Boldine treatment prevents chronic cognitive impairment and exaggerated fear learning in rats exposed to repetitive low-level blast injury.

Overview

1. Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, United States
2. Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, United States
3. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, United States
4. Mount Sinai Alzheimer’s Disease Research Center and Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, United States
5. Department of Geriatrics and Palliative Care, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, United States
6. Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
7. Spinal Cord Damage Research Center, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, United States
8. VA Sequencing Collaborations United for Research and Epidemiology, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, United States
9. Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, United States
10. Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, United States
11. Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, United States

Abstract

Many Veterans who experienced blast-related traumatic brain injuries (TBI) during their military service suffer from chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast injuries designed to mimic the type of blast-related mild TBI that was so common in the conflicts in Iraq and Afghanistan develop delayed and persistent cognitive and PTSD-related traits that remain present for over 1 year after exposure. Boldine, an alkaloid derived from the Chilean Boldo tree (Peumus boldus), is a widely used herbal remedy with anti-oxidant, anti-inflammatory, hepatoprotective, and connexin hemichannel-blocking properties. We studied whether oral administration of boldine prevented development of PTSD-related behavioral traits in rats exposed to repetitive low-level blast. Treatment with boldine prevented appearance of the blast-induced PTSD-like phenotype including object recognition deficits and exaggerated cued fear learning. Boldine also prevented blast-induced elevation of the metabotropic glutamate receptor 2 (mGluR2) and the N-methyl-D-aspartate receptor 2b (NMDAR2b), but did not reverse decreases in the serotonin 5-HT2A receptor. Iba1 immunofluorescence staining suggested that boldine reduced blast-associated microglial process retraction (indicative of activation) in the somatosensory cortex. Transcriptomics analysis of hippocampus mRNA did not identify individual genes that remained significant after FDR correction. Exploratory analysis of 85 nominally significant candidates suggested that boldine induced coordinated transcriptional changes related to GO terms “Cognition” and “Neurotransmitter Transport,” consistent with modulation of activity-regulated transcription factors and neuroimmune signaling. These studies suggest that boldine may be beneficial for the neurobehavioral syndromes that follow blast exposure in military Veterans.

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Data

Datasets cited

• geo:GSE338885, at NCBI GEO; found in the text, “RNA isolation, RNA-seq library preparation…”

Data availability statement

The sequencing datasets generated and analyzed during the current study are publicly available in the NCBI Gene Expression Omnibus (GEO) repository under accession number GSM9884033 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM9884033) and can be accessed at: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM9884033. All other data supporting the findings of this study are included in the article and/or its Supplementary material. Additional information may be obtained from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, pages, dates, 14 authors, 5 keywords, 3 funders, 63 references, 7 RRIDs.

Cite

This paper

Garcia, G. P., Perez, G. M., De Gasperi, R., Gama Sosa, M. A., Yeung, S., Zhu, C. W., Hof, P. R., Pan, J., Khalique, S., Kozlenkov, A., Zhao, W., Toro, C. A., Elder, G. A., & Cardozo, C. P. (2026). Boldine treatment prevents chronic cognitive impairment and exaggerated fear learning in rats exposed to repetitive low-level blast injury. Frontiers in cellular neuroscience, 20, 1894226. https://doi.org/10.3389/fncel.2026.1894226

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