Roberta Brinton

Interests

Research

My research has focused broadly on the mechanisms by which the aging brain develops late onset Alzheimer’s disease. I lead two large programs of research that are organized under two major themes; 1) Estrogen systems neurobiology and Aging Female Brain and 2) Allopregnanolone regenerative systems neurobiology and regenerative therapeutic for Alzheimer’s disease.

Courses

Scholarly Contributions

Journals/Publications

• Brinton, R., & Desai, M. (2019). Automimmune disease in women: Endocrine transition and risk across the lifespan. Front Endocrinol.
• Brinton, R., Bacon, E., Mishra, A., Wang, Y., Desai, M., & Yin, F. (2019). Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation. Neurobiol Aging.
• Brinton, R., Espeland, M., Hayden, K., Lockhart, S., Yassine, H., Horscheidt, S., Yasar, S., Luchsinger, J., Neiberg, R., & Charmichael, O. (2019). Sex-related differences in brain volumes and cerebral blood flow among overweight and obese adults with type 2 diabetes: Exploratory analyses from the action for health in diabetes brain magnetic resonance imaging study. J Gerontol A Biol Sci Med Sci.
• Brinton, R., Karim, R., Mack, W., Sripasert, I., Hodis, H., & Allayee, H. (2019). Effect of ApoE4 Genotype on the Association Between Metabolic Phenotype and Subclinical Atherosclerosis in Postmenopausal Women. Am J Cardiol.
• Brinton, R., Karin, R., Koc, M., Rettberg, J., Hodis, H., Henderson, V., St John, J., Allayee, H., & Mack, W. (2019). Apolipoprotein E4 genotype in combination with poor metabolic profile is associated with reduced cognitive performance in healthy postmenopausal women: implications for late onset Alzheimer’s disease.. Menopause.
• Brinton, R., Luo, M., Ma, W., Sand, Z., Finlayson, J., Wang, T., Willis, W., & Mandarino, L. J. (2019). Von Willebrand factor A domain-containing protein 8 (VWA8) localizes to the matrix side of the inner mitochondrial membrane. Biochem Biophys Res Commun.
• Brinton, R., Rahman, A., Jackson, H., Hristov, H., Issacson, R., Saif, N., Shetty, T., Etingin, O., Henchliffe, C., & Mosconi, L. (2019). Sex and Gender Driven Modifiers of Alzheimer’s: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks. Front Aging Neurosci..
• Brinton, R., Schneider, L., Hernandez, G., Zhao, L., Franke, A., Chen, Y., Pawluczyk, S., & Mack, W. (2019). Safety and feasibility of estrogen receptor-β targeted phytoSERM formulation for menopausal symptoms: phase 1b/2a randomized clinical trial. Menopause.
• Brinton, R., Wang, T., Yao, J., Chen, S., & Mao, J. (2019). Allopregnanolone Reverses Bioenergetic Deficits in Female Triple Transgenic Alzheimer’s Mouse Model. Neurotherapeutics.
• Brinton, R., Wang, Y., Hernandez, G., Mack, W., Schneider, L., & Yin, F. (2019). Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy. Menopause.
• Brinton, R., & Mishra, A. (2018). Inflamation: Bridging Age, Menopause and APOEε4 Genotype to Alzheimer’s Disease.. Front. Aging Neurosci.
• Brinton, R., & Mosconi, L. (2018). How would we combat menopause as an Alzheimer’s risk factor?. Expert Rev Neurother.
• Brinton, R., Bacon, E., Mishra, A., Wang, Y., Desai, M., & Yin, F. (2018). Neuroendocrine Aging Precedes Perimenopause and Is Regulated by DNA Methylation.. Neurobiology of Aging.
• Brinton, R., Chen, S., Mao, Z., & Sitruk-Ware, R. (2018). Therapeutic progestin segesterone acetate promotes neurogenesis: implications for sustaining regeneration in female brain.. Menopause.
• Brinton, R., Mosconi, L., Diaz, I., Wu, X., Scheyer, O., Hristov, H., Vallabhajosula, S., Isaacson, R., & de Leon, M. (2018). Increased Alzheimer’s risk during the menopause transition: A 3-year longitudinal brain imaging study. PLoS ONE.
• Geifman, N., Brinton, R., Kennedy, R., Schneider, L., & Butte, A. (2017). Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer's disease. Alzheimers Res Ther, 9(1), 10. doi:10.1186/s13195-017-0237-y
• Hernandez, G., Franke, L., Chen, Y., Mack, W., Brinton, R., & Schneider, L. (2018). Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor β-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women. Menopause. doi:10.1097/GME.0000000000000984
• Mosconi, L., Berti, V., Guyara-Quinn, C., McHugh, P., Petrongolo, G., Osorio, R., Connaughty, C., Pupi, A., Vallabhajosula, S., Isaacson, R., deLeon, M., Swerdlow, R., & Brinton, R. (2017). Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery. PLoS One, 12(10). doi:10.1371/journal.pone.0185926
• Mosconi, L., Berti, V., Quinn, C., McHugh, P., Petrongolo, G., Varsavsky, L., Osorio, R., Pupi, A., Vallabhajosula, S., Isaacson, R., deLeon, M., & Brinton, R. (2017). Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging. Neurology, 89(13), 1382-1390. doi:10.1212/WNL.0000000000004425
• Wang, J., Trivedi, A., Carrillo, N., Yang, J., Giulivi, C., Adams, P., Tassone, F., Kim, K., Rivera, S., Lubarr, N., Wu, C., Irwin, R., Brinton, R., Olichney, J., Rogawski, M., & Hagerman, R. (2017). Open-Label Allopregnanolone Treatment of Men with Fragile X-Associated Tremor/Ataxia Syndrome. Neurotherapeutics, 14(4), 1073-83. doi:10.1007/s13311-017-0555-6
• Yin, F., Yao, J., Brinton, R., & Cadenas, E. (2017). Editorial: The Metabolic-Inflammatory Axis in Brain Aging and Neurodegeneration. Front Aging Neurosci, 9, 209.
• Zissimopolous, J., Barthold, D., Brinton, R., & Joyce, G. (2017). Sex and Race Differences in the Association of Statin Use and Incidence of Alzheimer’s Disease. JAMA Neurol, 74(2), 225-232. doi:10.1001/jamaneurol.2016.3783
• Brinton, R. (2016). Neuroendocrinology: Oestrogen therapy affects brain structure but not function. Nat Rev Neurol, 12(10), 561-2.
• Karim, R., Dang, H., Henderson, H., Hodis, H., St.John, J., Brinton, R., & Mack, W. (2016). Effect of Reproductive History and Exogenous Hormone Use on Cognitive Function in Mid- and Late Life. J Am Geriatr Soc, 64(12), 2448-2456.
• Retberg, J., Dang, H., Hodis, H., Henderson, V., St. John, J., Mack, W., & Brinton, R. (2016). Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: Potential for detecting an at-Alzheimer's risk metabolic phenotype. Neurobiol Aging, 40, 155-63.
• Riedel, B. C., Thompson, P. M., & Brinton, R. D. (2016). Age, APOE and sex: Triad of risk of Alzheimer's disease. The Journal of steroid biochemistry and molecular biology, 160, 134-47.
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  Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer's disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ε4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ε4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ε4 allele. Paradoxically, men homozygous for APOE-ε4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer's disease, age, APOE-ε4 genotype and chromosomal sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the specific risk of the APOE-ε4 positive male which appears to emerge early in the aging process. Evidence for impact of the triad of AD risk factors is most evident in the temporal trajectory of AD progression and burden of pathology in relation to APOE genotype, age and sex. Collectively, the data indicate complex interactions between age, APOE genotype and gender that belies a one size fits all approach and argues for a precision medicine approach that integrates across the three main risk factors for Alzheimer's disease.
• Snyder, H., Athana, S., Craft, S., Brinton, R., Dubal, D., Espeland, M., Gatz, M., Mielke, M., & Raber, J. (2016). Sex biology contributions to vulnerability to Alzheimer’s disease: A think tank convened by the Women’s Alzheimer’s Research Initiative. Alzheimer’s & Dementia.
