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

Abstract

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.

• Authors: Xin Gao, Xi Can Tang
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 83 Issue 6 Pg. 1048-57 (May 01 2006) ISSN: 0360-4012 [Print] United States
• PMID: 16493671 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2006 Wiley-Liss, Inc.

Chemical References

• Alkaloids
• Amyloid beta-Peptides
• Neuroprotective Agents
• Peptides
• Reactive Oxygen Species
• Sesquiterpenes
• huperzine A
• Adenosine Triphosphate
• Sodium-Potassium-Exchanging ATPase

Topics

• Adenosine Triphosphate (metabolism)
• Alkaloids
• Amyloid beta-Peptides (toxicity)
• Analysis of Variance
• Animals
• Dose-Response Relationship, Drug
• Drug Interactions
• Energy Metabolism (drug effects)
• Fluorometry (methods)
• Microscopy, Electron (methods)
• Mitochondria (drug effects, physiology, ultrastructure)
• Neuroprotective Agents (pharmacology)
• PC12 Cells (drug effects, ultrastructure)
• Peptides (toxicity)
• Rats
• Reactive Oxygen Species (metabolism)
• Sesquiterpenes (pharmacology)
• Sodium-Potassium-Exchanging ATPase (metabolism)