Molecular mechanisms of neuroprotection by two natural antioxidant polyphenols.
Excessive activation of glutamate receptors, or excitotoxicity, contributes to acute and chronic neurological disorders including stroke. We previously showed that two natural polyphenol antioxidants, mangiferin and morin, are neuroprotective in a model of ischemic brain damage. In this study, we analyzed the molecular mechanisms underlying neuroprotection by mangiferin and morin in an in vitro model of excitotoxic neuronal death involving NMDA receptor overactivation. We observed that both polyphenols reduce the formation of reactive oxygen species, activate the enzymatic antioxidant system, and restore the mitochondrial membrane potential. Moreover, both antioxidants inhibit glutamate-induced activation of calpains, normalize the levels of phosphorylated Akt kinase and Erk1/2, as well as of cytosolic Bax, inhibit AIF release from mitochondria, and regulate the nuclear translocation of NF-kappaB. Each of these effects contributes to the substantial reduction of apoptotic neuronal death induced by glutamate. These results demonstrate that mangiferin and morin exhibit excellent antioxidant and antiapoptotic properties, supporting their clinical application as trial neuroprotectors in pathologies involving excitotoxic neuronal death.
Campos-Esparza
María Rosario
MR
Departamento de Neurociencias, Facultad de Medicina y Odontología. Universidad del País Vasco, and CIBERNED, Leioa, Spain.
Sánchez-Gómez
María Victoria
MV
Matute
Carlos
C
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D019610:Cytoprotection / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*; D047309:Flavones
D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D002154:Calpain; D020169:Caspases; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D018698:Glutamic Acid; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010636:Phenols; D059808:Polyphenols; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D044004:Xanthones; C013592:mangiferin; C008548:morin; D047309:Flavones