Neuroprotective Effects of Furanoditerpenes from Spongia (Spongia) Tubulifera through Cyclophilin D Modulation against Ischemia/Reperfusion Injury in BV2 Microglial Cells

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Abstract
Ischemia induces oxidative stress and mitochondrial dysfunction in microglia, contributing to neuro-inflammation and neuronal damage. Five furanoditerpenes 1–5, isolated from the marine sponge Spongia (Spongia) tubulifera, have previously shown neuroprotective effects related to their capacity to bind cyclophilin D (CypD), a protein involved in ischemia. In this study, the ability of compounds 1–5 to alleviate ischemic damage was evaluated on BV2 microglial cells. First, cells were incubated under oxygen deprivation for 6 h, and the five compounds were able to improve cell viability at micromolar concentrations (0.001–1 μM). Then, hypoxia was combined with the inflammatory stimulus lipopolysaccharide and with glucose deprivation, and Spongia tubulifera metabolites maintained their protective effects. When oxygen and glucose deprivation was followed by 6 h of reperfusion, compounds 1–5 also mitigated the damage produced on microglia. Moreover, these furanoditerpenes reduced reactive oxygen species overproduction and restored mitochondrial membrane potential, key factors in ischemic damage. This effect was mediated by the regulation of CypD since compounds 2, 4, and 5 reduced its expression under ischemia conditions. Finally, trans-well coculture experiments were performed between microglial and SH-SY5Y neuronal cells. In this assay, compounds 2, 4, and 5 protected neuronal cells from microglial-induced neurotoxicity under ischemia/reperfusion conditions. These findings suggest that S. tubulifera metabolites display mitochondrial-mediated antioxidant and cytoprotective effects under ischemic conditions through CypD modulation. Given the limitations of current Cyps inhibitors like cyclosporin A, compounds 1–5 are promising therapeutic candidates for ischemia-related diseases, such as stroke.
Funding Information
  • Ministerio de Ciencia, Innovación y Universidades (PID2023-149618OB-I00)
  • European Commission (HORIZON-CL6-2023-CIRCBIO-01 COMBO - 101135438)
  • European Commission (Interreg EAPA_0130/2024-REVALGAE)
  • European Commission (Interreg EAPA-0032/2022-BEAP-MAR)
  • Xunta de Galicia (ED481A_2023)
  • Ministerio de Ciencia, Tecnología e Innovación (CPP2021-008447)
  • NextGenerationEU (CPP2021-008447)
  • Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia (GI-1682-2025)

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