HMGB1 and Cognitive impairment: Further, to confirm that the berberine attenuates the downstream signaling through the HMGB1/RAGE axis, a RAGE−/− knock out mice model was used to examine the effect of berberine and it was found that berberine did not improve the cognitive impairment in the RAGE−/− mice, suggesting the inhibitory effect of berberine specifically via the HMGB1/RAGE axis [41].