Huperzine A attenuates mitochondrial dysfunction in beta-amyloid-treated PC12 cells by reducing oxygen free radicals accumulation and improving mitochondrial energy metabolism.

We observed previously that huperzine A (HupA), a selective acetylcholinesterase inhibitor, can counteract neuronal apoptosis and cell damage induced by several neurotoxic substances, and that this neuroprotective action somehow involves the mitochondria. We investigated the ability of HupA to reduce mitochondrial dysfunction in neuron-like rat pheochromocytoma (PC12) cells exposed in culture to the amyloid beta-peptide fragment 25-35 (Abeta(25-35)). After exposure to 1 microM Abeta(25-35) for various periods, cells exhibited a rapid decline of ATP levels and obvious disruption of mitochondrial membrane homeostasis and integrity as determined by characteristic morphologic alterations, reduced membrane potential, and decreased activity of ion transport proteins. In addition, Abeta(25-35) treatment also led to inhibition of key enzyme activities in the electron transport chain and the tricarboxylic acid cycle, as well as an increase of intracellular reactive oxygen species (ROS). Pre-incubation with HupA for 2 hr not only attenuated these signs of cellular stress caused by Abeta, but also enhanced ATP concentration and decreased ROS accumulation in unharmed normal cells. Those results indicate that HupA protects mitochondria against Abeta-induced damages, at least in part by inhibiting oxidative stress and improving energy metabolism, and that these protective effects reduce the apoptosis of neuronal cells exposed to this toxic peptide.