17-Oxime ethers of oxidized ecdysteroid derivatives modulate oxidative stress in human brain endothelial cells and dose-dependently might protect or damage the blood-brain barrier

Vágvölgyi, Máté

Laczkó, Dávid

Santa Maria, Anaraquel

Vigh, Judit Piroska

Walter, Fruzsina

Berkecz, Róbert

Deli, Mária Anna

Tóth, Gábor

Hunyadi, Attila

2024

RM Therapeutics. Pharmacology / terápia, gyógyszertan

20-Hydroxyecdysone and several of its oxidized derivatives exert cytoprotective effect in mammals including humans. Inspired by this bioactivity of ecdysteroids, in the current study it was our aim to prepare a set of sidechain-modified derivatives and to evaluate their potential to protect the blood-brain barrier (BBB) from oxidative stress. Six novel ecdysteroids, including an oxime and five oxime ethers, were obtained through regioselective synthesis from a sidechain-cleaved calonysterone derivative 2 and fully characterized by comprehensive NMR techniques revealing their complete 1 H and 13 C signal assignments. Surprisingly, several compounds sensitized hCMEC/D3 brain microvascular endothelial cells to tert -butyl hydroperoxide (tBHP)-induced oxidative damage as recorded by impedance measurements. Compound 8 , containing a benzyloxime ether moiety in its sidechain, was the only one that exerted a protective effect at a higher, 10 μM concentration, while at lower (10 nM– 1 μM) concentrations it promoted tBHP-induced cellular damage. Brain endothelial cells were protected from tBHP-induced barrier integrity decrease by treatment with 10 μM of compound 8 , which also mitigated the intracellular reactive oxygen species production elevated by tBHP. Based on our results, 17-oxime ethers of oxidized ecdysteroids modulate oxidative stress of the BBB in a way that may point towards unexpected toxicity. Further studies are needed to evaluate any possible risk connected to dietary ecdysteroid consumption and CNS pathologies in which BBB damage plays an important role.

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text

https://real.mtak.hu/217953/1/VagvolgyiM_17Oxime.pdf

Vágvölgyi, Máté and Laczkó, Dávid and Santa Maria, Anaraquel and Vigh, Judit Piroska and Walter, Fruzsina and Berkecz, Róbert and Deli, Mária Anna and Tóth, Gábor and Hunyadi, Attila (2024) 17-Oxime ethers of oxidized ecdysteroid derivatives modulate oxidative stress in human brain endothelial cells and dose-dependently might protect or damage the blood-brain barrier. PLOS ONE, 19 (2). No.-e0290526. ISSN 1932-6203

https://real.mtak.hu/217953/

https://doi.org/10.1371/journal.pone.0290526

MTMT:34691003 10.1371/journal.pone.0290526

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