The Protective Effect of (-)-Tetrahydroalstonine against OGD/R-Induced Neuronal Injury via Autophagy Regulation

Here, (-)-Tetrahydroalstonine (THA) was isolated from Alstonia scholaris and investigated for its neuroprotective effect towards oxygen–glucose deprivation/re-oxygenation (OGD/R)-induced neuronal damage. In this study, primary cortical neurons were pre-treated with THA and then subjected to OGD/R induction. The cell viability was tested by the MTT assay, and the states of the autophagy–lysosomal pathway and Akt/mTOR pathway were monitored by Western blot analysis. The findings suggested that THA administration increased the cell viability of OGD/R-induced cortical neurons. Autophagic activity and lysosomal dysfunction were found at the early stage of OGD/R, which were significantly ameliorated by THA treatment. Meanwhile, the protective effect of THA was significantly reversed by the lysosome inhibitor. Additionally, THA significantly activated the Akt/mTOR pathway, which was suppressed after OGD/R induction. In summary, THA exhibited promising protective effects against OGD/R-induced neuronal injury by autophagy regulation through the Akt/mTOR pathway.

[1]  F. Ren,et al.  mTORC2: a multifaceted regulator of autophagy , 2023, Cell Communication and Signaling.

[2]  Q. Niu,et al.  The inhibition of TRPML1/TFEB leads to lysosomal biogenesis disorder, contributes to developmental fluoride neurotoxicity. , 2023, Ecotoxicology and environmental safety.

[3]  Xiuqin Wang,et al.  Xuesaitong Combined with Dexmedetomidine Improves Cerebral Ischemia-Reperfusion Injury in Rats by Activating Keap1/Nrf2 Signaling and Mitophagy in Hippocampal Tissue , 2022, Oxidative medicine and cellular longevity.

[4]  Bo Han,et al.  Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets , 2022, Journal of Hematology & Oncology.

[5]  P. Liu,et al.  eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior , 2022, EMBO reports.

[6]  Yun-Li Zhao,et al.  Indole alkaloids of Alstonia scholaris (L.) R. Br. alleviated nonalcoholic fatty liver disease in mice fed with high-fat diet , 2022, Natural Products and Bioprospecting.

[7]  M. J. Pérez‐Álvarez,et al.  Dysregulation of mTOR Signaling after Brain Ischemia , 2022, International journal of molecular sciences.

[8]  Yun-Li Zhao,et al.  Anti-inflammatory and analgesic monoterpenoid indole alkaloids of Kopsia officinalis. , 2021, Journal of ethnopharmacology.

[9]  Manmei Li,et al.  Total Saponins of Panax notoginseng Activate Akt/mTOR Pathway and Exhibit Neuroprotection in vitro and in vivo against Ischemic Damage , 2021, Chinese Journal of Integrative Medicine.

[10]  Songtao Li,et al.  3'-Oxo-tabernaelegantine A (OTNA) selectively relaxes pulmonary arteries by inhibiting AhR. , 2021, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[11]  P. S. Gill,et al.  Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019 , 2021, The Lancet Neurology.

[12]  Jian Wang,et al.  Neuroprotective Effect for Cerebral Ischemia by Natural Products: A Review , 2021, Frontiers in Pharmacology.

[13]  Chunfu Wu,et al.  Pseudoginsenoside F11 ameliorates the dysfunction of the autophagy-lysosomal pathway by activating calcineurin-mediated TFEB nuclear translocation in neuron during permanent cerebral ischemia , 2021, Experimental Neurology.

[14]  Yun-Li Zhao,et al.  Anti-microbial Effects In Vitro and In Vivo of Alstonia scholaris , 2021, Natural products and bioprospecting.

[15]  Changzheng Chen,et al.  Efficacy of Vincamine treatment in a rat model of anterior ischemic optic neuropathy , 2020, European journal of ophthalmology.

[16]  Mengping Wei,et al.  Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons , 2020, Autophagy.