• Wang, Y., & Brinton, R. (2016). Triad of Risk for Late Onset Alzheimer's: Mitochondrial Haplotype, APOE Genotype and Chromosomal Sex. Frontiers in Aging Neuroscience, 8, 232.
• Zhang, L., Trushina, S., Christiansen, T., Bachmeier, B., Gateno, B., Schroeder, A., Yao, J., Itoh, K., Sesaki, H., Poon, W., Gylys, K., Patterson, E., Parisi, J., Brinton, R., Salisbury, J., & Trushina, E. (2016). Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease. Scientific Reports. doi:10.1038/srep18725
• Zhao, L., Mao, Z., Woody, S., & Brinton, R. (2016). Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer's disease.. Neurobiol Aging, 42, 69-79.
• Zissimopolous, J., Barthold, D., Brinton, R., & Joyce, G. (2016). Sex and Race Differences in the Association Between Statin Use and the Incidence of Alzheimer Disease. JAMA Neurol.
• Brinton, R., Yao, J., Yin, F., Mack, W., & Cardenas, E. (2015). Perimenopause as a neurological transition state. Nat Rev Endocrinol.
• Caldwell, C. C., Yao, J., & Brinton, R. D. (2015). Targeting the prodromal stage of Alzheimer's disease: bioenergetic and mitochondrial opportunities. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 12(1), 66-80.
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  Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.
• Esepland, M., Brinton, R., Hugenschmidt, C., Manson, J., Craft, S., Yaffe, K., Weitlauf, J., Vaughan, L., Johnson, K., Padula, C., Jackson, R., & Resnick, S. (2015). Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women.. Diabetes Care.
• Esepland, M., Brinton, R., Manson, J., Yaffe, K., Hugenschmidt, C., Vaughan, L., Craft, S., Edwards, B., Cassanova, R., Masaki, K., & Resnick, S. (2015). Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes. Neurology.
• Irwin, R., Solinsky, C., Loya, C., Salituro, F., Bauer, G., Rodgers, K. E., Rogawski, M., & Brinton, R. (2015). Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease.. PLoS One, 3(10).
• Karim, R., Stanczyk, F., Brinton, R., Rettberg, J., Hodis, H., & Mack, W. (2015). Association of Edogenous Sex Hormones with Adipokines and Ghrelin in Postmenopausal Women. Clinical Endocrinol Metab, 100(2), 508-15.
• Kosinski, L., Yao, J., Yin, F., Harrington, M., Christiansen, T., Trushina, E., & Brinton, R. (2015). White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease. EBioMedicine.
• Yin, F., Yao, J., Sancheti, H., Feng, T., Melcangi, R. C., Morgan, T. E., Finch, C. E., Pike, C. J., Mack, W. J., Cadenas, E., & Brinton, R. D. (2015). The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity. Neurobiology of aging, 36(7), 2282-95.
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  The perimenopause is an aging transition unique to the female that leads to reproductive senescence which can be characterized by multiple neurological symptoms. To better understand potential underlying mechanisms of neurological symptoms of perimenopause, the present study determined genomic, biochemical, brain metabolic, and electrophysiological transformations that occur during this transition using a rat model recapitulating fundamental characteristics of the human perimenopause. Gene expression analyses indicated two distinct aging programs: chronological and endocrine. A critical period emerged during the endocrine transition from regular to irregular cycling characterized by decline in bioenergetic gene expression, confirmed by deficits in fluorodeoxyglucose-positron emission tomography (FDG-PET) brain metabolism, mitochondrial function, and long-term potentiation. Bioinformatic analysis predicted insulin/insulin-like growth factor 1 and adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK/PGC1α) signaling pathways as upstream regulators. Onset of acyclicity was accompanied by a rise in genes required for fatty acid metabolism, inflammation, and mitochondrial function. Subsequent chronological aging resulted in decline of genes required for mitochondrial function and β-amyloid degradation. Emergence of glucose hypometabolism and impaired synaptic function in brain provide plausible mechanisms of neurological symptoms of perimenopause and may be predictive of later-life vulnerability to hypometabolic conditions such as Alzheimer's.
• Irwin, R. W., & Brinton, R. D. (2014). Allopregnanolone as regenerative therapeutic for Alzheimer's disease: Translational development and clinical promise. PROGRESS IN NEUROBIOLOGY, 113, 40-55.
• Rettberg, J. R., Yao, J., & Brinton, R. D. (2014). Estrogen: A master regulator of bioenergetic. systems in the brain and body. FRONTIERS IN NEUROENDOCRINOLOGY, 35(1), 8-30.
• Rettberg, J. R., Yao, J., & Brinton, R. D. (2014). Estrogen: a master regulator of bioenergetic systems in the brain and body. Frontiers in neuroendocrinology, 35(1), 8-30.
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  Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer's disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral metabolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as indicators of efficacy of hormone therapy or other preventative interventions.
• Sancheti, H., Kanamori, K., Patil, I., Brinton, R. D., Ross, B. D., & Cadenas, E. (2014). Reversal of metabolic deficits by lipoic acid in a triple transgenic mouse model of Alzheimer's disease: a C-13 NMR study. JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 34(2), 288-296.
• Brinton, R. (2013). Neurosteroids as regenerative agents in the brain: therapeutic implications. NATURE REVIEWS ENDOCRINOLOGY, 9(4), 241-250.
• Ding, F., Yao, J., Rettberg, J. R., Chen, S., & Brinton, R. D. (2013). Early Decline in Glucose Transport and Metabolism Precedes Shift to Ketogenic System in Female Aging and Alzheimer's Mouse Brain: Implication for Bioenergetic Intervention. PLOS ONE, 8(11).
• Ding, F., Yao, J., Rettberg, J. R., Chen, S., & Brinton, R. D. (2013). Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention. PloS one, 8(11), e79977.
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  We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3-15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6-9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential targets for preventing shifts to less efficient bioenergetic fuels and transition to the ketogenic phenotype of the Alzheimer's brain.
• Ding, F., Yao, J., Zhao, L., Mao, Z., Chen, S., & Brinton, R. D. (2013). Ovariectomy Induces a Shift in Fuel Availability and Metabolism in the Hippocampus of the Female Transgenic Model of Familial Alzheimer's. PLOS ONE, 8(3).
• Ding, F., Yao, J., Zhao, L., Mao, Z., Chen, S., & Brinton, R. D. (2013). Ovariectomy induces a shift in fuel availability and metabolism in the hippocampus of the female transgenic model of familial Alzheimer's. PloS one, 8(3), e59825.
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  Previously, we demonstrated that reproductive senescence in female triple transgenic Alzheimer's (3×TgAD) mice was paralleled by a shift towards a ketogenic profile with a concomitant decline in mitochondrial activity in brain, suggesting a potential association between ovarian hormone loss and alteration in the bioenergetic profile of the brain. In the present study, we investigated the impact of ovariectomy and 17β-estradiol replacement on brain energy substrate availability and metabolism in a mouse model of familial Alzheimer's (3×TgAD). Results of these analyses indicated that ovarian hormones deprivation by ovariectomy (OVX) induced a significant decrease in brain glucose uptake indicated by decline in 2-[(18)F]fluoro-2-deoxy-D-glucose uptake measured by microPET-imaging. Mechanistically, OVX induced a significant decline in blood-brain-barrier specific glucose transporter expression, hexokinase expression and activity. The decline in glucose availability was accompanied by a significant rise in glial LDH5 expression and LDH5/LDH1 ratio indicative of lactate generation and utilization. In parallel, a significant rise in ketone body concentration in serum occurred which was coupled to an increase in neuronal MCT2 expression and 3-oxoacid-CoA transferase (SCOT) required for conversion of ketone bodies to acetyl-CoA. In addition, OVX-induced decline in glucose metabolism was paralleled by a significant increase in Aβ oligomer levels. 17β-estradiol preserved brain glucose-driven metabolic capacity and partially prevented the OVX-induced shift in bioenergetic substrate as evidenced by glucose uptake, glucose transporter expression and gene expression associated with aerobic glycolysis. 17β-estradiol also partially prevented the OVX-induced increase in Aβ oligomer levels. Collectively, these data indicate that ovarian hormone loss in a preclinical model of Alzheimer's was paralleled by a shift towards the metabolic pathway required for metabolism of alternative fuels in brain with a concomitant decline in brain glucose transport and metabolism. These findings also indicate that estrogen plays a critical role in sustaining brain bioenergetic capacity through preservation of glucose metabolism.
