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oai:docta.ucm.es:20.500.14352/1185492025-03-18T11:47:39Zcom_20.500.14352_14col_20.500.14352_15

Neuroprotective effects of VCE-004.8 in a rat model of neonatal stroke Villa, María Martínez Vega, María Silva, Laura Romero, Ángela De Hoz Rivera, María Prados, María Eugenia Muñoz, Eduardo Martínez Orgado, José Antonio Neuroprotection Newborn Rats Stroke VCE-004.8 Ciencias Biomédicas Medicina 24 Ciencias de la Vida 32 Ciencias Médicas Fondos FEDER Background Currently there is no effective treatment for neonatal stroke, an acute neurologic syndrome with sequelae, due to focal ischemic, thrombotic, or hemorrhagic event occurring in the perinatal period. VCE-004.8, an aminoquinone exhibiting activity on CB2 and PPARγ receptors, is neuroprotective in adult mice models of acute and chronic brain damaging conditions. We hereby aimed to study VCE-004.8 neuroprotection in a rat model of neonatal stroke. Methods 7-day-old (P7) Wistar rats of both sexes were submitted to Middle Cerebral Artery Occlusion (MCAO), receiving i.p. 30 min after vehicle (MCAO + VEH) or VCE-004.8 5 mg/kg (MCAO + VCE). Non-occluded rats served as controls (SHAM). MCAO consequences were assessed at P14 by MRI, histological (TUNEL staining), biochemical (lactate/n-acetyl aspartate ratio by 1H-NMR spectroscopy) and motor studies (grasp test), and at P37 assessing myelination (MBP signal), hemiparesis and hyperlocomotion. Effects of VCE-004.8 on excitotoxicity (glutamate/n-acetyl aspartate, 1H-NMR), oxidative stress (protein nitrosylation, Oxyblot) and neuroinflammation (Toll-like receptor 4 and TNFa expression, Western blot) were assessed at P14. Therapeutic window was assessed by delaying drug administration for 12 or 18 h. Results Post-MCAO administration of VCE-004.8 reduced the volume of infarct and histological and biochemical brain damage, reducing hyperlocomotion, restoring motor performance and preserving myelination, in a manner linked to the modulation of excitotoxicity, oxidative stress and neuroinflammation. VCE-004.8 was still effective being administered 12–18 h post-insult. Conclusions These data suggest that this drug could be effective for the treatment of stroke in newborns. European Commission Instituto de Salud Carlos III (España) Depto. de Salud Pública y Materno - Infantil Fac. de Medicina TRUE pub 2025-03-06T08:02:49Z 2025-03-06T08:02:49Z 2024-03-22 journal article VoR https://hdl.handle.net/20.500.14352/118549 0014-2999 10.1016/J.EJPHAR.2024.176554 1879-0712 eng PI19/00927 info:eu-repo/grantAgreement/ISCIII/Plan Nacional de R + D + I, AES 2021-2023/RD21/0012/0023 Villa M, Martínez-Vega M, Silva L, Romero A, de Hoz-Rivera M, Prados ME, Muñoz E, Martínez-Orgado J. Neuroprotective effects of VCE-004.8 in a rat model of neonatal stroke. Eur J Pharmacol. 2024 Jun 5;972:176554. doi: 10.1016/j.ejphar.2024.176554 restricted access application/pdf Elsevier