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Indirect glutamate neurotoxicity
1Department of Surgery, St. Louis University Health Science Center, MO 63110-0250, USA.
Abstract:
Indirect glutamate toxicity can be demonstrated by exposing dissociated rat hippocampal cultures to the media of the same culture transiently exposed (1 min) to glutamate (0.5 mM). The toxicity was maximum when the media was collected 5 min after the glutamate exposure. While the primary glutamate toxicity was attenuated by ionotropic glutamate receptor antagonists, the transferred, indirect toxicity was unaffected by the same antagonists. The changes in nuclear morphology indicated chromatin condensation and nuclear fragmentation in both primary and transferred toxicity. The stain for DNA damage by TUNEL method also revealed cells staining positive in both primary and transferred glutamate toxicity. These observations demonstrate that glutamate-induced neurotoxicity can be propagated to the uninjured cells by an unknown toxin released into the extracellular space. This neurotoxin induced both apoptosis and necrosis in cultured rat hippocampal cells.
Insights
Glutamate exposure releases an unknown toxin that damages uninjured cells, causing cell death. This indirect neurotoxicity, unlike primary toxicity, is not blocked by receptor antagonists.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Glutamate is a key neurotransmitter.
- Excitotoxicity, or glutamate toxicity, is implicated in neuronal damage.
- Mechanisms of indirect glutamate toxicity are not fully understood.
Purpose of the Study:
- To investigate the propagation of glutamate-induced neurotoxicity to uninjured cells.
- To characterize the nature of the indirect toxic effect.
Main Methods:
- Dissociated rat hippocampal cultures were exposed to glutamate.
- Media from exposed cultures was collected and applied to naive cultures.
- Primary and transferred toxicity were assessed using morphological and molecular markers of cell death.
- The effect of ionotropic glutamate receptor antagonists was tested.
Main Results:
- Indirect glutamate toxicity was observed in naive cells exposed to conditioned media.
- This toxicity peaked 5 minutes after initial glutamate exposure.
- Unlike primary toxicity, indirect toxicity was not inhibited by ionotropic glutamate receptor antagonists.
- Both primary and indirect toxicity induced chromatin condensation, nuclear fragmentation, and DNA damage, indicative of apoptosis and necrosis.
Conclusions:
- Glutamate exposure releases an extracellular neurotoxin that induces cell death in uninjured neurons.
- This indirect neurotoxicity pathway is distinct from primary excitotoxicity and is not mediated by ionotropic glutamate receptors.
- The findings suggest a novel mechanism of neuronal damage propagation in the brain.