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Neuroprotective Effects of Ethyl Pyruvate against Aluminum Chloride-Induced Alzheimer’s Disease in Rats via Inhibiting Toll-Like Receptor 4

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the formation of insoluble deposits of β-amyloid (Aβ) plaques within the parenchyma of the brain. The present study aimed to investigate the neuroprotective role of ethyl pyruvate against in vitro and in vivo model of aluminum chloride (AlCl3)-induced AD. Effect of ethyl pyruvate (5, 10, 20, 40 mM) against AlCl3 (1250 μM)-induced neurotoxicity in primary neuron-glial mixed cell culture was evaluated using cell viability assays (MTT assay as well as calcein-AM/propidium iodide fluorescent dyes). In vivo model, AlCl3 (50 mg/kg) were given through intraperitoneal route (i.p.) once daily for 4 weeks in rats and after 2 weeks, ethyl pyruvate (50, 100, 200 mg/kg/day) was co-administered with AlCl3 once daily via the oral route. The present study, in addition to perform histopathology of the brain, also estimated oxidant and antioxidant parameters as well as memory impairment using pole test, plus maze, and Morris water maze test. The binding mode of ethyl pyruvate in the hMD-2 was also studied. Results of in vitro studies showed that the AlCl3 administration resulted in neuronal cell death. AlCl3 administration in rats resulted in memory loss, oxidative stress (increased lipid peroxide and nitric oxide), impairment of antioxidant mechanisms (superoxide dismutase, catalase, and reduced glutathione), and deposition of amyloid plaques in cerebral cortex region of the brain. AlCl3 also resulted in the overexpression of the TLR4 receptors in the brain tissues. Administration of ethyl pyruvate ameliorated the AlCl3-induced neurotoxicity in neuron-glial mixed cell culture as well as histopathological, neurochemical, and behavioral consequences of chronic administration of AlCl3 in the rat. Ethyl pyruvate showed a docking score of 4.048. Thus, ethyl pyruvate is effective against in vitro and in vivo models of AlCl3-induced AD.

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Acknowledgments

The manuscript is based on M.S. (Pharm.) Dissertation project work done by Ms. Vijaya Durga Chavali from July 2014 to June 2015 at the Department of Pharmacology and Toxicology, NIPER-Ahmedabad. However, the in silico work is done in the Institute of Pharmacy, Nirma University. The authors acknowledge B. V. Patel PERD Centre, Ahmedabad, for institutional support.

Funding

Authors recognize the Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Government of India, and National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, India, for financial support.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Palaj, Gandhinagar, Gujarat, 382355, India

    Vijaya Durga Chavali

  2. Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej, S.G. Highway, Ahmedabad, Gujarat, 380054, India

    Milee Agarwal

  3. Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, S.G. Highway, Ahmedabad, 382481, India

    Vivek Kumar Vyas

  4. Department of Pharmacology, Institute of Pharmacy, Nirma University, S.G. Highway, Ahmedabad, 382481, India

    Bhagawati Saxena

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  1. Vijaya Durga Chavali
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Correspondence to Bhagawati Saxena.

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Animal housing and handling were performed as per Good Laboratory Practice (GLP) mentioned in CPCSEA guidelines. Institutional Animal Ethics Committee (IAEC) approved the in vitro and in vivo experimentation protocol (Protocol No. PERD/IAEC/2014/005 and PERD/IAEC/2014/006).

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Chavali, V.D., Agarwal, M., Vyas, V.K. et al. Neuroprotective Effects of Ethyl Pyruvate against Aluminum Chloride-Induced Alzheimer’s Disease in Rats via Inhibiting Toll-Like Receptor 4. J Mol Neurosci 70, 836–850 (2020). https://doi.org/10.1007/s12031-020-01489-9

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