• Fuente-Martin, E., Garcia-Caceres, C., Morselli, E., Clegg, D. J., Chowen, J. A., Finan, B., Brinton, R. D., & Tschoep, M. H. (2013). Estrogen, astrocytes and the neuroendocrine control of metabolism. REVIEWS IN ENDOCRINE & METABOLIC DISORDERS, 14(4), 331-338.
• Fuente-Martin, E., Garcia-Caceres, C., Morselli, E., Clegg, D. J., Chowen, J. A., Finan, B., Brinton, R. D., & Tschöp, M. H. (2013). Estrogen, astrocytes and the neuroendocrine control of metabolism. Reviews in endocrine & metabolic disorders, 14(4), 331-8.
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  Obesity, and its associated comorbidities such as type 2 diabetes, cardiovascular diseases, and certain cancers, represent major health challenges. Importantly, there is a sexual dimorphism with respect to the prevalence of obesity and its associated metabolic diseases, implicating a role for gonadal hormones. Specifically, estrogens have been demonstrated to regulate metabolism perhaps by acting as a leptin mimetic in the central nervous system (CNS). CNS estrogen receptors (ERs) include ER alpha (ERα) and ER beta (ERβ), which are found in nuclear, cytoplasmic and membrane sites throughout the brain. Additionally, estrogens can bind to and activate a G protein-coupled estrogen receptor (GPER), which is a membrane-associated ER. ERs are expressed on neurons as well as glia, which are known to play a major role in providing nutrient supply for neurons and have recently received increasing attention for their potentially important involvement in the CNS regulation of systemic metabolism and energy balance. This brief overview summarizes data focusing on the potential role of astrocytic estrogen action as a key component of estrogenic modulation responsible for mediating the sexual dimorphism in body weight regulation and obesity.
• Jiang, T., Yin, F., Yao, J., Brinton, R. D., & Cadenas, E. (2013). Lipoic acid restores age-associated impairment of brain energy metabolism through the modulation of Akt/JNK signaling and PGC1 alpha transcriptional pathway. AGING CELL, 12(6), 1021-1031.
• Sancheti, H., Akopian, G., Yin, F., Brinton, R. D., Walsh, J. P., & Cadenas, E. (2013). Age-Dependent Modulation of Synaptic Plasticity and Insulin Mimetic Effect of Lipoic Acid on a Mouse Model of Alzheimer's Disease. PLOS ONE, 8(7).
• Sancheti, H., Akopian, G., Yin, F., Brinton, R. D., Walsh, J. P., & Cadenas, E. (2013). Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer's disease. PloS one, 8(7), e69830.
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  Alzheimer's disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity have been shown to be affected in the early stages of Alzheimer's disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer's disease (3xTg-AD) that shows progression of pathology as a function of age; two age groups: 6 months (young) and 12 months (old) were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O) and long term potentiation (LTP) (measured by electrophysiology). Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice.
• Yao, J., Zhao, L., Mao, Z., Chen, S., Wong, K. C., To, J., & Brinton, R. D. (2013). Potentiation of brain mitochondrial function by S-equol and R/S-equol estrogen receptor β-selective phytoSERM treatments. Brain research, 1514, 128-41.
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  Previously we developed an estrogen receptor β-selective phytoestrogenic (phytoSERM) combination, which contains a mixture of genistein, daidzein, and racemic R/S-equol. The phytoSERM combination was found neuroprotective and non-feminizing both in vitro and in vivo. Further, it prevented or alleviated physical and neurological changes associated with human menopause and Alzheimer's disease. In the current study, we conducted translational analyses to compare the effects of racemic R/S-equol-containing with S-equol-containing phytoSERM therapeutic combinations on mitochondrial markers in rat hippocampal neuronal cultures and in a female mouse ovariectomy (OVX) model. Data revealed that both the S-equol and R/S-equol phytoSERM treatments regulated mitochondrial function, with S-equol phytoSERM combination eliciting greater response in mitochondrial potentiation. Both phytoSERM combination treatments increased expression of key proteins and enzymes involved in energy production, restored the OVX-induced decrease in activity of key bioenergetic enzymes, and reduced OVX-induced increase in lipid peroxidation. Comparative analyses on gene expression profile revealed similar regulation between S-equol phytoSERM and R/S-equol phytoSERM treatments with minimal differences. Both combinations regulated genes involved in essential bioenergetic pathways, including glucose metabolism and energy sensing, lipid metabolism, cholesterol trafficking, redox homeostasis and β-amyloid production and clearance. Further, no uterotrophic response was induced by either of the phytoSERM combinations. These findings indicate translational validity for development of an ER β selective S-equol phytoSERM combination as a nutraceutical to prevent menopause-associated symptoms and to promote brain metabolic activity. This article is part of a Special Issue entitled Hormone Therapy.
• Zhao, L., Mao, Z., Chen, S., Schneider, L. S., & Brinton, R. D. (2013). Early Intervention with an Estrogen Receptor beta-Selective Phytoestrogenic Formulation Prolongs Survival, Improves Spatial Recognition Memory, and Slows Progression of Amyloid Pathology in a Female Mouse Model of Alzheimer's Disease. JOURNAL OF ALZHEIMERS DISEASE, 37(2), 403-419.
• Adeosun, S. O., Hou, X. u., Jiao, Y., Zheng, B., Henry, S., Hill, R., He, Z., Pani, A., Kyle, P., Ou, X., Mosley, T., Farley, J. M., Stockmeier, C., Paul, I., Bigler, S., Brinton, R. D., Smeyne, R., & Wang, J. M. (2012). Allopregnanolone Reinstates Tyrosine Hydroxylase Immunoreactive Neurons and Motor Performance in an MPTP-Lesioned Mouse Model of Parkinson's Disease. PLOS ONE, 7(11).
• Bali, N., Arimoto, J. M., Iwata, N., Lin, S. W., Zhao, L., Brinton, R. D., Morgan, T. E., & Finch, C. E. (2012). Differential Responses of Progesterone Receptor Membrane Component-1 (Pgrmc1) and the Classical Progesterone Receptor (Pgr) to 17 beta-Estradiol and Progesterone in Hippocampal Subregions that Support Synaptic Remodeling and Neurogenesis. ENDOCRINOLOGY, 153(2), 759-769.
• Irwin, R. W., Yao, J., To, J., Hamilton, R. T., Cadenas, E., & Brinton, R. D. (2012). Selective Oestrogen Receptor Modulators Differentially Potentiate Brain Mitochondrial Function. JOURNAL OF NEUROENDOCRINOLOGY, 24(1), 236-248.
• Jayaraman, A., Carroll, J. C., Morgan, T. E., Lin, S., Zhao, L., Arimoto, J. M., Murphy, M. P., Beckett, T. L., Finch, C. E., Brinton, R. D., & Pike, C. J. (2012). 17 beta-Estradiol and Progesterone Regulate Expression of beta-Amyloid Clearance Factors in Primary Neuron Cultures and Female Rat Brain. ENDOCRINOLOGY, 153(11), 5467-5479.
• Jayaraman, A., Carroll, J. C., Morgan, T. E., Lin, S., Zhao, L., Arimoto, J. M., Murphy, M. P., Beckett, T. L., Finch, C. E., Brinton, R. D., & Pike, C. J. (2012). 17β-estradiol and progesterone regulate expression of β-amyloid clearance factors in primary neuron cultures and female rat brain. Endocrinology, 153(11), 5467-79.
