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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

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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 Neuro-2a 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 cAMP-response 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.

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Abbreviations

HD:

Huntington’s disease

3-NP:

3-Nitropropionic acid

7,8-DHF:

7,8-Dihydroxyflavone

BDNF:

Brain-derived neurotrophic factor

ANA-12:

2N-[2-[[(Hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]benzo[b] thiophene-2-carboxamide

Wort:

Wortmannin

TrkB:

Tropomyosin-related kinase B

CREB:

CAMP-response element binding protein

PI3K:

Phosphatidylinositol 3-kinase

Akt:

Protein kinase B

Bad:

Bcl-2-associated death promoter

Bcl-2:

B-cell lymphoma 2

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Acknowledgements

The research fellowship was supported by the National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, under the aegis of Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India. The authors acknowledge NMHS Grant (GBPI/NMHS-2017-18/HSF-02), Ministry of Environment Forest and Climate Change, Government of India for providing financial support to carry out the research work. The authors also acknowledge DST-SAIF, All India Institute of Medical Sciences (AIIMS) New Delhi-India for helping with the tissue preparation and analysis of brain TEM samples.

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  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research-Guwahati, Sila Katamur, Halugurisuk, P.O.- Changsari, Kamrup, Assam, 781101, India

    Sahabuddin Ahmed, Mohit Kwatra, Basveshwar Gawali, Samir Ranjan Panda & V. G. M. Naidu

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  1. Sahabuddin Ahmed
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  2. Mohit Kwatra
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  3. Basveshwar Gawali
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Contributions

V.G.M. Naidu provided overall guidance from designing the experiment, model establishment, and manuscript writing. Sahabuddin Ahmed contributed to the in vitro and in vivo experimental design, model establishment, Immunohistochemistry and manuscript writing. Mohit Kwatra contributed for in vitro and in vivo experiments, manuscript writing, western blot estimation and electron microscopy. Basveshwar Gawali and Samir Ranjan Panda have done the animal behavior assessments and histopathology.

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Correspondence to V. G. M. Naidu.

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Ahmed, S., Kwatra, M., Gawali, B. et al. 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. Apoptosis 26, 52–70 (2021). https://doi.org/10.1007/s10495-020-01645-x

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