Fig. 6: EGCG increases NAD and provides neuroprotection through an NMN and NMNAT2-dependent mechanism.
From: NMNAT2 is a druggable target to drive neuronal NAD production
A Addition of FK866 (an NAMPT inhibitor which reduces the levels of NMN available to NMNAT2) significantly decreases the capacity of EGCG to produce additional NAD (n = 4 cortex for all conditions). B In the retinal axotomy model addition of FK866 does not significantly alter RGC survival compared to untreated controls. However, the neuroprotective effect of EGCG was completely abolished in the presence of FK866, suggesting that in the context of a RGC injury, EGCG’s neuroprotective effect is derived through an NMN-dependent mechanism (n = 6, all conditions). C Supporting this, in Nmnat2+/+ mice (100% Nmnat2) EGCG provides complete neuroprotection at 3 DEV (n = 4), but in Nmnat2gtBay/gtE mice (25% Nmnat2, n = 6), the neuroprotective effects of EGCG are significantly diminished (44% RGC loss, which is comparable to untreated Nmnat2+/+, Nmnat2+/gtBay, and Nmnat2+/gtE mice). This suggests that the neuroprotective effects of EGCG work through an NMNAT2-dependent mechanism. Scale bars = 25 µm in B and C. For A, B, and C, *P < 0.05, **P < 0.01, ***P < 0.001, NS = non-significant (P > 0.05); One-way ANOVA with Tukey’s HSD. For box plots, the centre hinge represents the median with upper and lower hinges representing the first and third quartiles; whiskers represent 1.5 times the interquartile range.
