TY - JOUR
T1 - Strain differences in the extent of brain injury in mice after tetramethylenedisulfotetramine-induced status epilepticus
AU - Calsbeek, Jonas J.
AU - González, Eduardo A.
AU - Boosalis, Casey A.
AU - Zolkowska, Dorota
AU - Bruun, Donald A.
AU - Rowland, Douglas J.
AU - Saito, Naomi H.
AU - Harvey, Danielle J.
AU - Chaudhari, Abhijit J.
AU - Rogawski, Michael A.
AU - Garbow, Joel R.
AU - Lein, Pamela J.
N1 - Funding Information:
The authors thank Dr. Suzette Smiley-Jewell for assistance in manuscript preparation and Dr. Andrew Katsifis for donating the precursor for synthesizing the PET radiotracer used in this study. This work was supported by the CounterACT Program, National Institutes of Health Office of the Director and the National Institute of Neurological Disorders and Stroke [ U54 NS079202 to P.J.L. ]. J.J.C. was supported by a predoctoral fellowship from the UC Davis School of Veterinary Medicine ; E.A.G. was supported by predoctoral fellowships from the National Institute of Neurological Disorders and Stroke [grant number F31 NS110522 ] and the National Institutes of Health Initiative for Maximizing Student Development [grant number R25 GM5676520 ]. D.J.R. was supported by the Chan Zuckerberg Initiative DAF, an advised fund of Silicon Valley Community Foundation [ 2019-198156 to D.J.R. ]. This project used core facilities supported by the UC Davis MIND Institute Intellectual and Developmental Disabilities Research Center (Eunice Kennedy Shriver National Institute of Child Health and Human Development grant P50 HD103526 ). The sponsors were not involved in the study design, in the collection, analysis, or interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/12
Y1 - 2021/12
N2 - Acute intoxication with tetramethylenedisulfotetramine (TETS) can trigger status epilepticus (SE) in humans. Survivors often exhibit long-term neurological effects, including electrographic abnormalities and cognitive deficits, but the pathogenic mechanisms linking the acute toxic effects of TETS to chronic outcomes are not known. Here, we use advanced in vivo imaging techniques to longitudinally monitor the neuropathological consequences of TETS-induced SE in two different mouse strains. Adult male NIH Swiss and C57BL/6J mice were injected with riluzole (10 mg/kg, i.p.), followed 10 min later by an acute dose of TETS (0.2 mg/kg in NIH Swiss; 0.3 mg/kg, i.p. in C57BL/6J) or an equal volume of vehicle (10% DMSO in 0.9% sterile saline). Different TETS doses were administered to trigger comparable seizure behavior between strains. Seizure behavior began within minutes of TETS exposure and rapidly progressed to SE that was terminated after 40 min by administration of midazolam (1.8 mg/kg, i.m.). The brains of vehicle and TETS-exposed mice were imaged using in vivo magnetic resonance (MR) and translocator protein (TSPO) positron emission tomography (PET) at 1, 3, 7, and 14 days post-exposure to monitor brain injury and neuroinflammation, respectively. When the brain scans of TETS mice were compared to those of vehicle controls, subtle and transient neuropathology was observed in both mouse strains, but more extensive and persistent TETS-induced neuropathology was observed in C57BL/6J mice. In addition, one NIH Swiss TETS mouse that did not respond to the midazolam therapy, but remained in SE for more than 2 h, displayed robust neuropathology as determined by in vivo imaging and confirmed by FluoroJade C staining and IBA-1 immunohistochemistry as readouts of neurodegeneration and neuroinflammation, respectively. These findings demonstrate that the extent of injury observed in the mouse brain after TETS-induced SE varied according to strain, dose of TETS and/or the duration of SE. These observations suggest that TETS-intoxicated humans who do not respond to antiseizure medication are at increased risk for brain injury.
AB - Acute intoxication with tetramethylenedisulfotetramine (TETS) can trigger status epilepticus (SE) in humans. Survivors often exhibit long-term neurological effects, including electrographic abnormalities and cognitive deficits, but the pathogenic mechanisms linking the acute toxic effects of TETS to chronic outcomes are not known. Here, we use advanced in vivo imaging techniques to longitudinally monitor the neuropathological consequences of TETS-induced SE in two different mouse strains. Adult male NIH Swiss and C57BL/6J mice were injected with riluzole (10 mg/kg, i.p.), followed 10 min later by an acute dose of TETS (0.2 mg/kg in NIH Swiss; 0.3 mg/kg, i.p. in C57BL/6J) or an equal volume of vehicle (10% DMSO in 0.9% sterile saline). Different TETS doses were administered to trigger comparable seizure behavior between strains. Seizure behavior began within minutes of TETS exposure and rapidly progressed to SE that was terminated after 40 min by administration of midazolam (1.8 mg/kg, i.m.). The brains of vehicle and TETS-exposed mice were imaged using in vivo magnetic resonance (MR) and translocator protein (TSPO) positron emission tomography (PET) at 1, 3, 7, and 14 days post-exposure to monitor brain injury and neuroinflammation, respectively. When the brain scans of TETS mice were compared to those of vehicle controls, subtle and transient neuropathology was observed in both mouse strains, but more extensive and persistent TETS-induced neuropathology was observed in C57BL/6J mice. In addition, one NIH Swiss TETS mouse that did not respond to the midazolam therapy, but remained in SE for more than 2 h, displayed robust neuropathology as determined by in vivo imaging and confirmed by FluoroJade C staining and IBA-1 immunohistochemistry as readouts of neurodegeneration and neuroinflammation, respectively. These findings demonstrate that the extent of injury observed in the mouse brain after TETS-induced SE varied according to strain, dose of TETS and/or the duration of SE. These observations suggest that TETS-intoxicated humans who do not respond to antiseizure medication are at increased risk for brain injury.
KW - MRI
KW - Neurodegeneration
KW - Neuroinflammation
KW - PET
KW - Tetramine
UR - http://www.scopus.com/inward/record.url?scp=85114161703&partnerID=8YFLogxK
U2 - 10.1016/j.neuro.2021.08.011
DO - 10.1016/j.neuro.2021.08.011
M3 - Article
C2 - 34478772
AN - SCOPUS:85114161703
SN - 0161-813X
VL - 87
SP - 43
EP - 50
JO - NeuroToxicology
JF - NeuroToxicology
ER -