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1.
Artículo en Inglés | MEDLINE | ID: mdl-39450372

RESUMEN

Sex as a biological variable has been recognized for decades to be a critical aspect of the drug development process, as differences in drug pharmacology and toxicity in female versus male subjects can drive the success or failure of new therapeutics. These concepts in development of traditional drug systems have only recently begun to be applied for advancing nanomedicine systems that are designed for drug delivery or imaging in the central nervous system (CNS). This review provides a comprehensive overview of the current state of two fields of research - nanomedicine and acute brain injury-centering on sex as a biological variable. We highlight areas of each field that provide foundational understanding of sex as a biological variable in nanomedicine, brain development, immune response, and pathophysiology of traumatic brain injury and stroke. We describe current knowledge on female versus male physiology as well as a growing number of empirical reports that directly address sex as a biological variable in these contexts. In sum, the data make clear two key observations. First, the manner in which sex affects nanomedicine distribution, toxicity, or efficacy is important, complex, and depends on the specific nanoparticle system under considerations; second, although field knowledge is accumulating to enable us to understand sex as a biological variable in the fields of nanomedicine and acute brain injury, there are critical gaps in knowledge that will need to be addressed. We anticipate that understanding sex as a biological variable in the development of nanomedicine systems to treat acute CNS injury will be an important determinant of their success.

2.
Neurotherapeutics ; 21(2): e00329, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38388224

RESUMEN

Cognitive impairment remains a persistent challenge in people living with HIV (PWLH) despite antiretroviral therapy (ART) due to ART's inability to eliminate brain HIV. HIV-induced cognitive dysfunction results from immune dysregulation, ongoing neuroinflammation, and the continuous virus presence, collectively contributing to cognitive deficits. Therefore, adjunctive therapies are needed to reduce cerebral HIV reservoirs, mitigate neuroinflammation, and impede cognitive dysfunction progression. Our study focused on Honokiol, known for its anti-inflammatory and neuroprotective properties, in an experimental mouse model simulating HIV-induced cognitive dysfunction. Using Honokiol Hexafluoro (HH), a synthetic analogue, we comprehensively evaluated its potential to ameliorate cognitive dysfunction and cerebral pathology in HIV-associated cognitive dysfunction. Our findings showed that HH treatment effectively reversed HIV-induced cognitive dysfunction, concurrently suppressing astrocyte activation, restoring neuronal dendritic arborization, and reducing microglial activation. Furthermore, HH remodeled the metabolic profile of HIV-infected human monocyte-derived macrophages, resulting in decreased activation and the promotion of a quiescent state in vitro.


Asunto(s)
Compuestos Alílicos , Compuestos de Bifenilo , Infecciones por VIH , Fenoles , Humanos , Ratones , Animales , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Enfermedades Neuroinflamatorias , Ratones SCID , Macrófagos
3.
Horm Behav ; 155: 105411, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37659358

RESUMEN

Premenopausal hysterectomy is associated with a greater relative risk of dementia. We previously demonstrated cognitive impairments in adult rats six weeks after hysterectomy with ovarian conservation compared with intact sham-controls and other gynecological surgery variations. Here, we investigated whether hysterectomy-induced cognitive impairments are transient or persistent. Adult rats received sham-control, ovariectomy (Ovx), hysterectomy, or Ovx-hysterectomy surgery. Spatial working memory, reference memory, and anxiety-like behavior were tested either six-weeks post-surgery, in adulthood; seven-months post-surgery, in early middle-age; or twelve-months post-surgery, in late middle-age. Hysterectomy in adulthood yielded spatial working memory deficits at short-, moderate-, and long-term post-surgery intervals. Serum hormone levels did not differ between ovary-intact, but differed from Ovx, groups. Hysterectomy had no significant impact on healthy ovarian follicle or corpora lutea counts for any post-surgery timepoint compared with intact sham-controls. Frontal cortex, dorsal hippocampus, and entorhinal cortex were assessed for activity-dependent markers. In entorhinal cortex, there were alterations in FOSB and ΔFOSB expression during the early middle-age timepoint, and phosphorylated ERK1/2 levels at the adult timepoint. Collectively, results suggest a primary role for the uterus in regulating cognition, and that memory-related neural pathways may be modified following gynecological surgery. This is the first preclinical report of long-term effects of hysterectomy with and without ovarian conservation on cognition, endocrine, ovarian, and brain assessments, initiating a comprehensive framework of gynecological surgery effects. Translationally, findings underscore critical needs to decipher how gynecological surgeries, especially those involving the uterus, impact the brain and its functions, the ovaries, and overall aging from a systems perspective.


Asunto(s)
Histerectomía , Ovario , Femenino , Humanos , Ratas , Animales , Ovariectomía/efectos adversos , Encéfalo , Cognición , Aprendizaje por Laberinto
4.
Behav Brain Res ; 448: 114442, 2023 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-37085118

