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Endoplasmic Reticulum Stress Instigates the Rotenone Induced Oxidative Apoptotic Neuronal Death: a Study in Rat Brain

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Abstract

The present study was conducted to evaluate the involvement of endoplasmic reticulum stress in rotenone-induced oxidative neuronal death in rat brain. Rotenone (6 μg/3 μl) was administered intranigrally, unilaterally (right side) in SD rat brain. Neuronal morphology, expression level of tyrosine hydroxylase (TH) and endoplasmic reticulum (ER) stress markers like glucose-regulated protein 78 (GRP78), growth arrest and DNA damage-inducible gene 153 (GADD153), eukaryotic translation initiation factor 2α (p-eIF2α/eIF2α) and cleaved caspase-12 were estimated in the rat brain. Levels of reactive oxygen species (ROS), reduced glutathione (GSH) and enzymatic activities of glutathione peroxidase (GPx) and glutathione reductase (GRd) were estimated to assess the rotenone induced oxidative stress. Apoptotic death of neurons was assessed by estimating the mRNA level of caspase-3. Rotenone administration caused altered neuronal morphology, decreased expression of TH, augmented ROS level, decreased level of GSH and decreased activities of GPx and GRd enzymes which were significantly attenuated with the pretreatment of ER stress inhibitor, salubrinal (1 mg/kg, intraperitoneal). Significantly increased levels of GRP78, GADD, dephosphorylated eIF2α and cleaved caspase-12 was also observed after rotenone administration, which was inhibited with the pretreatment of salubrinal. Rotenone-induced increased mRNA level of caspase-3 was also attenuated by pretreatment of salubrinal. Findings suggested that salubrinal treatment significantly inhibited the rotenone-induced neurotoxicity implicating that ER stress initiates the rotenone-induced oxidative stress and neuronal death.

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Abbreviations

ER:

Endoplasmic reticulum

GRP78:

Glucose-regulated protein 78

GADD153:

Growth arrest and DNA damage-inducible gene 153

eIF2α:

Eukaryotic translation initiation factor 2 subunit α

ROS:

Reactive oxygen species

HE:

Hematoxylin and eosin

CV:

Cresyl violet

STR:

Striatum

SN:

Substantia nigra

MB:

Midbrain

TH:

Tyrosine hydroxylase

IF:

Immunofluorescence

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Acknowledgments

Authors are thankful to the Department of Biotechnology, India (no. BT/PR4016/MED/30/674/2011) for providing the financial support. Authors are thankful to Dr. D.S. Upadhyay, Head, Division of Laboratory Animals, CSIR-CDRI, and his team for providing animals for study and Ms. Anupma Saxena for her technical help in histological studies. Poonam Goswami gratefully acknowledges the Indian Council of Medical Research (ICMR), India, for senior research fellowship and Academy of Scientific and Innovative Research (AcSIR) for providing opportunity to conduct research at CSIR-CDRI.

Conflict of interest

Authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Toxicology Division, CSIR-CDRI, Lucknow, 226031, Uttar Pradesh, India

    Poonam Goswami, Sonam Gupta, Joyshree Biswas, Sharad Sharma & Sarika Singh

  2. Academy of Scientific and Innovative Research (AcSIR), Lucknow, 226031, Uttar Pradesh, India

    Poonam Goswami & Sarika Singh

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  1. Poonam Goswami
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Correspondence to Sarika Singh.

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Goswami, P., Gupta, S., Biswas, J. et al. Endoplasmic Reticulum Stress Instigates the Rotenone Induced Oxidative Apoptotic Neuronal Death: a Study in Rat Brain. Mol Neurobiol 53, 5384–5400 (2016). https://doi.org/10.1007/s12035-015-9463-0

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