Fig. 8.

The protective mechanism of curcumin by the UPR-Nrf2 pathway after DAI. When ER stress appeared as a result of abnormal protein aggregation after DAI, curcumin increased the expression of Nrf2 and promoted its nuclear translocation. Moreover, curcumin also promoted PERK phosphorylation to dissociate Nrf2 from Keap1 in the cytoplasm and enable its translocation to the nucleus. Nrf2 in the nucleus combined with ARE and upregulated the expression of ATF4 to maintain intracellular homeostasis and promote cell survival by the following mechanisms: (i) The upregulation of the antioxidant response, such as HO-1, and other unfolded protein response-target genes such as XBP1; (ii) inhibition of the expression of BACE1 and GSK-3β to reduce β-APP and p-tau aggregation in neurons; and (iii) inhibition of the expression of ER-stress-associated apoptosis genes, such as CHOP, Bax, and caspase-3. On the basis of our study, we suggest that curcumin strengthens the unfolded protein response process by promoting the phosphorylation of PERK and the nuclear translocation of dissociated Nrf2. DAI, diffuse axonal injury; ER, endoplasmic reticulum.