Effect of a short-term in vitro exposure to the marine toxin domoic acid on viability, tumor necrosis factor-alpha, matrix metalloproteinase-9 and superoxide anion release by rat neonatal microglia |
| |
Authors: | Alejandro MS Mayer Mary Hall Michael J Fay Peter Lamar Celeste Pearson Walter C Prozialeck Virginia KB Lehmann Peer B Jacobson Anne M Romanic Tolga Uz Hari Manev |
| |
Affiliation: | 1. Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, 555 31st Street, 60515, Downers Grove, Illinois, USA 2. School of Chemical Sciences, University of Illinois at Urbana-Champaign, Urbana, 61801, Illinois, USA 3. Abbott Laboratories, Abbott Park, 60064, Illinois, USA 4. GlaxoSmithKline Pharmaceuticals, Department of Cardiovascular Pharmacology, King of Prussia, 19406, Pennsylvania, USA 5. The Psychiatric Institute, University of Illinois at Chicago, Chicago, 60612, Illinois, USA 6. The Psychiatric Institute, University of Illinois at Chicago, 60612, Chicago, Illinois, USA
|
| |
Abstract: | Background The excitatory amino acid domoic acid, a glutamate and kainic acid analog, is the causative agent of amnesic shellfish poisoning in humans. No studies to our knowledge have investigated the potential contribution to short-term neurotoxicity of the brain microglia, a cell type that constitutes circa 10% of the total glial population in the brain. We tested the hypothesis that a short-term in vitro exposure to domoic acid, might lead to the activation of rat neonatal microglia and the concomitant release of the putative neurotoxic mediators tumor necrosis factor-α (TNF-α), matrix metalloproteinases-2 and-9 (MMP-2 and -9) and superoxide anion (O2-). Results In vitro, domoic acid [10 μM-1 mM] was significantly neurotoxic to primary cerebellar granule neurons. Although neonatal rat microglia expressed ionotropic glutamate GluR4 receptors, exposure during 6 hours to domoic acid [10 μM-1 mM] had no significant effect on viability. By four hours, LPS (10 ng/mL) stimulated an increase in TNF-α mRNA and a 2,233 % increase in TNF-α protein In contrast, domoic acid (1 mM) induced a slight rise in TNF-α expression and a 53 % increase (p < 0.01) of immunoreactive TNF-α protein. Furthermore, though less potent than LPS, a 4-hour treatment with domoic acid (1 mM) yielded a 757% (p < 0.01) increase in MMP-9 release, but had no effect on MMP-2. Finally, while PMA (phorbol 12-myristate 13-acetate) stimulated O2- generation was elevated in 6 hour LPS-primed microglia, a similar pretreatment with domoic acid (1 mM) did not prime O2- release. Conclusions To our knowledge this is the first experimental evidence that domoic acid, at in vitro concentrations that are toxic to neuronal cells, can trigger a release of statistically significant amounts of TNF-α and MMP-9 by brain microglia. These observations are of considerable pathophysiological significance because domoic acid activates rat microglia several days after in vivo administration. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|