The neuroprotective activities of melatonin against the Alzheimer beta-protein are not mediated by melatonin membrane receptors

Exposure of neuronal cells to the Alzheimer's amyloid P protein (Abeta) results in extensive oxidative damage of bio-molecules that are profoundly harmful to neuronal homeostasis. It has been demonstrated that melatonin protects neurons against Abeta-mediated neurotoxicity, including cell death and a spectrum of oxidative lesions. We undertook the current study to determine whether melatonin membrane receptors are involved in the mechanism of neuroprotection against Abeta neurotoxicity. For this we characterized the free-radical scavenging potency of several purpose. compounds exhibiting various affinities for melatonin membrane receptors (MLT 1 a and 1 b). Abeta-mediated neurotoxicity was assessed in human neuroblastoma cells and in primary hippocampal neurons. In sharp contrast with melatonin. no neuroprotection against Abeta toxicity was observed, hen we used melatonin membrane receptor agonists that were devoid of antioxidant activity. In contrast, the cells were fully protected in parallel control experiments when either melatonin, or the structural I unrelated free-radical scavenger phenyl-N-t-butyl nitrone (PBN). were added to Abeta-containing culture media. This stud v demonstrates that the neuroprotective properties of melatonin against Abeta-mediated toxicity does not require binding of melatonin to a membrane receptor and is likely the result of the antioxidant and antiamyloidogenic features of the agent.