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  The accumulation of β-amyloid protein (Aβ) is a key risk factor in the development of Alzheimer's disease. The ovarian sex steroid hormones 17β-estradiol (E(2)) and progesterone (P(4)) have been shown to regulate Aβ accumulation, although the underlying mechanism(s) remain to be fully elucidated. In this study, we investigate the effects of E(2) and P(4) treatment on the expression levels of Aβ clearance factors including insulin-degrading enzyme, neprilysin, endothelin-converting enzyme 1 and 2, angiotensin-converting enzyme, and transthyretin, both in primary neuron cultures and female rat brains. Our results show that E(2) and P(4) affect the expression levels of several Aβ clearance factors in dose- and time-dependent manners. Most notably, expression of insulin-degrading enzyme is significantly increased by both hormones in cultured neurons and in vivo and is inversely associated with the soluble Aβ levels in vivo. These findings further define sex steroid hormone actions involved in regulation of Aβ, a relationship potentially important to therapeutic approaches aimed at reducing risk of Alzheimer's disease.
• Reiman, E. M., Brinton, R. D., Katz, R., Petersen, R. C., Negash, S., Mungas, D., & Aisen, P. S. (2012). Considerations in the design of clinical trials for cognitive aging. The journals of gerontology. Series A, Biological sciences and medical sciences, 67(7), 766-72.
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  What will it take to develop interventions for the treatment of age-related cognitive decline? Session V of the Summit provided perspectives on the design of clinical trials to evaluate promising but unproven interventions, and some of the steps needed to accelerate the discovery and evaluation of promising treatments. It considered strategies to further characterize the biological and cognitive changes associated with normal aging and their translation into the development of new treatments. It provided regulatory, scientific, and clinical perspectives about neurocognitive aging treatments, their potential benefits and risks, and the strategies and endpoints needed to evaluate them in the most rapid, rigorous, and clinically meaningful way. It considered lessons learned from the study of Alzheimer's disease, the promising roles of biomarkers in neurocognitive aging research, and ways to help galvanize the scientific study and treatment of neurocognitive aging.
• Singh, C., Liu, L., Wang, J. M., Irwin, R. W., Yao, J., Chen, S., Henry, S., Thompson, R. F., & Brinton, R. D. (2012). Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice. NEUROBIOLOGY OF AGING, 33(8), 1493-1506.
• Singh, C., Liu, L., Wang, J. M., Irwin, R. W., Yao, J., Chen, S., Henry, S., Thompson, R. F., & Brinton, R. D. (2012). Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice. Neurobiology of aging, 33(8), 1493-506.
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  We previously demonstrated that allopregnanolone (APα) increased proliferation of neural progenitor cells and reversed neurogenic and cognitive deficits prior to Alzheimer's disease (AD) pathology (Wang, J.M., Johnston, P.B., Ball, B.G., Brinton, R.D., 2005. The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J. Neurosci. 25, 4706-4718; Wang, J.M., Singh, C., Liu, L., Irwin, R.W., Chen, S., Chung, E.J., Thompson, R.F., Brinton, R.D., 2010. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 107, 6498-6503). Herein, we determined efficacy of APα to restore neural progenitor cell survival and associative learning and memory subsequent to AD pathology in male 3xTgAD mice and their nontransgenic (nonTg) counterparts. APα significantly increased survival of bromodeoxyuridine positive (BrdU+) cells and hippocampal-dependent associative learning and memory in 3xTgAD mice in the presence of intraneuronal amyloid beta (Aβ) whereas APα was ineffective subsequent to development of extraneuronal Aβ plaques. Restoration of hippocampal-dependent associative learning was maximal by the first day and sustained throughout behavioral training. Learning and memory function in APα-treated 3xTgAD mice was 100% greater than vehicle-treated and comparable to maximal normal nonTg performance. In aged 15-month-old nonTg mice, APα significantly increased survival of bromodeoxyuridine-positive cells and hippocampal-dependent associative learning and memory. Results provide preclinical evidence that APα promoted survival of newly generated cells and restored cognitive performance in the preplaque phase of AD pathology and in late-stage normal aging.
• Sun, C., Ou, X., Farley, J. M., Stockmeier, C., Bigler, S., Brinton, R. D., & Wang, J. M. (2012). Allopregnanolone Increases the Number of Dopaminergic Neurons in Substantia Nigra of a Triple Transgenic Mouse Model of Alzheimer's Disease. CURRENT ALZHEIMER RESEARCH, 9(4), 473-480.
• Sun, C., Ou, X., Farley, J. M., Stockmeier, C., Bigler, S., Brinton, R. D., & Wang, J. M. (2012). Allopregnanolone increases the number of dopaminergic neurons in substantia nigra of a triple transgenic mouse model of Alzheimer's disease. Current Alzheimer research, 9(4), 473-80.
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  More than a third of Alzheimer's disease (AD) patients show nigrostriatal pathway disturbances, resulting in akinesia (inability to initiate movement) and bradykinesia (slowness of movement). The high prevalence of this dysfunction of dopaminergic neuron in the nigrostriatal pathway in AD suggests that the risk factors for AD appear also significant risk factors for substantia nigra pars compacta (SNpc) lesions. Previously, we have demonstrated that allopregnanolone (APα) promotes neurogenesis and improves the cognitive function in a triple transgenic mouse model of AD (3xTgAD). In this study, we sought to exam 1) the SNpc lesions in 3xTgAD mice and 2) the impact of APα on promoting the regeneration of new dopaminergic neurons in SNpc of the 3xTgAD mice. The number of Nissl-stained total neurons, tyrosine hydroxylase (TH) positive neurons, and BrdU/TH double positive newly formed neurons were analyzed with unbiased stereology. In the SNpc of 3xTgAD mice, TH positive neurons was 47+- 18 % (p = 0.007), total neurons was 62 +-11.6 % (p = 0.016), of those in the SNpc of non-Tg mice, respectively. APα treatment increased the TH positive neurons in the SNpc of 3xTgAD mice to 93.2 +- 18.5 (p = 0.021 vs. 3xTgAD vehicle) and the total neurons to 84.9+- 6.6 (p = 0.046 vs. 3xTgAD vehicle) of non-Tg mice. These findings indicate that there is a loss of neurons, specifically the TH positive neurons in SNpc of 3xTgAD mice, and that APα reverses the lesion in SNpc of 3xTgAD by increasing the formation of new TH neurons.
• Wang, J. M., Hou, X. u., Adeosun, S., Hill, R., Henry, S., Paul, I., Irwin, R. W., Ou, X., Bigler, S., Stockmeier, C., Brinton, R. D., & Gomez-Sanchez, E. (2012). A Dominant Negative ER beta Splice Variant Determines the Effectiveness of Early or Late Estrogen Therapy after Ovariectomy in Rats. PLOS ONE, 7(3).
• Yao, J., & Brinton, R. D. (2012). Estrogen regulation of mitochondrial bioenergetics: implications for prevention of Alzheimer's disease. Advances in pharmacology (San Diego, Calif.), 64, 327-71.
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  Alzheimer's disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid. Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance. Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The "healthy cell bias of estrogen action" hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy.
• Yao, J., Irwin, R., Chen, S., Hamilton, R., Cadenas, E., & Brinton, R. D. (2012). Ovarian hormone loss induces bioenergetic deficits and mitochondrial beta-amyloid. NEUROBIOLOGY OF AGING, 33(8), 1507-1521.
• Yao, J., Irwin, R., Chen, S., Hamilton, R., Cadenas, E., & Brinton, R. D. (2012). Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid. Neurobiology of aging, 33(8), 1507-21.
