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.

Neuroprotection by two polyphenols following excitotoxicity and experimental ischemia.

Brain ischemia induces neuronal loss which is caused in part by excitotoxicity and free radical formation. Here, we report that mangiferin and morin, two antioxidant polyphenols, are neuroprotective in both in vitro and in vivo models of ischemia. Cell death caused by glutamate in neuronal cultures was decreased in the presence of submicromolar concentrations of mangiferin or morin which in turn attenuated receptor-mediated calcium influx, oxidative stress as well as apoptosis. In addition, both antioxidants diminished the generation of free radicals and neuronal loss in the hippocampal CA1 region due to transient forebrain ischemia in rats when administered after the insult. Importantly, neuroprotection by these antioxidants was functionally relevant since treated-ischemic rats performed significantly better in three hippocampal-dependent behavioral tests. Together, these results indicate that mangiferin and morin have potent neuroprotectant activity which may be of therapeutic value for the treatment of acute neuronal damage and disability.

Differential oxidative stress in oligodendrocytes and neurons after excitotoxic insults and protection by natural polyphenols.

Oligodendrocytes are vulnerable to overactivation of both their AMPA receptors and their high- and low-affinity kainate receptors. Depending on the intensity of the insult and the type of receptor activated, excitotoxic oligodendrocyte death mediated by these receptors has different characteristics. One important consequence at a cellular level is the ensuing oxidative stress, related to Ca2+-dependent alterations in mitochondrial functioning. We observed that oxidative stress associated with selective AMPA receptor activation is much higher than that associated with the selective activation of high- and low-affinity kainate receptors. Moreover, excitotoxic insults generate more intense oxidative stress in oligodendrocytes than in cortical neurons, though similar alterations in [Ca2+]i and mitochondrial potential were observed in both cell types. Nanomolar concentrations of mangiferin and morin, two natural polyphenols with antioxidant properties, partially protect oligodendrocytes as well as cortical neurons from mild, but not intense, insults mediated by AMPA receptors. In addition to presenting oxygen radical scavenging activity, mangiferin and morin attenuate the intracellular Ca2+ overload subsequent to the activation of AMPA receptors, a mechanism that may contribute to their protective properties. The inclusion of these antioxidant agents in therapeutic strategies for the treatment of diseases in which oligodendrocyte as well as neuron loss occurs may prove to be beneficial.