title: Novel multitarget ligand ITH33/IQM9.21 provides neuroprotection in in vitro and in vivo models related to brain ischemia.
abstract: ITH33/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 [Ca(2+)](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 Ca(2+) overload, providing mitochondrial protection and antioxidant actions.
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lorrio
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gómez-Rangel
authors.forename: Pilar
authors.initials: P
authors.lastname: Negredo
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.forename: Rafael
authors.initials: R
authors.lastname: Leon
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.forename: Tharine
authors.initials: T
authors.lastname: Dal-Cim
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Rodriguez-Franco
authors.forename: Santiago
authors.initials: S
authors.lastname: Conde
authors.forename: Mariana P
authors.initials: MP
authors.lastname: Arce
authors.forename: Jose María
authors.initials: JM
authors.lastname: Roda
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D018698:Glutamic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000378:metabolism; D009924:Organ Culture Techniques; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008024:Ligands; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D018698:Glutamic Acid