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Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models
- Source :
- Scientific Reports, Scientific Reports, Vol 10, Iss 1, Pp 1-17 (2020), Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- We herein report the synthesis, antioxidant power and neuroprotective properties of nine homo-bis-nitrones HBNs1–9 as alpha-phenyl-N-tert-butylnitrone (PBN) analogues for stroke therapy. In vitro neuroprotection studies of HBNs1–9 against Oligomycin A/Rotenone and in an oxygen-glucose-deprivation model of ischemia in human neuroblastoma cell cultures, indicate that (1Z,1′Z)-1,1′-(1,3-phenylene)bis(N-benzylmethanimine oxide) (HBN6) is a potent neuroprotective agent that prevents the decrease in neuronal metabolic activity (EC = 1.24 ± 0.39 μM) as well as necrotic and apoptotic cell death. HBN6 shows strong hydroxyl radical scavenger power (81%), and capacity to decrease superoxide production in human neuroblastoma cell cultures (maximal activity = 95.8 ± 3.6%), values significantly superior to the neuroprotective and antioxidant properties of the parent PBN. The higher neuroprotective ability of HBN6 has been rationalized by means of Density Functional Theory calculations. Calculated physicochemical and ADME properties confirmed HBN6 as a hit-agent showing suitable drug-like properties. Finally, the contribution of HBN6 to brain damage prevention was confirmed in a permanent MCAO setting by assessing infarct volume outcome 48 h after stroke in drug administered experimental animals, which provides evidence of a significant reduction of the brain lesion size and strongly suggests that HBN6 is a potential neuroprotective agent against stroke.<br />We would like to thank Soledad Martinez Montero for the excellent technical assistance. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2015-65586-R to JMC; CTQ2016- 78205-P and CTQ2016-81797-REDC to IF, and NEUROCENTRO-CM S2017/BMD3760 to RMM and DNG), and Camilo José Cela University (UCJC-2018-04) to MJOG. DDI thanks the University of Alcalá and Spanish Ministry of Science, Innovation and Universities for pre-doctoral FPU grants. BCG thanks the Spanish Ministry
- Subjects :
- Male
0301 basic medicine
Antioxidant
genetic structures
medicine.medical_treatment
Drug Evaluation, Preclinical
lcsh:Medicine
Apoptosis
Pharmacology
Brain Ischemia
Mice
Neuroblastoma
chemistry.chemical_compound
0302 clinical medicine
Lipoxygenase Inhibitors
lcsh:Science
Neurons
Multidisciplinary
Molecular Structure
Drug discovery
Chemistry
Superoxide
Infarction, Middle Cerebral Artery
Free Radical Scavengers
Neuroprotection
Neuroprotective Agents
Nitrogen Oxides
medicine.symptom
psychological phenomena and processes
Ischemia
Brain damage
behavioral disciplines and activities
Article
Cyclic N-Oxides
03 medical and health sciences
In vivo
Cell Line, Tumor
Rotenone
medicine
Animals
lcsh:R
medicine.disease
In vitro
Mice, Inbred C57BL
Oxygen
Disease Models, Animal
Glucose
030104 developmental biology
nervous system
lcsh:Q
Oligomycins
Lipid Peroxidation
030217 neurology & neurosurgery
Neuroscience
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....07c656562bee4970b214b0b18755d30a