Exploring the Effect of Endoplasmic Reticulum Stress Inhibition by 4-Phenylbutyric Acid on AMPA-Induced Hippocampal Excitotoxicity in Rat Brain
- 64 Downloads
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.
KeywordsExcitotoxicity ER stress Chemical chaperone Hippocampus Oxidative stress
This work was supported by the University Grant Commission-Basic Scientific Research (UGC-BSR) (F.25-1/2013-14(BSR)/7-209/2009(BSR).
Compliance with Ethical Standards
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.
Conflict of Interest
The authors declare that they have no conflict of interest.
- Hilton GD, Nunez JL, Bambrick L, Thompson SM, McCarthy MM (2006) Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol. Eur J Neurosci 24:3008–3016CrossRefPubMedPubMedCentralGoogle Scholar
- Pereira EPL, Braga-De-Souza S, Santos CC, Amparo J, Short Ferreira R, Nuñez-Figueredo Y, Gonzaga Fernandez L, Ribeiro PR, Braga-de-Souza S, Amaral da Silva VD, Lima Costa S (2017) Amburana cearensis seed extract protects brain mitochondria from oxidative stress and cerebellar cells from excitotoxicity induced by glutamate. Rev Bras 27:199–205Google Scholar
- Petegnief V, Saura J, Dewar D, Cummins DJ, Dragunow M, Mahy N (1999) Long-term effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione in the rat basal ganglia: calcification, changes in glutamate receptors and glial reactions. Neuroscience 94:105–115CrossRefPubMedGoogle Scholar
- Prentice H, Modi JP, Wu JY (2015) Mechanisms of neuronal protection against excitotoxicity, endoplasmic reticulum stress, and mitochondrial dysfunction in stroke and neurodegenerative diseases. Oxid Med Cell Longev 2015:7 pagesGoogle Scholar