1. Combined treatment with diazepam and allopregnanolone reverses tetramethylenedisulfotetramine (TETS)-induced calcium dysregulation in cultured neurons and protects TETS-intoxicated mice against lethal seizures.
- Author
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Bruun DA, Cao Z, Inceoglu B, Vito ST, Austin AT, Hulsizer S, Hammock BD, Tancredi DJ, Rogawski MA, Pessah IN, and Lein PJ
- Subjects
- Animals, Bridged-Ring Compounds, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Therapy, Combination, Hippocampus drug effects, Hippocampus pathology, Hippocampus physiopathology, Male, Mice, Neuroimmunomodulation drug effects, Neuroimmunomodulation physiology, Neurons drug effects, Neurons pathology, Neurons physiology, Seizures pathology, Seizures physiopathology, Anticonvulsants pharmacology, Calcium metabolism, Diazepam pharmacology, Pregnanolone pharmacology, Seizures drug therapy
- Abstract
Tetramethylenedisulfotetramine (TETS) is a potent convulsant GABAA receptor blocker. Mice receiving a lethal dose of TETS (0.15 mg/kg i.p.) are rescued from death by a high dose of diazepam (5 mg/kg i.p.) administered shortly after the second clonic seizure (∼20 min post-TETS). However, this high dose of diazepam significantly impairs blood pressure and mobility, and does not prevent TETS-induced neuroinflammation in the brain. We previously demonstrated that TETS alters synchronous Ca(2+) oscillations in primary mouse hippocampal neuronal cell cultures and that pretreatment with the combination of diazepam and allopregnanolone at concentrations having negligible effects individually prevents TETS effects on intracellular Ca(2+) dynamics. Here, we show that treatment with diazepam and allopregnanolone (0.1 μM) 20 min after TETS challenge normalizes synchronous Ca(2+) oscillations when added in combination but not when added singly. Similarly, doses (0.03-0.1 mg/kg i.p.) of diazepam and allopregnanolone that provide minimal protection when administered singly to TETS intoxicated mice increase survival from 10% to 90% when given in combination either 10 min prior to TETS or following the second clonic seizure. This therapeutic combination has negligible effects on blood pressure or mobility. Combined treatment with diazepam and allopregnanolone also decreases TETS-induced microglial activation. Diazepam and allopregnanolone have distinct actions as positive allosteric modulators of GABAA receptors that in combination enhance survival and mitigate neuropathology following TETS intoxication without the adverse side effects associated with high dose benzodiazepines. Combination therapy with a benzodiazepine and neurosteroid represents a novel neurotherapeutic strategy with potentially broad application., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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