Acute and chronic alterations in calcium homeostasis in 3-nitropropionic acid-treated human NT2-N neurons
Journal
Neuroscience
Journal Volume
113
Journal Issue
3
Pages
699-708
Date Issued
2002
Author(s)
Abstract
3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, induced ATP depletion and both necrosis and apoptosis in human NT2-N neurons. Necrosis occurred predominantly within the first two days, and increased in a dose-dependent fashion with the concentration of 3-NP, whereas apoptosis was observed after 24 h or later at a similar rate in 0.1 mM and 5 mM 3-NP. We focused our efforts on intracellular calcium homeostasis during the first 48 h in 1 mM 3-NP, a period during which 10% of the neurons died by necrosis and 3% by apoptosis. All NT2-N neurons showed a stereotyped [Ca2+]i rise, from 48±2 to 140±12 nM (mean ±S.E.M.), during the first 2 h in 3-NP. Despite severe ATP depletion, however, [Ca2+]i remained above 100 nM in only 17% and 25% of the NT2-N neurons after 24 and 48 h in 3-NP, respectively, indicating that most neurons were able to recover from acute [Ca2+]i rise, and suggesting that chronic [Ca2+]i dysregulation is a better indicator of subsequent necrosis. Blockade of N-methyl-D-aspartate-glutamate receptor by MK-801 substantially ameliorated 3-NP-induced ATP depletion, subsequent chronic [Ca2+]i elevation, and survival. Moreover, xestospongin C, an inhibitor of endoplasmic reticulum Ca2+ release, enhanced the capacity of NT2-N neurons to maintain [Ca2+]i homeostasis and resist necrosis while subjected to sustained energy deprivation. As far as we know, this report is the first to employ human neurons to study the pathophysiology of 3-NP neurotoxicity. © 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved.
Type
journal article