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Nicotine Exposure Along with Oral Contraceptive Treatment in Female Rats Exacerbates Post-cerebral Ischemic Hypoperfusion Potentially via Altered Histamine Metabolism

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Abstract

Smoking-derived nicotine (N) and oral contraceptives (OCs) synergistically exacerbate ischemic brain damage in the female, and the underlying mechanisms remain elusive. Our published study showed that N toxicity is exacerbated by OC via altered mitochondrial electron transport chain function. Because mitochondria play an important role in cellular metabolism, we investigated the global metabolomic profile of brains of adolescent and adult female Sprague-Dawley rats exposed to N with or without OC (N+/−OC). Rats were randomly exposed to saline or N+/−OC for 16–21 days followed by random allocation into two cohorts. The first cohort was used to characterize the cortical metabolome. Pathway enrichment analysis showed a significant increase in several histamine metabolites including 1-methylhistamine, 1-methyl-4-imidazoleacetate, and 1-ribosyl-imidazleacetate, along with carnosine and homocarnosine in adolescent and adult animals treated with N and N+OC in relation to respective saline controls, which may be reflective of altered histamine metabolism with nicotine treatment. We also observed reduced levels of the neurotransmitters N-acetyl-aspartyl-glutamate (NAAG), gamma-aminobutyrate (GABA), and N-methyl-GABA in N+OC treatment in adolescent animals. The second cohort underwent bilateral carotid artery occlusion and hypotension followed by cerebral blood flow (CBF) assessment a day later. Autoradiographic images of the brain 24 h after ischemic episodes showed severe reduction in cortical and hippocampal local CBF in N+/−OC-exposed rats compared with saline treated. Because GABA and histamine are critical for CBF maintenance, altered metabolism of these neurotransmitters may be responsible for observed severe post-ischemic hypoperfusion, which in turn exacerbates ischemic brain damage.

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Acknowledgments

We thank all the members of Peritz Scheinberg Cerebral Vascular Disease Research Laboratory for the scientific discussions of this study. We thank Dr. Brant Watson for critical reading of this manuscript, Ms. Isa Saul and Dr. Concepcion Furones for performing rat surgeries, and Ms. Sabrina Victoria Sharma for technical assistance.

Funding

This work was supported by an Endowment from Drs. Chantal and Peritz Scheinberg (Ami P. Raval), Florida Department of Health #7JK01 funds (Helen M. Bramlett and Ami P. Raval), # 20K09 (Ami P. Raval), and the American Heart Association Grant-in-aid # 16GRNT31300011 (Ami P. Raval). Kunjan Dave is supported by Florida Department of Health grant #9JK08.

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Authors and Affiliations

  1. Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, 1420 NW 9th Avenue, Neurology Research Building, Room # 203H, Miami, FL, 33136, USA

    Nathan d’Adesky, Miguel A. Perez-Pinzon, Kunjan R. Dave & Ami P. Raval

  2. Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA

    Francisca Diaz

  3. Biomedical Engineering, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA

    Weizhao Zhao

  4. Department of Neurological Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA

    Helen M. Bramlett

  5. Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA

    Helen M. Bramlett

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  1. Nathan d’Adesky
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  2. Francisca Diaz
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  7. Ami P. Raval
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Contributions

Drs. Raval, Dave, and Diaz conceived the scientific idea and designed the experiments. Drs. d’Adesky, Raval, and Dave performed experiments. Drs. Raval and d’Adesky wrote the paper and Drs. Dave, Perez-Pinzon, Bramlett, and Diaz provided discussions on the project throughout and also provided input in the writing of the manuscript. Dr. Zhao assisted with statistical analysis of images and data, respectively.

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Correspondence to Ami P. Raval.

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All institutional and national guidelines for the care and use of laboratory animals were followed. Animal usage and experimentation were approved by the Institutional Animal Care and Use Committee at the University of Miami and were in accordance with the US Public Health Service’s Policy on Humane Care and Use of Laboratory Animals.

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d’Adesky, N., Diaz, F., Zhao, W. et al. Nicotine Exposure Along with Oral Contraceptive Treatment in Female Rats Exacerbates Post-cerebral Ischemic Hypoperfusion Potentially via Altered Histamine Metabolism. Transl. Stroke Res. 12, 817–828 (2021). https://doi.org/10.1007/s12975-020-00854-5

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