Alkaloids from the hook-bearing branch of<i>Uncaria</i><i>rhynchophylla</i>and their neuroprotective effects against glutamate-induced HT22 cell death

Qi, Wen; Yue, Si-Jia; Sun, Jiahong; Simpkins, James W.; Zhang, Lin; Yuan, Dan

doi:10.1080/10286020.2014.918109

Cited by 33 publications

(26 citation statements)

References 17 publications

(16 reference statements)

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“…Only the CHCl3-soluble fraction was found to be significantly active, with the IC50 value of the CHCl3-soluble fraction being 5.7 μg/mL, suggesting that the indole alkaloids that were the major ingredients in the CHCl3-soluble fraction possess protective effects against glutamate-induced cytotoxicity. The current study evaluated GM protective effect because it is a major indole alkaloid found in the CHCl3-soluble fraction and has highest potency (Qi et al, 2014). However, it is unknown if Uncaria hook or other alkaloids extracted from Uncaria hook exert neuroprotective effects through the same mechanism, which needs to be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…GM was isolated from the extract of the hook-bearing branches of U. sinensis (Qi et al, 2014). Its structure (Supplemental Fig 1) was characterized by comparison of its 1 H-NMR, 13 C -NMR (Supplemental Table and Supplemental Fig 2) and ESI-QTOF-MS/MS data (Supplemental Fig 3).…”

Section: Methodsmentioning

confidence: 99%

“…ex Havil, against glutamate-induced oxidative toxicity in neuronal cells. Among them, geissoschizine methyl ether (GM) has the highest potency in the neuroprotection (Qi et al, 2014). Published study reported that GM could reach the brain by crossing the blood-brain barrier in rats following the oral administration of yokukansan.…”

Section: Introductionmentioning

confidence: 99%

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Geissoschizine methyl ether protects oxidative stress-mediated cytotoxicity in neurons through the ‘Neuronal Warburg Effect’

Sun

Ren

et al. 2016

Journal of Ethnopharmacology

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Ethnopharmacological relevance The rate of production of reactive oxygen species (ROS) is determined by mitochondrial metabolic rate. In turn, excessive ROS damage mitochondrial function, which is linked to aging and neurodegenerative conditions. One possible path to prevent oxidative stress could be achieved by reducing mitochondrial respiration in favor of less efficient ATP production via glycolysis. Such a shift in energy metabolism is known as the ‘Warburg effect’. Geissoschizine methyl ether (GM) is one of the active components responsible for the psychotropic effects of Yokukansan, an herbal preparation widely used in China and Japan. Aim of the study GM protects neurons from glutamate-induced oxidative cytotoxicity through regulating mitochondrial function and suppressing ROS generation. We investigated the protective mechanism of GM against glutamate-induced oxidative stress in neuronal cells. Materials and methods The current study was performed on primary neurons and HT22 cells, a hippocampus neuronal cell line. Cell viability was measured by Calcein AM assay. H2DCFDA staining was used for intracellular ROS measurement. GSH level was measured using the GSH-Glo™ luminescence-based assay. Mitochondrial respiration and glycolysis were measured by the Seahorse Bioscience XFe 96 Extracellular Flux Analyzer. Protein levels were analyzed by western blot analysis. Results GM prevented glutamate-induced cytotoxicity in an HT-22 neuronal cell line even with a 9-hour exposure delay. GM blocked glutamate-induced intracellular ROS accumulation through suppressing mitochondrial respiration. Further, we found that GM up-regulated glycolysis and the pentose-phosphate pathway, which is involved in the production of intracellular reducing agent, NADPH. In addition, GM protected primary cortical neurons from both glutamate and buthioninesulfoximine toxicity. Conclusion GM prevents glutamate-induced oxidative damage through reducing mitochondrial respiration, which further suppresses ROS generation. In addition, GM up-regulates glycolysis which compensate for the energy depletion induced by mitochondrial respiration inhibition. Overall, our study is the first to report that GM protects neurons from oxidative toxicity by shifting energy metabolism from mitochondrial respiration to glycolysis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Geissoschizine methyl ether protects oxidative stress-mediated cytotoxicity in neurons through the ‘Neuronal Warburg Effect’

Sun

Ren

et al. 2016

Journal of Ethnopharmacology

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“…Some evidences have indicated that URE possess a promising role in neuroprotective effect through anti-apoptosis and antioxidative stress [13,35]. An understanding of the mechanisms and drug targets of this neuroprotective effect will be beneficial to develop effective ways for improving or preventing the progression of PD.…”

