Tetramethylenedisulfotetramine alters Ca²⁺ dynamics in cultured hippocampal neurons: mitigation by NMDA receptor blockade and GABA(A) receptor-positive modulation.

doi:10.1093/toxsci/kfs244

Paper

Tetramethylenedisulfotetramine alters Ca²⁺ dynamics in cultured hippocampal neurons: mitigation by NMDA receptor blockade and GABA(A) receptor-positive modulation.

Published Dec 1, 2012 · Zhengyu Cao, B. Hammock, Mark R. McCoy

Toxicological sciences : an official journal of the Society of Toxicology

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42

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1

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Abstract

Tetramethylenedisulfotetramine (TETS) is a potent convulsant that is considered a chemical threat agent. We characterized TETS as an activator of spontaneous Ca²⁺ oscillations and electrical burst discharges in mouse hippocampal neuronal cultures at 13-17 days in vitro using FLIPR Fluo-4 fluorescence measurements and extracellular microelectrode array recording. Acute exposure to TETS (≥ 2 µM) reversibly altered the pattern of spontaneous neuronal discharges, producing clustered burst firing and an overall increase in discharge frequency. TETS also dramatically affected Ca²⁺ dynamics causing an immediate but transient elevation of neuronal intracellular Ca²⁺ followed by decreased frequency of Ca²⁺ oscillations but greater peak amplitude. The effect on Ca²⁺ dynamics was similar to that elicited by picrotoxin and bicuculline, supporting the view that TETS acts by inhibiting type A gamma-aminobutyric acid (GABA(A)) receptor function. The effect of TETS on Ca²⁺ dynamics requires activation of N-methyl-D-aspartic acid (NMDA) receptors, because the changes induced by TETS were prevented by MK-801 block of NMDA receptors, but not nifedipine block of L-type Ca²⁺ channels. Pretreatment with the GABA(A) receptor-positive modulators diazepam and allopregnanolone partially mitigated TETS-induced changes in Ca²⁺ dynamics. Moreover, low, minimally effective concentrations of diazepam (0.1 µM) and allopregnanolone (0.1 µM), when administered together, were highly effective in suppressing TETS-induced alterations in Ca²⁺ dynamics, suggesting that the combination of positive modulators of synaptic and extrasynaptic GABA(A) receptors may have therapeutic potential. These rapid throughput in vitro assays may assist in the identification of single agents or combinations that have utility in the treatment of TETS intoxication.

In Vitro Study

Rigorous Journal

Study Snapshot

TETS alters calcium dynamics in cultured hippocampal neurons, but NMDA receptor blockade and GABA(A) receptor-positive modulation can effectively mitigate these effects.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Tetramethylenedisulfotetramine alters Ca²⁺ dynamics in cultured hippocampal neurons: mitigation by NMDA receptor blockade and GABA(A) receptor-positive modulation.

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References

Clustered burst firing in FMR1 premutation hippocampal neurons: amelioration with allopregnanolone.

Allopregnanolone can improve functional impairments in preCGG hippocampal neurons, making it a potential therapeutic lead for fragile X-associated tremor/ataxia syndrome.

Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

TETS-induced seizures in mice and rats can cause death, but repeated sublethal doses do not cause persistent enhanced seizure responsivity.

PCB-95 Modulates the Calcium-Dependent Signaling Pathway Responsible for Activity-Dependent Dendritic Growth

PCB-95 enhances ryanodine receptor activity in hippocampal neurons, promoting dendritic growth through the CaMKI-CREB-Wnt2 signaling pathway, potentially posing environmental risk for neurodevelopmental disorders.

Tetramethylenedisulfotetramine intoxication presenting with de novo Status Epilepticus: a case series.

TETS intoxication, a neurotoxic rodenticide, can cause Convulsive Status Epilepticus and multiple organ dysfunction syndrome, with poor outcomes in rural China.

Tetramine poisoning: A case report and review of the literature.

Tetramine poisoning is a potential cause of death in cases of abnormal central nervous system activity, convulsions, hyperspasmia, and cerebral hemorrhage.

Citations

Investigations into hydrogen sulfide-induced suppression of neuronal activity in vivo and calcium dysregulation in vitro

Hydrogen sulfide exposure suppresses neuronal activity and disrupts breathing, with TRP channel modulators potentially offering therapeutic benefits.

Investigations into hydrogen sulfide-induced suppression of neuronal activity in vivo and calcium dysregulation in vitro

Hydrogen sulfide exposure suppresses neuronal activity and disrupts breathing, with TRP channel modulators potentially offering potential therapeutic benefits.

Structure-Activity Relationship of Neuroactive Steroids, Midazolam, and Perampanel towards Mitigating Tetramine-Triggered Activity in Murine Hippocampal Neuronal Networks.

Combinations of allopregnanolone and midazolam are more effective than either drug alone in normalizing tetramine-triggered electrical spike activity in hippocampal neuronal networks.