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  Previously, we demonstrated that reproductive senescence was associated with mitochondrial deficits comparable to those of female triple-transgenic Alzheimer's mice (3xTgAD). Herein, we investigated the impact of chronic ovarian hormone deprivation and 17β-estradiol (E2) replacement on mitochondrial function in nontransgenic (nonTg) and 3xTgAD female mouse brain. Depletion of ovarian hormones by ovariectomy (OVX) in nontransgenic mice significantly decreased brain bioenergetics, and induced mitochondrial dysfunction and oxidative stress. In 3xTgAD mice, OVX significantly exacerbated mitochondrial dysfunction and induced mitochondrial β-amyloid and β-amyloid (Aβ)-binding-alcohol-dehydrogenase (ABAD) expression. Treatment with E2 at OVX prevented OVX-induced mitochondrial deficits, sustained mitochondrial bioenergetic function, decreased oxidative stress, and prevented mitochondrial β-amyloid and ABAD accumulation. In vitro, E2 increased maximal mitochondrial respiration in neurons and basal and maximal respiration in glia. Collectively, these data demonstrate that ovarian hormone loss induced a mitochondrial phenotype comparable to a transgenic female model of Alzheimer's disease (AD), which was prevented by E2. These findings provide a plausible mechanism for increased risk of Alzheimer's disease in premenopausally oophorectomized women while also suggesting a therapeutic strategy for prevention.
• Zhao, L., Morgan, T. E., Mao, Z., Lin, S., Cadenas, E., Finch, C. E., Pike, C. J., Mack, W. J., & Brinton, R. D. (2012). Continuous versus Cyclic Progesterone Exposure Differentially Regulates Hippocampal Gene Expression and Functional Profiles. PLOS ONE, 7(2).
• Chen, S., Wang, J. M., Irwin, R. W., Yao, J., Liu, L., & Brinton, R. D. (2011). Allopregnanolone Promotes Regeneration and Reduces beta-Amyloid Burden in a Preclinical Model of Alzheimer's Disease. PLOS ONE, 6(8).
• Hamilton, R. T., Rettberg, J. R., Mao, Z., To, J., Zhao, L., Appt, S. E., Register, T. C., Kaplan, J. R., & Brinton, R. D. (2011). Hippocampal responsiveness to 17 beta-estradiol and equol after long-term ovariectomy: Implication for a therapeutic window of opportunity. BRAIN RESEARCH, 1379, 11-22.
• Irwin, R. W., Yao, J., Ahmed, S. S., Hamilton, R. T., Cadenas, E., & Brinton, R. D. (2011). Medroxyprogesterone Acetate Antagonizes Estrogen Up-Regulation of Brain Mitochondrial Function. ENDOCRINOLOGY, 152(2), 556-567.
• Rettberg, J. R., Hamilton, R. T., Mao, Z., To, J., Zhao, L., Appt, S. E., Register, T. C., Kaplan, J. R., & Brinton, R. D. (2011). The effect of dietary soy isoflavones before and after ovariectomy on hippocampal protein markers of mitochondrial bioenergetics and antioxidant activity in female monkeys. Brain research, 1379, 23-33.
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  Estrogen therapy can promote cognitive function if initiated within a 'critical window' during the menopausal transition. However, in the absence of a progestogen, estrogens increase endometrial cancer risk which has spurred research into developing estrogenic alternatives that have the beneficial effects of estrogen but which are clinically safer. Soy protein is rich in isoflavones, which are a class of potential estrogenic alternatives. We sought to determine the effects of two diets, one with casein-lactalbumin as the main protein source and the other with soy protein containing isoflavones, on protein markers of hippocampal bioenergetic capacity in adult female cynomolgus macaques (Macaca fascicularis). Further, we assessed the effects of dietary soy isoflavones before or after ovariectomy. Animals receiving soy diet premenopausally then casein/lactalbumin post-ovariectomy had higher relative hippocampal content of glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase and pyruvate dehydrogenase subunit e1α. Post-ovariectomy consumption of soy was associated with higher succinate dehydrogenase α levels and lower levels of isocitrate dehydrogenase, both proteins involved in the tricarboxylic acid cycle, significantly decreased expression of the antioxidant enzyme peroxiredoxin-V, and a non-significant trend towards decreased manganese superoxide dismutase expression. None of the diet paradigms significantly affected expression levels of oxidative phosphorylation enzyme complexes, or of mitochondrial fission and fusion proteins. Together, these data suggest that long-term soy diet produces minimal effects on hippocampal expression of proteins involved in bioenergetics, but that switching between a diet containing primarily animal protein and one containing soy isoflavones before and after menopause may result in complex effects on brain chemistry.
• Wu, T., Chen, S., & Brinton, R. D. (2011). Membrane estrogen receptors mediate calcium signaling and MAP kinase activation in individual hippocampal neurons. BRAIN RESEARCH, 1379, 34-43.
• Yao, J., & Brinton, R. D. (2011). Targeting mitochondrial bioenergetics for Alzheimer's prevention and treatment. Current pharmaceutical design, 17(31), 3474-9.
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  Alzheimer's is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. The progressive and multifaceted degenerative phenotype of Alzheimer's suggests that successful treatment strategies necessarily will be equally multi-faceted and disease stage specific. Traditional therapeutic strategies based on the pathological aspect of the disease have achieved success in preclinical models which has not translated into clinical therapeutic efficacy. Meanwhile, increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. The essential role of mitochondrial bioenergetics and the unique trajectory of alterations in brain metabolic capacity enable a bioenergetic- centric strategy that targets disease-stage specific pattern of brain metabolism for disease prevention and treatment. A combination of nutraceutical and pharmaceutical intervention that enhances glucose-driven metabolic activity and potentiates mitochondrial bioenergetic function could prevent the antecedent decline in brain glucose metabolism, promote healthy aging and prevent AD. Alternatively, during the prodromal incipient phase of AD, sustained activation of ketogenic metabolic pathways coupled with supplement of the alternative fuel source, ketone bodies, could sustain mitochondrial bioenergetic function to prevent or delay further progression of the disease.
• Yao, J., Chen, S., Cadenas, E., & Brinton, R. D. (2011). Estrogen protection against mitochondrial toxin-induced cell death in hippocampal neurons: Antagonism by progesterone. BRAIN RESEARCH, 1379, 2-10.
• Yao, J., Chen, S., Mao, Z., Cadenas, E., & Brinton, R. D. (2011). 2-Deoxy-D-Glucose Treatment Induces Ketogenesis, Sustains Mitochondrial Function, and Reduces Pathology in Female Mouse Model of Alzheimer's Disease. PLOS ONE, 6(7).
• Yao, J., Rettberg, J. R., Klosinski, L. P., Cadenas, E., & Brinton, R. D. (2011). Shift in brain metabolism in late onset Alzheimer's disease: Implications for biomarkers and therapeutic interventions. MOLECULAR ASPECTS OF MEDICINE, 32(4-6), 247-257.
• Yao, J., Rettberg, J. R., Klosinski, L. P., Cadenas, E., & Brinton, R. D. (2011). Shift in brain metabolism in late onset Alzheimer's disease: implications for biomarkers and therapeutic interventions. Molecular aspects of medicine, 32(4-6), 247-57.
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  Alzheimer's is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised mitochondrial bioenergetics lead to over-production of and mitochondrial accumulation of β-amyloid, which is coupled with oxidative stress. Collectively, this results in a shift in brain metabolic profile from glucose-driven bioenergetics towards a compensatory, but less efficient, ketogenic pathway. We propose that the compensatory shift from a primarily aerobic glycolysis pathway to a ketogenic/fatty acid β-oxidation pathway eventually leads to white matter degeneration. The essential role of mitochondrial bioenergetics and the unique trajectory of compensatory metabolic adaptations in brain enable a bioenergetic-centric strategy for development of biomarkers. From a therapeutic perspective, this trajectory of alterations in brain metabolic capacity enables disease-stage specific strategies to target brain metabolism for disease prevention and treatment. A combination of nutraceutical and pharmaceutical interventions that enhance glucose-driven metabolic activity and potentiate mitochondrial bioenergetic function could prevent the antecedent decline in brain glucose metabolism, promote healthy aging and prevent AD. Alternatively, during the prodromal incipient phase of AD, sustained activation of ketogenic metabolic pathways coupled with supplementation of the alternative fuel source, ketone bodies, could sustain mitochondrial bioenergetic function to prevent or delay further progression of the disease.
