Get access

Neuroprotective effect of melatonin against ischemia is partially mediated by alpha-7 nicotinic receptor modulation and HO-1 overexpression

Authors

  • Esther Parada,

    1. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
    Search for more papers by this author
  • Izaskun Buendia,

    1. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
    Search for more papers by this author
  • Rafael León,

    1. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
    2. Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain
    Search for more papers by this author
  • Pilar Negredo,

    1. Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
    Search for more papers by this author
  • Alejandro Romero,

    1. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
    Current affiliation:
    1. Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain
    Search for more papers by this author
  • Antonio Cuadrado,

    1. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
    2. Department of Biochemistry, Faculty of Medicine, Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Instituto de Investigaciones Biomédicas ‘Alberto Sols’ UAM-CSIC, Autonomous University of Madrid, Madrid, Spain
    Search for more papers by this author
  • Manuela G. López,

    1. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
    2. Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain
    Search for more papers by this author
  • Javier Egea

    Corresponding author
    1. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
    2. Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain
    • Address reprint requests to Javier Egea, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo, 4. 28029 Madrid, Spain.

      E-mail: javier.egea@uam.es

    Search for more papers by this author

Abstract

Melatonin has been widely studied as a protective agent against oxidative stress. However, the molecular mechanisms underlying neuroprotection in neurodegeneration and ischemic stroke are not yet well understood. In this study, we evaluated the neuroprotective/antioxidant mechanism of action of melatonin in organotypic hippocampal cultures (OHCs) as well as in photothrombotic stroke model in vivo. Melatonin (0.1, 1, and 10 μm) incubated postoxygen and glucose deprivation (OGD) showed a concentration-dependent protection; maximum protection was achieved at 10 μm (90% protection). Next, OHCs were exposed to 10 μm melatonin at different post-OGD times; the protective effect of melatonin was maintained at 0, 1, and 2 hr post-OGD treatment, but it was lost at 6 hr post-OGD. The protective effect of melatonin and the reduction in OGD-induced ROS were prevented by luzindole (melatonin antagonist) and α-bungarotoxin (α-Bgt, a selective α7 nAChR antagonist). In Nrf2 knockout mice, the protective effect of melatonin was reduced by 40% compared with controls. Melatonin, incubated 0, 1, and 2 hr post-OGD, increased the expression of heme oxygenase-1 (HO-1), and this overexpression was prevented by luzindole and α-bungarotoxin. Finally, administration of 15 mg/kg melatonin following the induction of photothrombotic stroke in vivo, reduced infarct size (50%), and improved motor skills; this effect was partially lost in 0.1 mg/kg methyllycaconitine (MLA, selective α7 nAChR antagonist)-treated mice. Taken together, these results demonstrate that postincubation of melatonin provides a protective effect that, at least in part, depends on nicotinic receptor activation and overexpression of HO-1.

Get access to the full text of this article

Ancillary