NP04634 prevents cell damage caused by calcium overload and mitochondrial disruption in bovine chromaffin cells.
Marine sponges are becoming a rich source of potential new medicines. NP04634 is a synthetic derivative of 11,19 dideoxyfistularin, a natural product of the Mediterranean sponge Aplysina cavernicola. We report the cytoprotective effects of this new compound in isolated bovine chromaffin cells exposed to cytotoxic stimuli that have been related to neuronal cell death, i.e. Ca(2+) overload and mitochondrial dysfunction. Cell death was achieved by: (i) causing Ca(2+) overload through voltage-dependent calcium channels by exposing the cells to 30 mM K(+), 5 mM Ca(2+) plus 0.3 microM FPL64176 (an L-type Ca(2+)-channel activator); (ii) incubating the cells with veratridine, causing cytosolic Ca(2+) concentration ([Ca(2+)](c)) oscillations and mitochondrial disruption; and (iii) blocking mitochondrial complexes I and V using a combination of 30 microM rotenone and 10 microM oligomycin. At 10 microM, NP04634 caused significant protection against 30K(+)/5Ca(2+)/FPL-induced toxicity. NP04634 caused a concentration-dependent reduction in [Ca(2+)](c) induced by 70 mM K(+) in cells loaded with Fluo-4; maximum blockade was 67% at 30 microM. Veratridine caused continuous [Ca(2+)](c) oscillations that translated into 43.4+/-2% cell death. In this model, NP04634 caused 42% and 67% protection at 3 and 10 microM, respectively. NP04634 reduced [Ca(2+)](c) oscillations and mitochondrial depolarization caused by veratridine. NP04634 at 10 microM also protected against mitochondrial disruption caused by rotenone plus oligomycin. In conclusion, NP04634 is a novel compound of marine origin with cytoprotective properties that might have potential therapeutic implications under pathological circumstances involving Ca(2+) overload and mitochondrial disruption, such as in certain neurodegenerative diseases and/or stroke.
Valero
Teresa
T
Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Spain.
del Barrio
Laura
L
Egea
Javier
J
Cañas
Noelia
N
Martínez
Ana
A
García
Antonio G
AG
Villarroya
Mercedes
M
López
Manuela G
MG
D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008928:Mitochondria / Q000187:drug effects; D011161:Porifera / Q000737:chemistry; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*
D001549:Benzamides; D020746:Calcium Channels, L-Type; C541784:NP 04634; D020011:Protective Agents; D002118:Calcium