PI3K/Akt and ERK1/2 Signalling Are Involved in Quercetin-Mediated Neuroprotection against Copper-Induced Injury

Figure 7

Schematic representation of copper/quercetin interactions in P19 neurons. Depending on the severity of copper-induced oxidative injury and concentration of quercetin used, both prosurvival and prodeath effects were observed because of copper/quercetin interactions. In moderate oxidative injury, 150 μM quercetin promotes neuronal survival by reducing the production of ROS and through the activation of the PI3K/Akt and ERK1/2 signalling pathways. We hypothesize that the quercetin-induced activation of these pathways may exert antiapoptotic effects, stimulate an antioxidative response by activating the transcription factor Nrf2, and inhibit the activity of glycogen synthase kinase-3β (GSK-3β), thus indirectly attenuating ROS formation. The antioxidative effects of quercetin are probably mediated through direct ROS scavenging and Cu complexation which prevents Fenton’s chemistry. The antioxidative activity and modulation of intracellular signalling ultimately reduce the death cascade, prevent PUMA upregulation, and stimulate the expression of the NME1 protein. In severe oxidative stress conditions, 30 μM quercetin exacerbated the toxic effect of copper. We suggest that at this concentration of quercetin, ROS formation is promoted due to the ability of quercetin to reduce copper and initiate Fenton’s reaction and the production of hydroxyl radicals. An increase in ROS further leads to apoptotic and necrotic changes, and ultimately neuronal death. At 150 μM quercetin, probably more copper ions are complexed, thus holding the initiation of Fenton’s chemistry, and more quercetin molecules are available to act as ROS scavengers. However, as both copper and quercetin are present at relatively high concentrations, the sum of all antioxidative and prooxidative activities (depicted in Figure 1) in the end does not affect neuronal survival.