Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-κB) prior to seizure in transgenic NF-κB/EGFP reporter mice

Authors

• James A. Miller, Center for Environmental Medicine, Colorado State University, USA.
• Kelly A. Kirkley, Center for Environmental Medicine, Colorado State University, USA.
• Rachel Padmanabhan, Center for Environmental Medicine, Colorado State University, USA.
• Li-Ping Liang, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
• Yogendra H. Raol, Department of Pediatrics, Division of Neurology, Translational Epilepsy Research Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
• Manisha Patel, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
• Russell A. Bialecki, AstraZeneca, Department of Drug Safety and Metabolism, USA.
• Ronald B. Tjalkens, Center for Environmental Medicine, Colorado State University, USA. Electronic address: Ron.Tjalkens@colostate.edu.

Document Type

Article

Abstract

Predicting seizurogenic properties of pharmacologically active compounds is difficult due to the complex nature of the mechanisms involved and because of the low sensitivity and high variability associated with current behavioral-based methods. To identify early neuronal signaling events predictive of seizure, we exposed transgenic NF-κB/EGFP reporter mice to multiple low doses of kainic acid (KA), postulating that activation of the stress-responsive NF-κB pathway could be a sensitive indicator of seizurogenic potential. The sub-threshold dose level proximal to the induction of seizure was determined as 2.5mg/kg KA, using video EEG monitoring. Subsequent analysis of reporter expression demonstrated significant increases in NF-κB activation in the CA3 and CA1 regions of the hippocampus 24h after a single dose of 2.5mg/kg KA. This response was primarily observed in pyramidal neurons with little non-neuronal expression. Neuronal NF-κB/EGFP expression was observed in the absence of glial activation, indicating a lack of neurodegeneration-induced neuroinflammation. Protein expression of the immediate-early gene, Nurr1, increased in neurons in parallel to NF-κB activation, supporting that the sub-threshold doses of KA employed directly caused neuronal stress. Lastly, KA also stimulated NF-κB activation in organotypic hippocampal slice cultures established from NF-κB/EGFP reporter mice. Collectively, these data demonstrate the potential advantages of using genetically encoded stress pathway reporter models in the screening of seizurogenic properties of new pharamacologically active compounds.

Keywords

Kainic acid, NF-κB, Neurotoxicity, Safety assessment, Seizure

Medical Subject Headings

Animals; Brain (metabolism, pathology, physiopathology); Female; Genes, Reporter; Gliosis; Green Fluorescent Proteins; Hippocampus (metabolism); Kainic Acid (administration & dosage, toxicity); Male; Mice; Mice, Transgenic; NF-kappa B (genetics, metabolism); Pyramidal Cells; Seizures (chemically induced, metabolism); Signal Transduction (drug effects)

Publication Date

9-1-2014

Publication Title

Neurotoxicology

E-ISSN

1872-9711

Volume

44

First Page

39

Last Page

47

PubMed ID

24813937

Digital Object Identifier (DOI)

10.1016/j.neuro.2014.04.010

Recommended Citation

Miller, James A.; Kirkley, Kelly A.; Padmanabhan, Rachel; Liang, Li-Ping; Raol, Yogendra H.; Patel, Manisha; Bialecki, Russell A.; and Tjalkens, Ronald B., "Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-κB) prior to seizure in transgenic NF-κB/EGFP reporter mice" (2014). Translational Neuroscience. 2561.
https://scholar.barrowneuro.org/neurobiology/2561