Nicotine Exposure Along with Oral Contraceptive Treatment in Female Rats Exacerbates Post-cerebral Ischemic Hypoperfusio
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ORIGINAL ARTICLE
Nicotine Exposure Along with Oral Contraceptive Treatment in Female Rats Exacerbates Post-cerebral Ischemic Hypoperfusion Potentially via Altered Histamine Metabolism Nathan d’Adesky 1 & Francisca Diaz 2 & Weizhao Zhao 3 & Helen M. Bramlett 4,5 & Miguel A. Perez-Pinzon 1 & Kunjan R. Dave 1 & Ami P. Raval 1 Received: 13 July 2020 / Revised: 19 September 2020 / Accepted: 23 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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-ribosylimidazleacetate, 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-methylGABA 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. Keywords Global cerebral ischemia . Histamine . Carnosine synthase 1 . Glutamic acid decarboxylase (GAD) . Autoradiography Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12975-020-00854-5) contains supplementary material, which is available to authorized users. * Ami P. Raval [email protected] 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
2
Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
3
Biomedical Engineering, Leonard M. Miller School of Medicine, University of Miami,
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