title: Melatonin-sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a 'drug-prodrug' mechanism of action.
abstract: OBJECTIVE
  Neurodegenerative diseases are a major problem afflicting ageing populations; however, there are no effective treatments to stop their progression. Oxidative stress and neuroinflammation are common factors in their pathogenesis. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of oxidative stress, and melatonin is an endogenous hormone with antioxidative properties that reduces its levels with ageing. We have designed a new compound that combines the effects of melatonin with Nrf2 induction properties, with the idea of achieving improved neuroprotective properties.
  
  
  METHODS
  Compound ITH12674 is a hybrid of melatonin and sulforaphane designed to exert a dual drug-prodrug mechanism of action. We obtained the proposed hybrid in a single step. To test its neuroprotective properties, we used different in vitro models of oxidative stress related to neurodegenerative diseases and brain ischaemia.
  
  
  RESULTS
  ITH12674 showed an improved neuroprotective profile compared to that of melatonin and sulforaphane. ITH12674 (i) mediated a concentration-dependent protective effect in cortical neurons subjected to oxidative stress; (ii) decreased reactive oxygen species production; (iii) augmented GSH concentrations in cortical neurons; (iv) enhanced the Nrf2-antioxidant response element transcriptional response in transfected HEK293T cells; and (v) protected organotypic cultures of hippocampal slices subjected to oxygen and glucose deprivation and re-oxygenation from stress by increasing the expression of haem oxygenase-1 and reducing free radical production.
  
  
  CONCLUSIONS
  ITH12674 combines the signalling pathways of the parent compounds to improve its neuroprotective properties. This opens a new line of research for such hybrid compounds to treat neurodegenerative diseases.
authors.affiliation: Departamento de Farmacología y Terapéutica, Instituto Teófilo Hernando de I + D del medicamento Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.forename: Izaskun
authors.initials: I
authors.lastname: Buendia
authors.forename: Esther
authors.initials: E
authors.lastname: Parada
authors.forename: Elisa
authors.initials: E
authors.lastname: Navarro
authors.forename: Patricia
authors.initials: P
authors.lastname: Rada
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.forename: Rafael
authors.initials: R
authors.lastname: León
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D008550:Melatonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011355:Prodrugs / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013454:Sulfoxides
chemical_list: C000603666:ITH12674; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D011355:Prodrugs; D013454:Sulfoxides; D005982:Glutathione Transferase; C016766:sulforaphane; D005978:Glutathione; D008550:Melatonin