Spongionella Secondary Metabolites Protect Mitochondrial Function in Cortical Neurons against Oxidative Stress

Abstract

The marine habitat provides a large number of structurally-diverse bioactive compounds for drug development. Marine sponges have been studied over many years and are found to be a rich source of these bioactive chemicals. This study is focused on the evaluation of the activity of six diterpene derivatives isolated from Spongionella sp. on mitochondrial function using an oxidative in vitro stress model. The test compounds include the Gracilins (A, H, K, J and L) and tetrahydroaplysulphurin-1. Compounds were co-incubated with hydrogen peroxide for 12 hours to determine their protective capacities and their effect on markers of apoptosis and Nrf2/ARE pathways was evaluated. Results conclude that Gracilins preserve neurons against oxidative damage, and that in particular, tetrahydroaplysulphurin-1 shows a complete neuroprotective activity. Oxidative stress is linked to mitochondrial dysfunction and consequently to neurodegenerative disorders like Parkinson and Alzheimer diseases, Friedreich ataxia or Amyotrophic lateral sclerosis. This neuroprotection against oxidation conditions suggest that these metabolites could be interesting lead candidates in drug development for neurodegenerative diseases.

Spongionella Secondary Metabolites Regulate Store Operated Calcium Entry Modulating Mitochondrial Functioning in SH-SY5Y Neuroblastoma Cells

“…Thus, as for CsA, Spongionella compounds inhibited the mPTP opening induced by FCCP. Moreover, in previous papers Spongionella compounds were described to preserve neurons against oxidative damage and to block apoptosis markers production, caspase-3, in mouse cortical neurons [15]. These results are in accordance with the effects observed by these compounds over mPTP.…”

“…Spongionella compounds were reported to be active against hydrogen peroxidation in primary cortical neurons through an effect closely linked to mitochondrial dysfunction [15]. Ca 2+ dyshomeostasis is a key factor in the development of pathophysiological disorders such as neurodegenerative, autoimmune or inflammatory diseases, among others [9,17,18].…”

“…In this sense, Spongionella derived compounds have shown high activity to protect mitochondrial function in vitro and they have been described as promising compounds for diseases where ROS have a central role, as in AD. Thus, in vivo assays revealed that some of Spongionella compounds were able to reduced Amyloid-β peptide (Aβ) and hyperphosphorylated tau levels [15,16]. There is a strong relationship between mitochondrial Aβ and Cyp D interaction and the accumulation and production of mitochondrial ROS as a result of this interaction that leads in the Cyp D recruitment and the increased susceptibility to induce mPTP opening [9].…”

“…In this sense, bisnorditerpene gracilin H, norditerpene gracilin A, 12-hydroxy derivative gracilin L and the diterpenoid 3´-norspongionlactone tetrahydroaplysulphurin-1 are secondary metabolites isolated from the marine sponge Spongionella with unusual structural characteristics and unknown mechanism of action [14]. In previous works these Spongionella compounds were described as neuroprotective modulating mitochondrial functioning and preserving neurons against oxidative damage [15]. The neuroprotection against oxidation conditions suggested that these metabolites could be interesting lead candidates in drug development for Chemicals Carboxymethyl dextran (CM5) sensor chips, Hank´s Balance Solution Surfactant P20 (HBS-EP) buffer (pH 7.4, 0.01 M 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 0.15 M NaCl, 3 mM Ethylenediamine tetraacetic acid (EDTA), 0.005% polysorbate), sodium acetate, glycine-HCl and amine coupling kit (1-ethyl-3-(3-dimetylaminopropyl) carbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS) and ethanolamine-HCl were supplied by BiacoreAB (Uppsala, Sweden).…”

“…Therefore, since Spongionella compounds had some effect over these organelles [15,16], it was important to clarify to which extent the inhibitory effect on SOC fluxes of these compounds was influenced by mitochondrion. To do this FCCP and CsA were used.…”