Neuroprotective Effect of 1,4-Naphthoquinones in an In Vitro Model of Paraquat and 6-OHDA-Induced Neurotoxicity.

Ekaterina Menchinskaya,Ekaterina Chingizova,Galina Likhatskaya,Yuri Sabutski,Dmitry Pelageev,Evgeny Pislyagin,Sergei Polonik,Dmitry Aminin

doi:10.3390/ijms22189933

Abstract

Targeted screening using the MTT cell viability test with a mini-library of natural and synthetic 1,4-naphthoquinones and their derivatives was performed in order to increase the survival of Neuro-2a neuroblastoma cells in in vitro paraquat and 6-hydroxydopamine models of Parkinson’s disease. As a result, 10 compounds were selected that could protect neuronal cells from the cytotoxic effects of both paraquat and 6-hydroxydopamine. The five most active compounds at low concentrations were found to significantly protect the activity of nonspecific esterase from the inhibitory effects of neurotoxins, defend cell biomembranes from lytic destruction in the presence of paraquat and 6-hydroxydopamine, and normalize the cell cycle. The protective effects of these compounds are associated with the suppression of oxidative stress, decreased expression of reactive oxygen species and nitric oxide formation in cells and normalization of mitochondrial function, and restoration of the mitochondrial membrane potential altered by neurotoxins. It was suggested that the neuroprotective activity of the studied 1,4-NQs is attributable to their pronounced antioxidant and free radical scavenging activity and their ability to reduce the amount of reactive oxygen species formed by paraquat and 6-hydroxydopamine action on neuronal cells. The significant correlation between the neuroprotective properties of 1,4-naphthoquinones and Quantitative Structure–Activity Relationship descriptors describing the physicochemical properties of these compounds means that the hydrophobicity, polarity, charge, and shape of the molecules can be of decisive importance in determining the biological activity of studied substances.

Highlights

Parkinson’s disease (PD) is an age-dependent and slowly progressive chronic neurodegenerative disease
We synthesized a library of 5,8-dihydroxy-1,4-naphthoquinone derivatives (44 compounds) and studied their cytotoxic properties against mouse neuronal Neuro-2a cells using the Quantitative Structure-Activity Relationship (QSAR) approach [14]. We evaluated whether these 1,4-NQ derivatives protect Neuro-2a cells and increase cell viability in two in vitro models of PD induced by the PQ and 6-OHDA neurotoxins
Our results indicate that among the 1,4-naphthoquinones and their derivatives synthesized by us and composing a combinatorial mini-library, compounds with pronounced neuroprotective properties were found

Summary

Introduction

Parkinson’s disease (PD) is an age-dependent and slowly progressive chronic neurodegenerative disease. PD is caused by the progressive destruction and death of neurons that produce the neurotransmitter dopamine, primarily in the substantia nigra and in other parts of the central nervous system. It is the second most common neurodegenerative disease worldwide [1,2]. Paraquat (PQ) is N,N -dimethyl-4,4 -dipyridylium dichloride, a highly toxic compound used in a number of countries as a potent herbicide. PQ was one of the first compounds used to model PD. This, in turn, induces the increased production of reactive oxygen species (ROS) and increases the levels of α-synuclein and tau protein, α-tubulin hyperacetylation, inhibition of proteasomes, and dysfunction of axonal autophagy, which result in symptoms of PD [3]

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