• Zhao, L., Yao, J., Mao, Z., Chen, S., Wang, Y., & Brinton, R. D. (2011). 17 beta-Estradiol regulates insulin-degrading enzyme expression via an ER beta/PI3-K pathway in hippocampus: Relevance to Alzheimer's prevention. NEUROBIOLOGY OF AGING, 32(11), 1949-1963.
• Henderson, V. W., & Brinton, R. D. (2010). Menopause and mitochondria: Windows into Estrogen effects on Alzheimer's disease risk and therapy. NEUROENDOCRINOLOGY: PATHOLOGICAL SITUATIONS AND DISEASES, 182, 77-96.
• Liu, L., Zhao, L., She, H., Chen, S., Wang, J. M., Wong, C., McClure, K., Sitruk-Ware, R., & Brinton, R. D. (2010). Clinically Relevant Progestins Regulate Neurogenic and Neuroprotective Responses in Vitro and in Vivo. ENDOCRINOLOGY, 151(12), 5782-5794.
• Wang, J. M., Singh, C., Liu, L., Irwin, R. W., Chen, S., Chung, E. J., Thompson, R. F., & Brinton, R. D. (2010). Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 107(14), 6498-6503.
• Yao, J., Hamilton, R. T., Cadenas, E., & Brinton, R. D. (2010). Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1800(10), 1121-1126.
• Yao, J., Hamilton, R. T., Cadenas, E., & Brinton, R. D. (2010). Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence. Biochimica et biophysica acta, 1800(10), 1121-6.
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  We have previously demonstrated that mitochondrial bioenergetic deficits precede Alzheimer's pathology in the female triple transgenic Alzheimer's (3xTgAD) mouse model. Herein, we sought to determine the impact of reproductive senescence on mitochondrial function in the normal non-transgenic (nonTg) and 3xTgAD female mouse model of AD.
• Asthana, S., Brinton, R. D., Henderson, V. W., McEwen, B. S., Morrison, J. H., & Schmidt, P. J. (2009). Frontiers proposal. National Institute on Aging "bench to bedside: estrogen as a case study". AGE, 31(3), 199-210.
• Liu, L., Wang, J., Zhao, L., Nilsen, J., McClure, K., Wong, K., & Brinton, R. D. (2009). Progesterone Increases Rat Neural Progenitor Cell Cycle Gene Expression and Proliferation Via Extracellularly Regulated Kinase and Progesterone Receptor Membrane Components 1 and 2. ENDOCRINOLOGY, 150(7), 3186-3196.
• Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., & Brinton, R. D. (2009). Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 106(34), 14670-14675.
• Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., & Brinton, R. D. (2009). Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 106(34), 14670-5.
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  Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (Abeta) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of Abeta binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.
• Zhao, L., Mao, Z., & Brinton, R. D. (2009). A Select Combination of Clinically Relevant Phytoestrogens Enhances Estrogen Receptor beta-Binding Selectivity and Neuroprotective Activities in Vitro and in Vivo. ENDOCRINOLOGY, 150(2), 770-783.
• Brinton, R. D., Thompson, R. F., Foy, M. R., Baudry, M., Wang, J., Finch, C. E., Morgan, T. E., Pike, C. J., Mack, W. J., Stanczyk, F. Z., & Nilsen, J. (2008). Progesterone receptors: Form and function in brain. FRONTIERS IN NEUROENDOCRINOLOGY, 29(2), 313-339.
• Foy, M. R., Baudry, M., Brinton, R. D., & Thompson, R. F. (2008). Estrogen and Hippocampal Plasticity in Rodent Models. JOURNAL OF ALZHEIMERS DISEASE, 15(4), 589-603.
• Irwin, R. W., Yao, J., Hamilton, R. T., Cadenas, E., Brinton, R. D., & Nilsen, J. (2008). Progesterone and estrogen regulate oxidative metabolism in brain mitochondria. ENDOCRINOLOGY, 149(6), 3167-3175.
• Wang, J. M., & Brinton, R. D. (2008). Allopregnanolone-induced rise in intracellular calcium in embryonic hippocampal neurons parallels their proliferative potential. BMC NEUROSCIENCE, 9.
• Wang, J. M., Liu, L., & Brinton, R. D. (2008). Estradiol-17 beta-induced human neural progenitor cell proliferation is mediated by an estrogen receptor beta-phosphorylated extracellularly regulated kinase pathway. ENDOCRINOLOGY, 149(1), 208-218.
• Wang, J. M., Liu, L., Irwin, R. W., Chen, S., & Brinton, R. D. (2008). Regenerative potential of allopregnanolone. BRAIN RESEARCH REVIEWS, 57(2), 398-409.
• Nilsen, J., Irwin, R. W., Gallaher, T. K., & Brinton, R. D. (2007). Estradiol In Vivo regulation of brain mitochondrial proteome. JOURNAL OF NEUROSCIENCE, 27(51), 14069-14077.
• Soussou, W. V., Yoon, G. J., Brinton, R. D., & Berger, T. W. (2007). Neuronal network morphology and electrophysiology of hippocampal neurons cultured on surface-treated multielectrode arrays. IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, 54(7), 1309-1320.
• Wang, J. M., Irwin, R. W., Liu, L., Chen, S., & Brinton, R. D. (2007). Regeneration in a degenerating brain: Potential of allopregnanolone as a neuroregenerative agent. CURRENT ALZHEIMER RESEARCH, 4(5), 510-517.
• Zhao, L., & Brinton, R. D. (2007). Estrogen receptor alpha and beta differentially regulate intracellular Ca2+ dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons. BRAIN RESEARCH, 1172, 48-59.
• Zhao, L., Jin, C., Mao, Z., Gopinathan, M. B., Rehder, K., & Brinton, R. D. (2007). Design, synthesis, and Estrogenic activity of a novel estrogen receptor modulator - A hybrid structure of 17 beta-estradiol and vitamin E in hippocampal neurons. JOURNAL OF MEDICINAL CHEMISTRY, 50(18), 4471-4481.
• Brewer, G. J., Reichensperger, J. D., & Brinton, R. D. (2006). Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons. NEUROBIOLOGY OF AGING, 27(2), 306-317.
• Brewer, G. J., Reichensperger, J. D., & Brinton, R. D. (2006). Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons. Neurobiology of aging, 27(2), 306-17.
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  To determine the impact of aging and 17beta-estradiol on neuronal Ca2+ homeostasis, intracellular Fura-2 Ca2+-imaging was conducted during 20-pulses of glutamate in hippocampal neurons cultured from embryonic (E18), middle-age (10 months) and old (24 months) rat brain. Marked age-related differences in intracellular Ca2+ ([Ca2+]i) homeostasis and striking regulation by 17beta-estradiol were seen. Embryonic neurons exhibited the greatest capacity to regulate Ca2+ homeostasis followed by middle-age neurons. In old neurons, the first peak [Ca2+]i was substantially greater than at other ages and the return to baseline Ca2+ rapidly dysregulated with an inability to restore [Ca2+]i following the first glutamate pulse which persisted throughout the 20 pulses. 17beta-Estradiol pretreatment of old neurons profoundly attenuated the peak [Ca2+]i rise and delayed the age-associated dysregulation of baseline [Ca2+]i, normalizing responses to those of middle-age neurons treated with estradiol. The efficacy of 17beta-estradiol extended below 10 pg/ml with full protection against toxicity from glutamate and Abeta (1-40). These results demonstrate age-associated dysregulation of [Ca2+]i homeostasis which was largely prevented by 17beta-estradiol with implications for estrogen/hormone therapy.
• Chen, S., Nilsen, J., & Brinton, R. D. (2006). Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: Therapeutic implications. ENDOCRINOLOGY, 147(11), 5303-5313.
