The plant natural product 2-methoxy-1,4-naphthoquinone stimulates therapeutic neural repair properties of olfactory ensheathing cells

Abstract

Olfactory ensheathing cells (OECs) are crucial for promoting the regeneration of the primary olfactory nervous system that occurs throughout life. Transplantation of OECs has emerged as a promising therapy for nervous system injuries, in particular for spinal cord injury repair. Functional outcomes in both animals and humans are, however, highly variable, primarily because it is difficult to rapidly obtain enough OECs for transplantation. Compounds which can stimulate OEC proliferation without changing the phenotype of the cells are therefore highly sought after. Additionally, compounds which can stimulate favourable cell behaviours such as migration and phagocytic activity are desirable. We conducted a medium-throughput screen testing the Davis open access natural product-based library (472 compounds) and subsequently identified the known plant natural product 2-methoxy-1,4naphthoquinone as a stimulant of OEC viability. We showed that 2-methoxy-1,4-naphthoquinone: (i) strongly stimulates proliferation over several weeks in culture whilst maintaining the OEC phenotype; (ii) stimulates the phagocytic activity of OECs, and (iii) modulates the cell cycle. We also identified the transcription factor Nrf2 as the compound's potential molecular target. From these extensive investigations we conclude that 2-methoxy-1,4-naphthoquinone may enhance the therapeutic potential of OECs by stimulating proliferation prior to transplantation.

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

“…These compounds have been found to exhibit antibacterial, antifungal, antioxidant, hepatoprotective, cardioprotective, anti-ischaemic properties and other properties. Their role in protecting against neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease has also been established [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. One of the 1,4-NQs synthesized by our group, U-133, exhibited a promising neuroprotective effect in an in vivo PD rat model [ 13 ].…”

Antimicrobial responses of peripheral and central nervous system glia against Staphylococcus aureus

“…The capacity for phagocytosis by transplanted OECs is also likely beneficial, as the cells can help clear cell debris present at the injury site. Compounds that can stimulate the phagocytic activity of OECs without causing a strong pro-inflammatory response have been suggested to potentially increase the therapeutic potential of these cells 64 – 68 . Thus, it is important to characterise which cytokines are expressed by OECs under various conditions.…”

Phagocytosis by Peripheral Glia: Importance for Nervous System Functions and Implications in Injury and Disease

“…Several studies have to date identified compounds that can stimulate OEC phagocytosis (as well as autophagy -a topic which remains to be studied in itself). We, along with laboratories around the world, have identified various agents that can increase OEC phagocytosis, including the natural products 2-methoxy-1,4-naphthoquinone (Chen et al, 2020), the serrulatane diterpenoids 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid and 3,7,8-trihydroxyserrulat-14-en-19-oic acid (Chen et al, 2018), curcumin (Velasquez et al, 2014); curcumin in combination with E. coli-derived LPS (Hao et al, 2017), and anti-inflammatory cytokine TGF-β (Li et al, 2017). In vitro injury assays (neurons co-cultured with OECs accompanied by neuronal debris addition), showed that increased OEC clearance of debris due to application of stimuli (LPS + curcumin Hao et al, 2017or TGF-β Li et al, 2017 promoted neuronal survival.…”