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

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.