Potential role of TrkB agonist in neuronal survival by promoting CREB/BDNF and PI3K/Akt signaling in vitro and in vivo m
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Potential role of TrkB agonist in neuronal survival by promoting CREB/BDNF and PI3K/Akt signaling in vitro and in vivo model of 3‑nitropropionic acid (3‑NP)‑induced neuronal death Sahabuddin Ahmed1 · Mohit Kwatra1 · Basveshwar Gawali1 · Samir Ranjan Panda1 · V. G. M. Naidu.1 Accepted: 3 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Striatal neurons depends on an afferent supply of brain-derived neurotrophic factor-(BDNF) that explicitly interacts with tropomyosin receptor kinase B (TrkB) receptor and performs sundry functions including synaptic plasticity, neuronal differentiation and growth. Therefore, we aimed to scrutinize an active molecule that functions identical to BDNF in activating TrkB receptor and it’s downstream targets for restoring neuronal survival in Huntington disease (HD). Data from in vitro Neuro2a cell line showed that treatment with 7,8-dihydroxyflavone (7,8-DHF), improved 3-nitropropionic acid (3-NP) induced neuronal death by stabilizing the loss of mitochondrial membrane potential and transiently increased the activity of cAMPresponse element-binding protein (CREB) and BDNF via TrkB receptor activation. Consistent with in vitro findings, our in vivo results stated that treatment with 7,8-DHF at a dose of 10 mg/kg body weight ameliorated various behavior alterations caused by 3-NP intoxication. Further histopathological and electron microscopy evidences from striatal region of 3-NP mice brain treated with 7,8-DHF showed more improved neurons with intact mitochondria and less autophagic vacuoles. Protein expression analysis of both in vitro and in vivo study showed that 7,8-DHF promotes neuronal survival through upregulation and phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt at serine-473/threonine-308). Akt phosphorylation additionally phosphorylates Bad at serine-136 and inhibits its translocation to mitochondria thereby promoting mitochondrial biogenesis, enhanced ATP production and inhibit apoptosis mediated neuronal death. These aforementioned findings help in strengthening our hypothesis and has come up with a novel neuroprotective mechanism of 7,8-DHF against 3-NP induced neuronal death. Keywords Huntington’s disease · TrkB/CREB/BDNF signaling · PI3K Akt pathway · Mitochondrial damage · Apoptosis · 7,8-Dihydroxyflavone Abbreviations HD Huntington’s disease 3-NP 3-Nitropropionic acid 7,8-DHF 7,8-Dihydroxyflavone BDNF Brain-derived neurotrophic factor
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10495-020-01645-x) contains supplementary material, which is available to authorized users. * V. G. M. Naidu [email protected]; [email protected] 1
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and ResearchGuwahati, Sila Katamur, Halugurisuk, P.O.‑ Changsari, Kamrup, Assam 781101, India
ANA-12 2N-[2-[[(Hexahydro-2-oxo-1H-azepin3-yl)amino]carbonyl]phenyl]benzo[b] thiophene-2-carboxamide Wort Wortmannin TrkB Tropomy
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