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Title

Novel multitarget ligand ITH33/IQM9.21 provides neuroprotection in in vitro and in vivo models related to brain ischemia

AuthorsLorrio, Silvia; Gómez-Rangel, Vanessa; Negredo, Pilar; Egea, Javier; León, Rafael ; Romero, Alejandro CSIC ORCID; Dal-Cim, Tharine.; Villarroya, Mercedes; Rodríguez-Franco, María Isabel CSIC ORCID ; Conde, Santiago CSIC; Arce, Mariana P. CSIC; Roda, José María; García, Antonio G.; López, Manuela G.
KeywordsFree radicals
Photothrombotic stroke
Oxygen and glucose deprivation
ITH33/IQM9.21
Hippocampal slices
GSH
iNOS
Neuroprotection
Issue Date2013
PublisherElsevier
CitationNeuropharmacology 67: 403- 411 (2013)
AbstractITH33/IQM9.21 is a novel compound belonging to a family of glutamic acid derivatives, synthesized under the hypothesis implying that multitarget ligands may provide more efficient neuroprotection than single-targeted compounds. In rat hippocampal slices, oxygen plus glucose deprivation followed by re-oxygenation (OGD/Reox) elicited 42% cell death. At 1 μM, ITH33/IQM9.21 mitigated this damage by 26% and by 55% at 3 μM. OGD/Reox also elicited mitochondrial depolarization, overproduction of reactive oxygen species (ROS), enhanced expression of nitric oxide synthase (iNOS) and reduction of GSH levels. These changes were almost fully prevented when 3 μM ITH33/IQM9.21 was present during slice treatment with OGD/Reox. In isolated hippocampal neurons, ITH33/IQM9.21 reduced [Ca2+]c transients induced by a high K+ depolarizing solution or glutamate. In a photothrombotic model of stroke in mice, intraperitoneal injection of ITH33/IQM9.21 at 1.25 mg/kg, 2.5 mg/kg or 5 mg/kg given before and during 2 days after stroke induction, reduced infarct volume by over 45%. Furthermore, when the compound was administered 1 h post-stroke, a similar effect was observed. In conclusion, these in vitro and in vivo results suggest that ITH33/IQM9.21 exhibits neuroprotective effects to protect the vulnerable neurons at the ischemic penumbra by an effective and multifaceted mechanism, mediated by reduction of Ca2+ overload, providing mitochondrial protection and antioxidant actions.
URIhttp://hdl.handle.net/10261/103294
DOI10.1016/j.neuropharm.2012.12.001
Identifiersdoi: 10.1016/j.neuropharm.2012.12.001
issn: 0028-3908
e-issn: 1873-7064
Appears in Collections:(IQM) Artículos

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