The Cholinergic Antagonist Gymnodimine Improves Aβ and Tau Neuropathology in an <i>in Vitro</i> Model of Alzheimer Disease

Abstract

Gymnodimine (GYM) is a marine phycotoxin with a macrocyclic imine structure, isolated from extracts of the dinoflagellate Karenia selliformis known to act as a cholinergic antagonist with subtype selectivity. However, no data on the chronic effects of this compound has been reported so far. In this work, we evaluated the effect of long term exposure of cortical neurons to gymnodimine in the progress of Alzheimer disease (AD) pathology in vitro. Treatment of cortical neurons with 50 nM gymnodimine decreased the intracellular amyloid beta (Aβ) accumulation and the levels of the hyperphosphorylated isoforms of tau protein recognized by AT8 and AT100 antibodies. These results are suggested to be mediated by the increase in the inactive isoform of the glycogen synthase kinase-3 (phospho GSK-3 Ser9), the decrease in the levels of the active isoform of the ERK1/2 kinase and the increase in acetylcholine (Ach) synthesis elicited by long term exposure of cortical neurons to the toxin. Moreover, gymnodimine decreased glutamate-induced neurotoxicity in vitro. Altogether these results indicate that the marine phycotoxin gymnodimine may constitute a valuable tool for the development of drugs to treat neurodegenerative diseases.

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

“…The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide) assay was the test selected to analyzed cell viability as previously described [38,39]. Primary cortical neurons were grown in 96 well plates and exposed to different compound concentrations (0.01, 0.05, 0.1 and 1 µM) added to the culture medium.…”

(5S)-5-[(4aR,8aS,9E,11S,13R,14S,16R,17R,19S)-11,19-Dihydroxy-8,10,13,16-tetramethyl-18-methylidene-3,4,5,6,8a,11,12,13,14,15,16,17,18,19,20,21-hexadecahydro-2H-14,17-epoxybenzo[2,3]cyclohexadeca[1,2-b]pyridine-7-yl]-3-methylfuran-2(5H)-one (12-Methylgymnodimine B)

“…This new congener of the gymnodimine class of spiroimine toxins further expands the structural variety of this group and hence needs to be incorporated into any shellfish monitoring program. In addition to the fast acting toxicity profile for spiroimine toxins, recent literature indicates potential therapeutic value for these compounds in combating neurodegenerative diseases such as Alzheimer's disease, including the closely related gymnodimine C [15,16] as well as the spirolides [17,18]. Increasing the library of structurally diverse spiroimines available for this research is important for enhancing drug discovery efforts.…”

Mechanism of protein phosphatase-2Aregulating phosphorylation of amyloid precursor proteosome and Aβ generation

“…We have known very well that C-terminal intracellular fragment could be phosphorylated by multiple phosphokinases and the sites (17). It is considered that two elements in the APP intracellular domain could specifi cally regulate APP, could be severed by secretases, engulfed by cells or Aβ generation.…”