The Antidiabetic Drug Liraglutide Minimizes the Non-Cholinergic Neurotoxicity of the Pesticide Mipafox in SH-SY5Y Cells.

Abstract

Organophosphorus (OPs) compounds have been widely used in agriculture, industry, and household, and the neurotoxicity induced by them is still a cause of concern. The main toxic mechanism of OPs is the inhibition of acetylcholinesterase (AChE); however, the delayed neuropathy induced by OPs (OPIDN) is mediated by other mechanisms such as the irreversible inhibition of 70% of NTE activity (neuropathy target esterase) that leads to axonal degeneration. Liraglutide is a long-lasting GLP-1 analog clinically used as antidiabetic. Its neurotrophic and neuroprotective effects have been demonstrated in vitro and in experimental models of neurodegenerative diseases. As in OPIDN, axonal degeneration also plays a role in neurodegenerative diseases. Therefore, this study investigated the protective potential of liraglutide against the neurotoxicity of OPs by using mipafox as a neuropathic agent (at a concentration able to inhibit and age 70% of NTE activity) and a neuronal model with SH-SY5Y neuroblastoma cells, which express both esterases. Liraglutide protected cells against the neurotoxicity of mipafox by increasing neuritogenesis, the uptake of glucose, the levels of cytoskeleton proteins, and synaptic-plasticity modulators, besides decreasing the pro-inflammatory cytokine interleukin 1β and caspase-3 activity. This is the first study to suggest that liraglutide might induce beneficial effects against the delayed, non-cholinergic neurotoxicity of OPs.