Characterization of a CholesteroNitrone (ISQ-201), a Novel Drug Candidate for the Treatment of Ischemic Stroke
Martínez-Alonso, Emma (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Escobar-Peso, Alejandro (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Ayuso, Maria I. (Instituto de Biomedicina de Sevilla)
Gonzalo Gobernado, Rafael (Instituto de Biomedicina de Sevilla)
Chioua, Mourad (Laboratory of Medicinal Chemistry (Madrid))
Montoya, Juan J. (Isquaemia Biotech (Córdoba))
Montaner, Joan (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Fernández, Israel (Universidad Complutense de Madrid)
Marco-Contelles, José (Laboratory of Medicinal Chemistry (Madrid))
Alcázar, Alberto (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Universitat Autònoma de Barcelona

Data:	2020
Resum:	Nitrones have a well-recognized capacity as spin-traps and are considered powerful free radical scavengers, which are two important issues in hypoxia-induced oxidative stress and cell death in brain ischemia. Consequently, nitrones have been proposed as therapeutic agents in acute ischemic stroke (AIS). In this paper, we update the biological and pharmacological characterization of ISQ-201, a previously identified cholesteronitrone hybrid with antioxidant and neuroprotective activity. This study characterizes ISQ-201 as a neuroprotective agent against the hypoxia-induced ischemic injury. Transitory four-vessel occlusion and middle cerebral artery occlusion (tMCAO) were used to induce cerebral ischemia. Functional outcomes were determined using neurofunctional tests. Infarct area, neuronal death, and apoptosis induction were evaluated. In addition, ISQ-201 reactivity towards free radicals was studied in a theoretical model. ISQ-201 significantly decreased the ischemia-induced neuronal death and apoptosis, in a dose-dependent manner, showing its therapeutic effect when administered up until 6 h after post-ischemic reperfusion onset, effects that remained after 3 months from the ischemic episode. Furthermore, ISQ-201 significantly reduced infarct volume, leading to recovery of the motor function in the tMCAO model. Finally, the theoretical study confirmed the reactivity of ISQ-201 towards hydroxyl radicals. The results reported here prompted us to suggest ISQ-201 as a promising candidate for the treatment of AIS.
Ajuts:	Instituto de Salud Carlos III PI18/00255 Ministerio de Economía y Competitividad RETICS RD16/0019/0006 Ministerio de Economía y Competitividad CTQ2016-78205-P Ministerio de Economía y Competitividad CTQ2016-81797-REDC Instituto de Salud Carlos III IFI18/00011
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Antioxidant ; Brain ischemia ; Hydroxyl radical ; Ischemic stroke ; Neuroprotection ; Nitrones ; Steroids ; Reactive oxygen species
Publicat a:	Antioxidants, Vol. 9 (march 2020) , ISSN 2076-3921

DOI: 10.3390/antiox9040291
PMID: 32244303

21 p, 3.7 MB

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