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

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.

Keywords: Alzheimer’s disease; Ethyl pyruvate; Memory loss; Neuroinflammation; Toll-like receptor 4.