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

ITH33/IQM9.21 is a novel compound belonging to a family of glutamic acid derivatives...

Autores: Lorrio S, Gómez-Rangel V, Negredo P, Egea J, Leon R, Romero A, Dal-Cim T, Villarroya M, Rodriguez-Franco MI, Conde S, Arce MP, Roda JM, García AG, López MG.

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.

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Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid, Spain.


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