase KW - phosphatidylinositol (3,4,5) trisphosphate KW - phosphatidylinositol (4,5) bisphosphate KW - phosphatidylinositol 3-kinase KW - protein kinase B KW - reactive oxygen species KW - scaffolding protein rapamycin-insensitive companion of mTOR KW - scaffolding protein regulatory-associated protein of mTOR KW - sodium dodecyl sulfate-polyacrylamide gel electrophoresis KW - standard deviation KW - t-PA KW - tensin homolog KW - tissue-plasminogen activator KW - total superoxide dismutase KW - tris-buffered saline containing 0.1% Tween-20 KW - v: v KW - volume: volume KW - w/v KW - weigh/volume SP - 270 EP - 80 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 149 IS - 1 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du-Decotion (HLJDD, Hwangryun-Hae-Dok-Decotion in Japan), an ancient antipyretic and detoxifying traditional Chinese medicine formula, was reported to have protective effect on ischemic stroke. AIM OF THE RESEARCH: To investigate the therapeutic effect of HLJDD on ischemic stroke and explore its mode of action. MATERIAL AND METHODS: A model of ischemic stroke in the rat was established after transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Rats were assigned randomly to groups of control, sham, transient ischemia/reperfusion (I/R), and three treatment groups by HLJDD at 2.5, 5.0, 10.0mg/kg. The neurological deficit, the cerebral infarct size, morphology abnormality, biochemical parameters were examined, and the levels of relevant proteins were determined by immunoblotting analysis to evaluate the protective effects of HLJDD on ischemic stroke and explore the underlying mechanism. RESULTS: Compared with I/R group, HLJDD significantly ameliorated neurological deficit and histopathology changes, decreased infarct area, and restored the levels of biochemical indicators including nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), total superoxide dismutase (T-SOD), Cu/Zn-SOD, Mn-SOD and glutathione peroxidase (GSH-PX). HLJDD also notably elevated the levels of microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and other autophagy related genes (Atgs), promoted the activation of extracellular signal-regulated kinases (ERK), protein kinase B (Akt), 3-phosphoinositide-dependent kinase (PDK1), and inhibited the activation of mammalian target of rapamycin (mTOR), c-Jun N-terminal protein kinases (JNK), p38, phosphatase and tensin homolog (PTEN). CONCLUSION: HLJDD showed neuroprotective effects on ischemic stroke, at least in part to the induced protective autophagy via the regulation of mitogen-activated protein kinase (MAPK) signals. This Akt-independent protective autophagy is favorable in the treatment of stroke, avoiding unfavorable side-effects associated with the inactivation of Akt. The efficacy of HLJDD on ischemic stroke and its safety warranted by its long-term clinical use in traditional Chinese medicine favored further study to develop HLJDD as an effective therapeutic agent to treat ischemic stroke. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/23811213/Huang_Lian_Jie_Du_Decotion_induced_protective_autophagy_against_the_injury_of_cerebral_ischemia/reperfusion_via_MAPK_mTOR_signaling_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-8741(13)00455-8 DB - PRIME DP - Unbound Medicine ER -