• Kim, M. T., Soussou, W., Gholmieh, G., Ahuja, A., Tanguay, A., Berger, T. W., & Brinton, R. D. (2006). 17 beta-estradiol potentiates field excitatory postsynaptic potentials within each subfield of the hippocampus with greatest potentiation of the associational/commissural afferents of CA3. NEUROSCIENCE, 141(1), 391-406.
• Mannella, P., & Brinton, R. D. (2006). Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: A unified mechanism of estrogen action. JOURNAL OF NEUROSCIENCE, 26(37), 9439-9447.
• Morrison, J. H., Brinton, R. D., Schmidt, P. J., & Gore, A. C. (2006). Estrogen, menopause, and the aging brain: How basic neuroscience can inform hormone therapy in women. JOURNAL OF NEUROSCIENCE, 26(41), 10332-10348.
• Nilsen, J., Chen, S., Irwin, R. W., Iwamoto, S., & Brinton, R. D. (2006). Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC NEUROSCIENCE, 7.
• Nilsen, J., Morales, A., & Brinton, R. D. (2006). Medroxyprogesterone acetate exacerbates glutamate excitotoxicity. GYNECOLOGICAL ENDOCRINOLOGY, 22(7), 355-361.
• Wang, J. M., Irwin, R. W., & Brinton, R. D. (2006). Activation of estrogen receptor alpha increases and estrogen receptor beta decreases apolipoprotein E expression in hippocampus in vitro and in vivo. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 103(45), 16983-16988.
• Zhao, L. Q., & Brinton, R. D. (2006). Select estrogens within the complex formulation of conjugated equine estrogens (Premarin (R)) are protective against neurodegenerative insults: Implications for a composition of estrogen therapy to promote neuronal function and prevent Alzheimer's disease. BMC NEUROSCIENCE, 7.
• Zhao, L., O'Neill, K., & Brinton, R. D. (2006). Estrogenic agonist activity of ICI 182,780 (Faslodex) in hippocampal neurons: Implications for basic science understanding of estrogen signaling and development of estrogen modulators with a dual therapeutic profile. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 319(3), 1124-1132.
• Wang, J. M., Johnston, P. B., Ball, B. G., & Brinton, R. D. (2005). The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. JOURNAL OF NEUROSCIENCE, 25(19), 4706-4718.
• Wu, T. W., Wang, J. M., Chen, S., & Brinton, R. D. (2005). 17 beta-Estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-amp response element binding protein signal pathway and Bcl-2 expression in rat hippocampal neurons: A potential initiation mechanism for estrogen-induced neuroprotection. NEUROSCIENCE, 135(1), 59-72.
• Zhao, L. Q., & Brinton, R. D. (2005). Structure-based virtual screening for plant-based ER beta-selective ligands as potential preventative therapy against age-related neurodegenerative diseases. JOURNAL OF MEDICINAL CHEMISTRY, 48(10), 3463-3466.
• Zhao, L. Q., O'Neill, K., & Brinton, R. D. (2005). Selective estrogen receptor modulators (SERMs) for the brain: Current status and remaining challenges for developing NeuroSERMs. BRAIN RESEARCH REVIEWS, 49(3), 472-493.
• Zhao, L., Chen, S., Wang, J. M., & Brinton, R. D. (2005). 17 beta-estradiol induces Ca2+ influx, dendritic and nuclear Ca2+ rise and subsequent cyclic amp response element-binding protein activation in hippocampal neurons: A potential initiation mechanism for estrogen neurotrophism. NEUROSCIENCE, 132(2), 299-311.
• O'Neill, K., Chen, S. H., & Brinton, R. D. (2004). Impact of the selective estrogen receptor modulator, raloxifene, on neuronal survival and outgrowth following toxic insults associated with aging and Alzheimer's disease. EXPERIMENTAL NEUROLOGY, 185(1), 63-80.
• O'Neill, K., Chen, S. H., & Brinton, R. D. (2004). Impact of the selective estrogen receptor modulator, tamoxifen, on neuronal outgrowth and survival following toxic insults associated with aging and Alzheimer's disease. EXPERIMENTAL NEUROLOGY, 188(2), 268-278.
• Zhao, L. Q., Wu, T. W., & Brinton, R. D. (2004). Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neurons. BRAIN RESEARCH, 1010(1-2), 22-34.
• Zhao, L. X., & Brinton, R. D. (2004). Suppression of proinflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha in astrocytes by a V-1 vasopressin receptor agonist: A cAMP response element-binding protein-dependent mechanism. JOURNAL OF NEUROSCIENCE, 24(9), 2226-2235.
• Brinton, R. D., & Nilsen, J. (2003). Effects of estrogen plus progestin on risk of dementia. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 290(13), 1706-1706.
• Nilsen, J., & Brinton, R. D. (2003). Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 100(18), 10506-10511.
• Nilsen, J., & Brinton, R. D. (2003). Mechanism of estrogen-mediated neuroprotection: Regulation of mitochondrial calcium and Bcl-2 expression. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 100(5), 2842-2847.
• Zhao, L. X., & Brinton, R. D. (2003). Vasopressin-induced cytoplasmic and nuclear calcium signaling in embryonic cortical astrocytes: Dynamics of calcium and calcium-dependent kinase translocation. JOURNAL OF NEUROSCIENCE, 23(10), 4228-4239.
• Zhao, L. X., Chen, S. H., & Brinton, R. D. (2003). An estrogen replacement therapy containing nine synthetic plant-based conjugated estrogens promotes neuronal survival. EXPERIMENTAL BIOLOGY AND MEDICINE, 228(7), 823-835.
• Brownson, E. A., Brinton, R. D., & Chambers, K. C. (2002). Vasopressin content in select brain regions during extinction of a conditioned taste aversion. Brain research bulletin, 59(2), 125-34.
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  Previous studies have shown that low levels of vasopressin during extinction of conditioned taste avoidance are associated with a faster extinction, that fluid deprivation differentially alters vasopressin levels in various neural areas, and that extinction of conditioned taste avoidance is accelerated in fluid deprived male rats. The following study was designed to identify areas of the brain in which vasopressin levels are different in fluid deprived and nondeprived males during extinction of conditioned taste avoidance. Arginine vasopressin content was determined by radioimmunoassay in the paraventricular nucleus (PVN), medial amygdala (AMe), bed nucleus of the stria terminalis (BNST), nucleus tractus solitarius (NTS), medial septum (MS), lateral septum (LS), and insular cortex (IC) of unconditioned nondeprived males and conditioned males that were maintained on a 23-h fluid deprivation schedule or that were nondeprived. Vasopressin content in the PVN of deprived and nondeprived males differed during extinction. Based on comparisons with unconditioned nondeprived males, this difference was due to an elevation in the vasopressin content of the nondeprived but not the deprived males. These results raise the possibility that a vasopressinergic system in the PVN plays a critical role in the differential extinction rate of fluid deprived and nondeprived males, which will need to be verified by manipulating vasopressin levels in this brain site during extinction of a conditioned taste avoidance.
• Nilsen, J., & Brinton, R. D. (2002). Impact of progestins on estradiol potentiation of the glutamate calcium response. NEUROREPORT, 13(6), 825-830.
• Nilsen, J., & Brinton, R. D. (2002). Impact of progestins on estrogen-induced neuroprotection: Synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. ENDOCRINOLOGY, 143(1), 205-212.
• Nilsen, J., Chen, S. H., & Brinton, R. D. (2002). Dual action of estrogen on glutamate-induced calcium signaling: mechanisms requiring interaction between estrogen receptors and src/mitogen activated protein kinase pathway. BRAIN RESEARCH, 930(1-2), 216-234.
• Zhao, L. X., & Brinton, R. D. (2002). Vasopressin-induced cytoplasmic and nuclear calcium signaling in cultured cortical astrocytes. BRAIN RESEARCH, 943(1), 117-131.
• Zhao, L. X., Chen, Q., & Brinton, R. D. (2002). Neuroprotective and neurotrophic efficacy of phytoestrogens in cultured hippocampal neurons. EXPERIMENTAL BIOLOGY AND MEDICINE, 227(7), 509-519.