BmK NSPK, a Potent Potassium Channel Inhibitor from Scorpion Buthus martensii Karsch, Promotes Neurite Outgrowth via NGF/TrkA Signaling Pathway

BmK NSPK, a new scorpion toxin, promotes neurite outgrowth in spinal cord neurons through the NGF/TrkA signaling pathway, offering potential for developing treatments for spinal cord injury.

Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

Allopregnanolone and perampanel are potential adjuncts to midazolam for treating benzodiazepine-resistant organophosphate nerve agent-induced status epilepticus in rats.

Chemical Weapons

Chemical weapons cause various injuries to humans and animals through their asphyxiating, toxic, irritant, paralyzing, growth-regulating, anti-lubricating, or catalytic properties.

Tetramethylenedisulfotetramine neurotoxicity: What have we learned in the past 70 years?

Tetramethylenedisulfotetramine (TETS) is a neurotoxic chemical with potential as a food adulterant and chemical agent of terror, with no known antidote or targeted treatment.

Susceptibility of larval zebrafish to the seizurogenic activity of GABA type A receptor antagonists.

Larvae of three GABA A receptor antagonists, TETS, PTX, and PTZ, can trigger seizures, making them a valuable screening platform for antiseizure therapeutics.

Tetramethylenedisulfotetramine alters Ca²⁺ dynamics in cultured hippocampal neurons: mitigation by NMDA receptor blockade and GABA(A) receptor-positive modulation.

Sign up to use Study Snapshot

References

Clustered burst firing in FMR1 premutation hippocampal neurons: amelioration with allopregnanolone.

Allopregnanolone can improve functional impairments in preCGG hippocampal neurons, making it a potential therapeutic lead for fragile X-associated tremor/ataxia syndrome.

Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

TETS-induced seizures in mice and rats can cause death, but repeated sublethal doses do not cause persistent enhanced seizure responsivity.

PCB-95 Modulates the Calcium-Dependent Signaling Pathway Responsible for Activity-Dependent Dendritic Growth

PCB-95 enhances ryanodine receptor activity in hippocampal neurons, promoting dendritic growth through the CaMKI-CREB-Wnt2 signaling pathway, potentially posing environmental risk for neurodevelopmental disorders.

Tetramethylenedisulfotetramine intoxication presenting with de novo Status Epilepticus: a case series.

TETS intoxication, a neurotoxic rodenticide, can cause Convulsive Status Epilepticus and multiple organ dysfunction syndrome, with poor outcomes in rural China.

Tetramine poisoning: A case report and review of the literature.

Tetramine poisoning is a potential cause of death in cases of abnormal central nervous system activity, convulsions, hyperspasmia, and cerebral hemorrhage.

Citations

Investigations into hydrogen sulfide-induced suppression of neuronal activity in vivo and calcium dysregulation in vitro

Hydrogen sulfide exposure suppresses neuronal activity and disrupts breathing, with TRP channel modulators potentially offering therapeutic benefits.

Investigations into hydrogen sulfide-induced suppression of neuronal activity in vivo and calcium dysregulation in vitro

Hydrogen sulfide exposure suppresses neuronal activity and disrupts breathing, with TRP channel modulators potentially offering potential therapeutic benefits.

Structure-Activity Relationship of Neuroactive Steroids, Midazolam, and Perampanel towards Mitigating Tetramine-Triggered Activity in Murine Hippocampal Neuronal Networks.

Combinations of allopregnanolone and midazolam are more effective than either drug alone in normalizing tetramine-triggered electrical spike activity in hippocampal neuronal networks.

BmK NSPK, a Potent Potassium Channel Inhibitor from Scorpion Buthus martensii Karsch, Promotes Neurite Outgrowth via NGF/TrkA Signaling Pathway

BmK NSPK, a new scorpion toxin, promotes neurite outgrowth in spinal cord neurons through the NGF/TrkA signaling pathway, offering potential for developing treatments for spinal cord injury.

Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

Allopregnanolone and perampanel are potential adjuncts to midazolam for treating benzodiazepine-resistant organophosphate nerve agent-induced status epilepticus in rats.

Chemical Weapons

Chemical weapons cause various injuries to humans and animals through their asphyxiating, toxic, irritant, paralyzing, growth-regulating, anti-lubricating, or catalytic properties.

Tetramethylenedisulfotetramine neurotoxicity: What have we learned in the past 70 years?

Tetramethylenedisulfotetramine (TETS) is a neurotoxic chemical with potential as a food adulterant and chemical agent of terror, with no known antidote or targeted treatment.

Susceptibility of larval zebrafish to the seizurogenic activity of GABA type A receptor antagonists.

Larvae of three GABA A receptor antagonists, TETS, PTX, and PTZ, can trigger seizures, making them a valuable screening platform for antiseizure therapeutics.

Tetramethylenedisulfotetramine neurotoxicity: What have we learned in the past 70 years?