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Exploring the Effect of Endoplasmic Reticulum Stress Inhibition by 4-Phenylbutyric Acid on AMPA-Induced Hippocampal Excitotoxicity in Rat Brain

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Abstract

Excessive stimulation of ionotropic glutamate receptor is associated with glutamate-mediated excitotoxicity, thereby causing oxidative imbalance and mitochondrial dysfunction, resulting in the excitotoxic death of neurons. Eminent role of endoplasmic reticulum under glutamate-induced excitotoxicity has been highlighted in numerous literatures which have been observed to trigger endoplasmic reticulum stress (ER stress) as well as regulating oxidative stress. However, combating ER stress in excitotoxic neurons can provide a novel approach to alleviate the mitochondrial dysfunctioning and ROS generation. Therefore, we propose to investigate the cross-communication of α-amino-3-hydroxy-5-methyl-4-isoxzole-propionate (AMPA) excitotoxicity-induced oxidative injury with ER stress by employing ER stress inhibitor—4-phenlybutyric acid (4-PBA). Male SD rats were divided into four groups viz sham group (group 1), AMPA (10 mM)-induced excitotoxic group (group 2), curative group of AMPA-induced excitotoxic animals given 4-PBA at a dose of 100 mg/kg body weight (group 3), and alone 4-PBA treatment group (100 mg/kg body weight) (group 4). Animals were sacrificed after 15 days of treatment, and hippocampi were analyzed for histopathological examination, ROS, inflammatory markers, mitochondrial dysfunction, and ER stress markers. AMPA-induced excitotoxicity exhibited a significant increase in the levels of ROS, upregulated ER stress markers, inflammation markers, and compromised mitochondrial functioning in the hippocampus. However, 4-PBA administration significantly curtailed the AMPA-induced excitotoxic insult. This study suggests that targeting ER stress with a chemical chaperone can provide a better therapeutic intervention for neurological disorders involving excitotoxicity, and thus, it opens a new avenue to screen chemical chaperones for the therapeutic modalities.

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Funding Source

This work was supported by the University Grant Commission-Basic Scientific Research (UGC-BSR) (F.25-1/2013-14(BSR)/7-209/2009(BSR).

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Authors and Affiliations

  1. Department of Biophysics, Panjab University, Chandigarh, 160014, India

    Ankita Bhardwaj, Rishi Bhardwaj, Devinder Kumar Dhawan & Tanzeer Kaur

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  1. Ankita Bhardwaj
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  2. Rishi Bhardwaj
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  3. Devinder Kumar Dhawan
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  4. Tanzeer Kaur
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Corresponding author

Correspondence to Tanzeer Kaur.

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Animals were maintained as per the principles and guidelines of the Ethics Committee of the Animal Care of Panjab University in accordance with the Indian national law on animal care and use. The animal experimental protocols were approved by Institutional Animal Ethics Committee (reference no. PU/IAEC/S/15/42) and conducted according to the Indian National Science Academy Guidelines for the use and care of experimental animals.

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Bhardwaj, A., Bhardwaj, R., Dhawan, D.K. et al. Exploring the Effect of Endoplasmic Reticulum Stress Inhibition by 4-Phenylbutyric Acid on AMPA-Induced Hippocampal Excitotoxicity in Rat Brain. Neurotox Res 35, 83–91 (2019). https://doi.org/10.1007/s12640-018-9932-0

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