title: The new iminothiadiazole derivative VP1.14 ameliorates hippocampal damage after an excitotoxic injury.
abstract: Increased levels of glutamate causing excitotoxic damage accompany many neurological disorders. A well-characterized model of excitotoxic damage involves administration of kainic acid (KA), which causes limbic seizure activity and subsequent neuronal death, particularly in the CA1 and CA3 areas of the hippocampus. Inhibition of the enzyme glycogen synthase kinase-3 (GSK-3) and cAMP levels might play an important role in neuroprotection. As intracellular cAMP levels depend, in part, on the activity of the phosphodiesterase enzymes (PDEs), these enzymes have recently emerged as potential therapeutic targets for the treatment of several diseases. In previous works, we have shown a potent anti-inflammatory and neuroprotective effect of GSK-3 inhibition in a model of excitotoxicity, as well as a reduction of nigrostriatal dopaminergic neuronal cell death after phosphodiesterase 7 inhibition, which leads to an increase in cAMP levels. This study was undertaken to determine whether simultaneous inhibition of GSK-3 and PDE-7 by a novel 5-imino-1,2,4-thiadiazole compound, named VP1.14, could prevent the massive neuronal loss in the hippocampus evoked by intrahippocampal injection of KA. Here, we show that rats treated with VP1.14 showed a reduced inflammatory response after KA injection, and exhibited a significant reduction in pyramidal cell loss in the CA1 and CA3 areas of the hippocampus. Studies with hippocampal HT22 cells in vitro also showed a clear neuroprotective effect of VP1.14 and an anti-inflammatory effect shown by a decrease in the nitrite liberation and in the expression of pro-inflammatory cytokines by primary cultures of astrocytes treated with lipopolysaccharide.
authors: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas CSIC-UAM, Arturo Duperier, 4 and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Cristina
authors: C
authors: Susín
authors: Jose A
authors: JA
authors: Morales-Garcia
authors: Diana
authors: D
authors: Aguilar-Morante
authors: Valle
authors: V
authors: Palomo
authors: Marina
authors: M
authors: Sanz-Sancristobal
authors: Sandra
authors: S
authors: Alonso-Gil
authors: Carmen
authors: C
authors: Gil
authors: Angel
authors: A
authors: Santos
authors: Ana
authors: A
authors: Martinez
authors: Ana
authors: A
authors: Perez-Castillo
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D015552:Injections, Intralesional; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: C576317:5-imino-1,2,4-thiadiazole VP1.14; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D013830:Thiadiazoles