Abstract
Realgar is a type of mineral drug containing arsenic. The nervous system toxicity of realgar has received extensive attention. However, the underlying mechanisms of realgar-induced neurotoxicity have not been clearly elucidated. To explore the mechanisms that contribute to realgar-induced neurotoxicity, weanling rats were exposed to realgar (0, 0.3, 0.9, 2.7 g/kg) for 6 weeks, and cognitive ability was tested using the Morris water maze (MWM) test and object recognition task (ORT). The levels of arsenic in the blood and hippocampus were monitored. The ultrastructures of hippocampal neurons were observed. The levels of glutamate (Glu) and glutamine (Gln) in the hippocampus and hippocampal CA1 region; the activities of glutamine synthetase (GS) and phosphate-activated glutaminase (PAG); the mRNA and protein expression of glutamate transporter 1 (GLT-1), glutamate/aspartate transporter (GLAST), and N-methyl-d-aspartate (NMDA) receptors; and the level of intracellular Ca2+ were also investigated. The results indicate that the rats developed deficiencies in cognitive ability after a 6-week exposure to realgar. The arsenic contained in realgar and the arsenic metabolites passed through the blood-brain barrier (BBB) and accumulated in the hippocampus, which resulted in the excessive accumulation of Glu in the extracellular space. The excessive accumulation of Glu in the extracellular space induced excitotoxicity, which was shown by enhanced GS and PAG activities, inhibition of GLT-1 mRNA and protein expression, alterations in NMDA receptor mRNA and protein expression, disturbance of intracellular Ca2+ homeostasis, and ultrastructural changes in hippocampal neurons. In conclusion, the findings from our study indicate that exposure to realgar induces excitotoxicity and that the mechanism by which this occurs may be associated with disturbances in Glu metabolism and transportation and alterations in NMDA receptor expression.
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Abbreviations
- TCMs:
-
Traditional Chinese medicines
- BBB:
-
Blood-brain barrier
- MWM:
-
Morris water maze
- ORT:
-
Object recognition task
- Glu:
-
Glutamate
- CNS:
-
Central nervous system
- GLT-1:
-
Glutamate transporter 1
- GLAST:
-
Glutamate/aspartate transporter
- GS:
-
Glutamine synthetase
- Gln:
-
Glutamine
- PAG:
-
Phosphate-activated glutaminase
- NMDA:
-
N-Methyl-d-aspartate
- iAs:
-
Inorganic arsenic
- MMA:
-
Methyl arsine
- DMA:
-
Dimethyl arsine
- ECL:
-
Enhanced chemiluminescence
- CMC-Na:
-
Sodium carboxymethylcellulose
- MD:
-
Microdialysis
- NE:
-
Northeast
- NW:
-
Northwest
- SE:
-
Southeast
- SW:
-
Southwest
- AAS:
-
Atomic absorption spectrophotometry
- TAs:
-
Total arsenic
- HPLC:
-
High-performance liquid chromatography
- PVDF:
-
Polyvinylidene difluoride
- TBS:
-
Tris-buffered saline
- PBS:
-
Phosphate-buffered saline
- NOAEL:
-
No observed adverse effect level
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Acknowledgments
The work is financially supported by the National Natural Science Foundation of China (81073144), the China Postdoctoral Science Foundation on the 51th grant program (2012M510848), and the Higher Education Department of Liaoning Province (L2010708).
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The authors declare that they have no conflicts of interest.
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Huo, Tg., Li, Wk., Zhang, Yh. et al. Excitotoxicity Induced by Realgar in the Rat Hippocampus: the Involvement of Learning Memory Injury, Dysfunction of Glutamate Metabolism and NMDA Receptors. Mol Neurobiol 51, 980–994 (2015). https://doi.org/10.1007/s12035-014-8753-2
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DOI: https://doi.org/10.1007/s12035-014-8753-2