Excitotoxicity Induced by Realgar in the Rat Hippocampus: the Involvement of Learning Memory Injury, Dysfunction of Glutamate Metabolism and NMDA Receptors

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 Ca(2+) 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 Ca(2+) 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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“…It has a presumed role in excitatory synaptic transmission, learning, memory, and nociceptive pathways (Huo et al, 2015; Wang et al, 2015). Excessive stimulation of the NMDAR induces neuronal injury via an excitotoxic mechanism (Bonfoco et al, 1995; Prentice et al, 2015).…”

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“…Excess of extracellular glutamate was observed in hippocampus. Glutamate accumulation in the synaptic cleft was related to decreased expression of NR1 and up-regulation of NR2A subunit leading to calcium overload, down-regulation of GLT1 and ultrastructural changes in hippocampal neurons (Tao-guang et al, 2014 ). Interestingly, increased activity of xCT transport is accompanied with an increase in glutamate levels and neuronal death via overstimulation NMDAR (Jackman et al, 2012 ).…”

Exercise Prevents Memory Impairment Induced by Arsenic Exposure in Mice: Implication of Hippocampal BDNF and CREB

“…Daily exposure to 15 mg/ kg sodium arsenite significantly disrupted the performance in the Morris water maze and Y maze tasks [ 8 ]. Exposure to realgar, an arsenic sulfide mineral, for 6 weeks also affected the cognitive ability of weaned rats in the Morris water maze test and object recognition task [ 9 ].…”

“…Moreover, the arsenic metabolites of realgar are permeable through the blood-brain barrier and accumulate in the hippocampus, which induces excessive glutamate in the extracellular space and excitotoxicity. The excessive glutamate subsequently promotes the activities of glutamine synthetase and phosphate-activated glutaminase, inhibits glutamate transporter 1 expression, and alters NMDAR expression [ 9 ]. Arsenic can also change the ultrastructure in hippocampal neurons and induce pathological alterations of neurons and endothelial cells in the hippocampus [ 9 , 10 ].…”