<EM>DICTYOTA</EM> SPP. DITERPENOIDS PROTECT MICROGLIA FROM ISCHEMIA-REPERFUSION INJURY BY MODULATING STRESS-RELATED PATHWAYS

The aim of this study was to evaluate the protective effects of four diterpenoids (1, 2, 3 and 4) purified from two species of brown seaweeds of the genus Dictyota under ischemia/reperfusion conditions. For this purpose, BV2 microglial cells were subjected to oxygen-glucose deprivation (OGD) followed by reperfusion (REP) together with compounds. In these conditions, cell viability, mitochondrial membrane potential (∆Ψm) and the activation of hypoxia-inducible factor 1α (HIF-1α) were evaluated in order to assess the mitochondrial protective effects of compounds. Interestingly, compounds 1, 2, 3 and 4 protected microglial cells from OGD/REP injury with better outcomes than the immunosuppressant drug cyclosporin A (CsA). In addition, results showed that these metabolites were as potent as CsA reducing the impact of ischemia by restoring ∆Ψm, indicating mitochondrial-protective properties. Finally, compounds 1, 3 and 4 enhanced the activation of HIF1⍺, a transcription factor involved in hypoxia adaptation and redox homeostasis, while CsA, an inhibitor of cyclophilins (Cyps), proteins involved in inflammation, was uneffective. In summary, this study identifies diterpenoids from Dictyota spp. as promising protective agents against ischemia/reperfusion injury through the modulation of stress-response pathways.