Section: Discussionmentioning

confidence: 99%

Uncaria rhynchophylla Ameliorates Parkinson’s Disease by Inhibiting HSP90 Expression: Insights from Quantitative Proteomics

Lan

Zhou

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Uncaria rhynchophylla, known as “Gou-teng”, is a traditional Chinese medicine (TCM) used to extinguish wind, clear heat, arrest convulsions, and pacify the liver. Although U. rhynchophylla has a long history of being often used to treat central nervous system (CNS) diseases, its efficacy and potential mechanism are still uncertain. This study investigated neuroprotective effect and the underlying mechanism of U. rhynchophylla extract (URE) in MPP⁺-induced SH-SY5Y cells and MPTP-induced mice. Methods: MPP⁺-induced SH-SY5Y cells and MPTP-induced mice were used to established Parkinson’s disease (PD) models. Quantitative proteomics and bioinformatics were used to uncover proteomics changes of URE. Western blotting was used to validate main differentially expressed proteins and test HSP90 client proteins (apoptosis-related, autophagy-related, MAPKs, PI3K, and AKT proteins). Flow cytometry and JC-1 staining assay were further used to confirm the effect of URE on MPP⁺-induced apoptosis in SH-SY5Y cells. Gait analysis was used to detect the behavioral changes in MPTP-induced mice. The levels of dopamine (DA) and their metabolites were examined in striatum (STR) by HPLC-EC. The positive expression of tyrosine hydroxylase (TH) was detected by immunohischemical staining and Western blotting. Results: URE dose-dependently increased the cell viability in MPP⁺-induced SH-SY5Y cells. Quantitative proteomics and bioinformatics results confirmed that HSP90 was an important differentially expressed protein of URE. URE inhibited the expression of HSP90, which further reversed MPP⁺-induced cell apoptosis and autophagy by increasing the expressions of Bcl-2, Cyclin D1, p-ERK, p-PI3K p85, PI3K p110α, p-AKT, and LC3-I and decreasing cleaved caspase 3, Bax, p-JNK, p-p38, and LC3-II. URE also markedly decreased the apoptotic ratio and elevated mitochondrial transmembrane potential (DΨ_m). Furthermore, URE treatment ameliorated behavioral impairments, increased the contents of DA and its metabolites and elevated the positive expressions of TH in SN and STR as well as the TH protein. Conclusions: URE possessed the neuroprotective effect in vivo and in vitro, regulated MAPK and PI3K-AKT signal pathways, and inhibited the expression of HSP90. U. rhynchophylla has potentials as therapeutic agent in PD treatment.

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“…In that report, the authors describe villocarine A as a new indole alkaloid, however the structure 7 is identical to the indole alkaloid 3-epi-geissoschizine methyl ether (22). Villocarine A showed potent vasorelaxant effects at 30 µM in rat aortic ring assays, revealed some inhibition effect on vasocontraction of depolarized aorta with high concentration potassium, and showed inhibition effect on phenylephrine (PE)-induced contraction in the presence of nicardipine in a Ca 2+ concentration-dependent manner.…”

Section: Hirsutine (4) Hirsuteine (5) Geissoschizine Methyl Ether (mentioning

confidence: 99%

Indolo[2,3-a]quinolizidines and Derivatives: Bioactivity and Asymmetric Synthesis

Pérez

Espadinha²,

Santos

2015

CPD

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Corynantheine alkaloids with a tetracyclic indole[2,3-a]-quinolizidine motif are an important issue in academia and in the life science industries due to their broad bioactivity profile ranging from antiarthritic, analgesic, anti-inflammatory, antiallergic, antibacterial, to antiviral activities.For that reason, in the last decades, numerous efforts have been invested in the development of novel synthetic strategies to obtain the indole[2,3-a]-quinolizidine system. This review focuses on the synthetic methodologies developed to target the most important alkaloids of this family, and highlights the potential use of these alkaloids or analogs to treat several diseases, ranging from cancer to neurodegenerative disorders.

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Alkaloids from the hook-bearing branch ofUncariarhynchophyllaand their neuroprotective effects against glutamate-induced HT22 cell death

Cited by 33 publications

References 17 publications

Geissoschizine methyl ether protects oxidative stress-mediated cytotoxicity in neurons through the ‘Neuronal Warburg Effect’

Geissoschizine methyl ether protects oxidative stress-mediated cytotoxicity in neurons through the ‘Neuronal Warburg Effect’

Uncaria rhynchophylla Ameliorates Parkinson’s Disease by Inhibiting HSP90 Expression: Insights from Quantitative Proteomics

Indolo[2,3-a]quinolizidines and Derivatives: Bioactivity and Asymmetric Synthesis

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