title: Neuroprotective mechanism of the novel melatonin derivative Neu-P11 in brain ischemia related models.
abstract: Stopping the ischemic cascade by targeting its components is a potential strategy for acute ischemic stroke treatment. During ischemia and especially over reperfusion, oxidative stress plays a major role in causing neuronal cell death. Melatonin has been previously reported to provide neuroprotective effects in in vivo models of stroke by a mechanism that implicates melatonin receptors. In this context, this study was planned to test the potential neuroprotective effects of the novel melatonin MT1/MT2 receptor agonist, Neu-P11, against brain ischemia in in vitro and in vivo models, and to elucidate its underlying mechanism of action. Neu-P11 proved to be a good antioxidant, to protect against glutamate-induced excitotoxicity and oxygen and glucose deprivation in hippocampal slices, and to reduce infarct volume in an in vivo stroke model. Regarding its mechanism of action, the protective effect of Neu-P11 was reverted by luzindole (melatonin receptor antagonist), AG490 (JAK2 inhibitor), LY294002 (PI3/AKT inhibitor) and PD98059 (MEK/ERK1/2 inhibitor). In conclusion, Neu-P11 affords neuroprotection against brain ischemia in in vitro and in vivo models by activating a pro-survival signaling pathway that involves melatonin receptors, JAK/STAT, PI3K/Akt and MEK/ERK1/2.
authors.affiliation: Instituto Teófilo Hernando (ITH), Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Buendia
authors.affiliation: Instituto Teófilo Hernando (ITH), Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gómez-Rangel
authors.affiliation: Instituto Teófilo Hernando (ITH), Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: González-Lafuente
authors.affiliation: Instituto Teófilo Hernando (ITH), Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Parada
authors.affiliation: Instituto Teófilo Hernando (ITH), Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: León
authors.affiliation: Instituto Teófilo Hernando (ITH), Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gameiro
authors.affiliation: Instituto Teófilo Hernando (ITH), Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Michalska
authors.affiliation: Neurim Pharmaceuticals Ltd., 27 Habarzel St, Tel-Aviv 6971039, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Laudon
authors.affiliation: Instituto Teófilo Hernando (ITH), Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.affiliation: Instituto Teófilo Hernando (ITH), Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: manuela.garcia@uam.es.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005947:Glucose / Q000172:deficiency; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011714:Pyrans / Q000494:pharmacology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D044094:Receptors, Melatonin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D000975:Antioxidants; D007211:Indoles; D018696:Neuroprotective Agents; D011714:Pyrans; D044094:Receptors, Melatonin; D005947:Glucose; D008550:Melatonin; C581609:N-(2-(5-methoxy-indol-3-yl)-ethyl)-4-oxo-4H-pyran-2-carboxamide
keywords: Brain ischemia; In vitro; In vivo; JAK2/AKT/ERK1/2; Neu-P11; Neuroprotection