[17]  W. Ye,et al.  Alstolarines A and B, two unusual monoterpenoid indole alkaloids with an acetal moiety from Alstonia scholaris , 2020 .

[18]  M. Shirali,et al.  The expression of Terpenoid Indole Alkaloid (TIAs) pathway genes in Catharanthus roseus in response to salicylic acid treatment , 2020, Molecular Biology Reports.

[19]  Weiwei Hu,et al.  Tomatidine protects against ischemic neuronal injury by improving lysosomal function. , 2020, European journal of pharmacology.

[20]  Min Zhang,et al.  Electroacupuncture Inhibits Neuronal Autophagy and Apoptosis via the PI3K/AKT Pathway Following Ischemic Stroke , 2020, Frontiers in Cellular Neuroscience.

[21]  Qing-Wen Zhang,et al.  Dimeric Diarylheptanoids with Neuroprotective Activities from Rhizomes of Alpinia officinarum , 2020, ACS omega.

[22]  S. Oparil,et al.  Reserpine Substantially Lowers Blood Pressure in Patients with Refractory Hypertension: A Proof of Concept Study. , 2020, American journal of hypertension.

[23]  Yan Xu,et al.  11-Methoxytabersonine Induces Necroptosis with Autophagy through AMPK/mTOR and JNK Pathways in Human Lung Cancer Cells. , 2020, Chemical & pharmaceutical bulletin.

[24]  Yinyi Sun,et al.  Autophagy and inflammation in ischemic stroke , 2020, Neural regeneration research.

[25]  T. Wollert.  Autophagy , 2019, Current Biology.

[26]  Yinghui Peng,et al.  A natural diarylheptanoid protects cortical neurons against oxygen–glucose deprivation‐induced autophagy and apoptosis , 2019, The Journal of pharmacy and pharmacology.

[27]  Yunman Li,et al.  The progress of neuronal autophagy in cerebral ischemia stroke: Mechanisms, roles and research methods , 2019, Journal of the Neurological Sciences.

[28]  Jin Fan,et al.  Edaravone inhibits autophagy after neuronal oxygen-glucose deprivation/recovery injury , 2019, The International journal of neuroscience.

[29]  Hao Zhang,et al.  Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia , 2018, Autophagy.

[30]  Y. Gürsoy-Özdemir,et al.  Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options , 2018, Current neuropharmacology.

[31]  J. Hájíček,et al.  Solution of the multistep pathway for assembly of corynanthean, strychnos, iboga, and aspidosperma monoterpenoid indole alkaloids from 19E-geissoschizine , 2018, Proceedings of the National Academy of Sciences.

[32]  Xiaotao Xu,et al.  bFGF plays a neuroprotective role by suppressing excessive autophagy and apoptosis after transient global cerebral ischemia in rats , 2018, Cell Death & Disease.

[33]  W. Ye,et al.  Ervaoffines E–G, three iboga-type alkaloids featuring ring C cleavage and rearrangement from Ervatamia officinalis , 2017 .

[34]  Rohit Arora,et al.  Ameliorative potential of Alstonia scholaris (Linn.) R. Br. against chronic constriction injury-induced neuropathic pain in rats , 2017, BMC Complementary and Alternative Medicine.

[35]  K. Maiese.  Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders. , 2016, British journal of clinical pharmacology.

[36]  Heng-shan Wang,et al.  Effect of total alkaloids from Alstonia scholaris on airway inflammation in rats. , 2016, Journal of ethnopharmacology.

[37]  Qiong Chen,et al.  A review on recent developments of indole-containing antiviral agents , 2014, European Journal of Medicinal Chemistry.

[38]  K. Chowdary,et al.  Ethanolic extracts of Alstonia Scholaris and Bacopa Monniera possess neuroleptic activity due to anti-dopaminergic effect , 2014, Pharmacognosy research.

[39]  A. Buchan,et al.  Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy , 2013, Nature Medicine.