Inhibiting mitochondrial inflammation through Drp1/HK1/NLRP3 pathway: A mechanism of alpinetin attenuated aging‐associated cognitive impairment

Abstract Mitochondrial inflammation triggered by abnormal mitochondrial division and regulated by the Drp1/HK1/NLRP3 pathway is correlated with the progression of aging‐associated cognitive impairment (AACI). Alpinetin is a novel flavonoid derived from Zingiberaceae that has many bioactivities such as antiinflammation and anti‐oxidation. However, whether alpinetin alleviates AACI by suppressing Drp1/HK1/NLRP3 pathway‐inhibited mitochondrial inflammation is still unknown. In the present study, D‐galactose (D‐gal)‐induced aging mice and BV‐2 cells were used, and the effects of alpinetin on learning and memory function, neuroprotection and activation of the Drp1/HK1/NLRP3 pathway were investigated. Our data indicated that alpinetin significantly alleviated cognitive dysfunction and neuronal damage in the CA1 and CA3 regions of D‐gal‐treated mice. Moreover, D‐gal‐induced microglial activation was markedly reduced by alpinetin by inhibiting the Drp1/HK1/NLRP3 pathway‐suppressed mitochondrial inflammation, down‐regulating the levels of p‐Drp1 (s616), VDAC, NLRP3, ASC, Cleaved‐caspase 1, IL‐18, and IL‐1β, and up‐regulating the expression of HK1. Furthermore, after Drp1 inhibition by Mdivi‐1 in vitro, the inhibitory effect of alpinetin on Drp1/HK1/NLRP3 pathway was more evident. In summary, the current results implied that alpinetin attenuated aging‐related cognitive deficits by inhibiting the Drp1/HK1/NLRP3 pathway and suppressing mitochondrial inflammation, suggesting that the inhibition of the Drp1/HK1/NLRP3 pathway is one of the mechanisms by which alpinetin attenuates AACI.