• Berger, T. W., Baudry, M., Brinton, R. D., Liaw, J. S., Marmarelis, V. Z., Park, A. Y., Sheu, B. J., & Tanguay, A. R. (2001). Brain-implantable biomimetic electronics as the next era in neural prosthetics. PROCEEDINGS OF THE IEEE, 89(7), 993-1012.
• Brinton, R. D., Chen, S. H., Montoya, M., Hsieh, D., & Minaya, J. (2000). The estrogen replacement therapy of the Women's Health Initiative promotes the cellular mechanisms of memory and neuronal survival in neurons vulnerable to Alzheimer's disease. MATURITAS, 34, S35-S52.
• Brinton, R. D., Chen, S. H., Montoya, M., Hsieh, D., Minaya, J., Kim, J., & Chu, H. P. (2000). The women's health initiative estrogen replacement therapy is neurotrophic and neuroprotective. NEUROBIOLOGY OF AGING, 21(3), 475-496.
• Chen, Q., Patel, R., Sales, A., Oji, G., Kim, J., Monreal, A. W., & Brinton, R. D. (2000). Vasopressin-induced neurotrophism in cultured neurons of the cerebral cortex: Dependency on calcium signaling and protein kinase C activity. NEUROSCIENCE, 101(1), 19-26.
• Davies, D. L., Bolger, M. B., Brinton, R. D., Finn, D. A., & Alkana, R. L. (1999). In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for ethanol. Psychopharmacology, 141(4), 339-50.
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  The present study uses increased atmospheric pressure as an ethanol antagonist to test the hypothesis that allosteric coupling pathways in the GABA(A) receptor complex represent initial sites of action for ethanol. This was accomplished using behavioral and in vitro measures to determine the effects of pressure on ethanol and other GABAergic drugs in C57BL/6 and LS mice. Behaviorally, exposure to 12 times normal atmospheric pressure (ATA) of a helium-oxygen gas mixture (heliox) antagonized loss of righting reflex (LORR) induced by the allosteric modulators ethanol and pentobarbital, but did not antagonize LORR induced by the direct GABA agonist 4,5,6,7-tetrahydroisoxazolo-pyridin-3-ol (THIP). Similarly, exposure to 12 ATA heliox antagonized the anticonvulsant effects verses isoniazid of ethanol, diazepam and pentobarbital. Biochemically, exposure to 12 ATA heliox antagonized potentiation of GABA-activated 36Cl-uptake by ethanol, flunitrazepam and pentobarbital in LS mouse brain preparations, but did not alter GABA-activated 36Cl- uptake per se. In contrast to its antagonist effect versus other allosteric modulators, pressure did not antagonize these behavioral or in vitro effects induced by the neuroactive steroid, 3alpha-hydroxy-5beta-pregnan-20-one (3alpha,5beta-P). These findings add to evidence that pressure directly and selectively antagonizes drug effects mediated through allosteric coupling pathways. The results fit predictions, and thus support the hypothesis that allosteric coupling pathways in GABA(A) receptors represent initial sites of action for ethanol. Collectively, the results suggest that there may be common physicochemical and underlying structural characteristics that define ethanol sensitive regions of receptor proteins and/or their associated membranes that can be identified by pressure within (e.g., GABA(A)) and possibly across (e.g., GABA(A), NMDA, 5HT3) receptors.
• Foy, M. R., Xu, J., Xie, X., Brinton, R. D., Thompson, R. F., & Berger, T. W. (1999). 17 beta-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation. JOURNAL OF NEUROPHYSIOLOGY, 81(2), 925-929.
• Brinton, R. D., & Yamazaki, R. S. (1998). Advances and challenges in the prevention and treatment of Alzheimer's disease. PHARMACEUTICAL RESEARCH, 15(3), 386-398.
• Son, M. C., & Brinton, R. D. (1998). Vasopressin-induced calcium signaling in cultured cortical neurons. BRAIN RESEARCH, 793(1-2), 244-254.
• Brinton, R. D., Proffitt, P., Tran, J., & Luu, R. (1997). Equilin, a principal component of the estrogen replacement therapy premarin, increases the growth of cortical neurons via an NMDA receptor-dependent mechanism. EXPERIMENTAL NEUROLOGY, 147(2), 211-220.
• Brinton, R. D., Tran, J., Proffitt, P., & Montoya, M. (1997). 17 beta-estradiol enhances the outgrowth and survival of neocortical neurons in culture. NEUROCHEMICAL RESEARCH, 22(11), 1339-1351.
• Yamazaki, R. S., Chen, Q., Schreiber, S. S., & Brinton, R. D. (1997). Localization of V1a vasopressin receptor mRNA expression in cultured neurons, astroglia, and oligodendroglia of rat cerebral cortex. MOLECULAR BRAIN RESEARCH, 45(1), 138-140.
• Davies, D. L., Bejanian, M., Parker, E. S., Mørland, J., Bolger, M. B., Brinton, R. D., & Alkana, R. L. (1996). Low level hyperbaric antagonism of diazepam's locomotor depressant and anticonvulsant properties in mice. The Journal of pharmacology and experimental therapeutics, 276(2), 667-75.
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  Exposure to 12 atmospheres absolute (12 ATA) helium oxygen gas (heliox) (low level hyperbaric exposure) antagonizes the behavioral effects of ethanol and n-propanol, but not morphine. These and other results indicate that the mechanism of the antagonism is direct (pharmacodynamic) and selective. Our study further investigates the selectivity of low level hyperbaric antagonism by testing its effectiveness against diazepam, a high affinity binding drug that acts via allosteric modulation of GABAA receptors. C57BL/6J mice received injections i.p. of vehicle or diazepam, and were then exposed to 1 ATA air, 1 ATA heliox or 12 ATA heliox. Exposure to 12 ATA heliox antagonized the locomotor depressant effect of 4 and 6 mg/kg, but not 8 mg/kg diazepam. Hyperbaric exposure also antagonized the anticonvulsant effect of 8 and 24 mg/kg, but not 4 mg/kg, diazepam vs. 300 mg/kg isoniazid. Exposure to 12 ATA heliox did not significantly affect blood concentrations of diazepam or its metabolite n-desmethyl diazepam. The pharmacological characteristics of the antagonism (direct, surmountable, rightward shift in diazepam's dose-response curve) closely matched those seen in previous studies for hyperbaric antagonism of ethanol. The results add to the evidence that low level hyperbaric exposure is a direct, mechanistic antagonist that selectively antagonizes drugs that act via perturbation or allosteric modulation of receptor function. Moreover, the results suggest that allosteric coupling pathways, which transduce binding events on ligand-gated ion channels, may represent initial sites of action for ethanol.
• BRINTON, R. D., GONZALEZ, T. M., & CHEUNG, W. S. (1994). VASOPRESSIN-INDUCED CALCIUM SIGNALING IN CULTURED HIPPOCAMPAL NEURONS. BRAIN RESEARCH, 661(1-2), 274-282.
• BRINTON, R. D., MONREAL, A. W., & FERNANDEZ, J. G. (1994). VASOPRESSIN-INDUCED NEUROTROPHISM IN CULTURED HIPPOCAMPAL-NEURONS VIA V-1 RECEPTOR ACTIVATION. JOURNAL OF NEUROBIOLOGY, 25(4), 380-394.
• BRINTON, R. D., & BROWNSON, E. A. (1993). VASOPRESSIN-INDUCTION OF CYCLIC-AMP IN CULTURED HIPPOCAMPAL-NEURONS. DEVELOPMENTAL BRAIN RESEARCH, 71(1), 101-105.
• CHEN, C., BRINTON, R. D., SHORS, T. J., & THOMPSON, R. F. (1993). VASOPRESSIN INDUCTION OF LONG-LASTING POTENTIATION OF SYNAPTIC TRANSMISSION IN THE DENTATE GYRUS. HIPPOCAMPUS, 3(2), 193-204.

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• Brinton, R. (2016, September). Neuroendocrinology: Oestrogen therapy affects brain structure but not function. Bat Rev Neurol.