RESUMEN

Progestogens are a key component of menopausal hormone therapies. While some progestogens can be detrimental to cognition, there is preclinical evidence that progestogens with a strong progesterone-receptor affinity benefit some molecular mechanisms believed to underlie cognitive function. Thus, a progestin that maximizes progesterone-receptor affinity and minimizes affinities to other receptors may be cognitively beneficial. We evaluated segesterone-acetate (SGA), a 19-norprogesterone derivative with a strong progesterone-receptor affinity and no androgenic or estrogenic-receptor activity, hypothesizing that it would enhance cognition. Middle-aged rats underwent Sham or Ovariectomy (Ovx) surgery followed by administration of medroxyprogesterone-acetate (MPA; used as a positive control as we have previously shown MPA-induced cognitive deficits), SGA (low or high dose), or vehicle (one Sham and one Ovx group). Spatial working and reference memory, delayed retention, and anxiety-like behavior were assessed, as were memory- and hormone- related protein assays within the frontal cortex, dorsal hippocampus, and entorhinal cortex. Low-dose SGA impaired spatial working memory, while high-dose SGA had a more extensive detrimental impact, negatively affecting spatial reference memory and delayed retention. Replicating previous findings, MPA impaired spatial reference memory and delayed retention. SGA, but not MPA, alleviated Ovx-induced anxiety-like behaviors. On two working memory measures, IGF-1R expression correlated with better working memory only in rats without hormone manipulation; any hormone manipulation or combination of hormone manipulations used herein altered this relationship. These findings suggest that SGA impairs spatial cognition after surgical menopause, and that surgical menopause with or without progestin administration disrupts relationships between a growth factor critical to neuroplasticity.


Asunto(s)
Progesterona , Progestinas , Animales , Femenino , Ratas , Acetatos , Ansiedad/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular , Menopausia/fisiología , Ovariectomía , Progesterona/farmacología , Progestinas/farmacología
5.
Maturitas ; 167: 113-122, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36395695

RESUMEN

OBJECTIVES: To examine associations of pituitary-ovarian hormone levels with cognition before and after different formulations of hormone therapy (HT) or placebo independent of treatment group. METHODS: Recently menopausal, healthy women were randomized to 0.45 mg/day oral conjugated equine estrogens (o-CEE, n = 109), 50 µg/day transdermal 17ß (tE2, n = 107) or placebo pills and patches (n = 146); women on active treatment received oral 200 mg/day micronized progesterone for 12 days per month. Levels of estrone, 17ß-estradiol, follicle stimulating hormone, luteinizing hormone, androstenedione, and testosterone were determined prior to and after 48 months of study participation. Neuropsychological testing was administered at baseline, and months 18, 36 and 48. Latent growth curve models controlling for education level, age, APOE allele status, waist circumference, and treatment examined the trajectories of each cognitive domain after accounting for the effect of hormone levels at baseline and months 18, 36 and 48. A linear multivariate mixed model examined the effect of changes in hormone levels on changes in trajectories of complex attention tasks with varying degrees of difficulty. RESULTS: All women were adherent to treatment at month 48. Higher baseline estrone levels were associated with poorer global cognition, auditory attention and working memory, visual attention, and executive function, but not working memory. Higher levels of baseline 17ß-E2 were associated with poorer cognitive performance, with marginal significance at baseline in speeded language and mental flexibility (p = 0.013). Other hormone levels were not associated with cognition. Controlling for all treatments, hormone levels at baseline and at month 48 did not have any significant correlation with cognitive trajectories over time. SUMMARY: In healthy, recently menopausal women, baseline estrone levels were inversely associated with selected cognitive factors independent of two types of HT or placebo during 4 years of follow-up. Baseline levels of the other pituitary-ovarian hormones studied were not associated with baseline cognition, nor were changes in any hormones associated with changes in cognition during the study. The marginal association between estradiol levels and cognitive factors warrants further investigation. GOV NUMBERS: NCT00154180, NCT00623311.


Asunto(s)
Estrona , Menopausia , Femenino , Humanos , Caballos , Animales , Hormonas Hipofisarias , Cognición , Estradiol
6.
Artículo en Inglés | MEDLINE | ID: mdl-39484630

RESUMEN

Midlife in women typically includes the menopausal transition, a time of hormonal transformation, adaptation, and reorganization. Coincident with this dynamic period of physiological change, there are putatively modifiable factors that influence disease, short-term and long-term health outcomes, symptom emergence, and longevity. The menopause transition could be considered a window of vulnerability; however, it is also a window of opportunity for intervention. Thus, the menopause transition is a critical sensitive window whereby there is opportunity for turning points for healthy aging trajectories. Preclinical research can aid in this pursuit of scientific discovery for modifiable factors and treatments, and their particular parameters. Rodent menopause models include surgical and transitional variations, allowing detection of precise determinants impacting menopause-related outcomes. These models permit systematic manipulation of endogenous and exogenous hormone exposures across the lifespan, with infinite outcome measurements ranging from molecular to behavioral. This research is uniquely poised to address complex, interactive hypotheses with extensive control in a relatively short timeframe, including dissociation of age and menopause effects. To understand the many dynamic changes with menopause, iterative and reciprocal communication between clinical and preclinical domains of science is key.

7.
Sci Rep ; 12(1): 14596, 2022 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-36028737

RESUMEN

The TgF344 rat model of Alzheimer's disease (AD) provides a comprehensive neuropathology presentation, with age-dependent development of tau tangles, amyloid-beta (A[Formula: see text]) plaques, neuronal loss, and increased gliosis. The behavioral trajectory of this model, particularly relating to spatial learning and memory, has yet to be fully characterized. The current experiment evaluated spatial working and reference memory performance, as well as several physiological markers of health, at 3 key age points in female TgF344-AD rats: 6-months, 9-months, and 12-months. At 6 months of age, indications of working and reference memory impairments were observed in transgenic (Tg) rats on the water radial-arm maze, a complex task that requires working and reference memory simultaneously; at 12 months old, Tg impairments were observed for two working memory measures on this task. Notably, no impairments were observed at the 9-month timepoint on this maze. For the Morris maze, a measure of spatial reference memory, Tg rats demonstrated significant impairment relative to wildtype (WT) controls at all 3 age-points. Frontal cortex, entorhinal cortex, and dorsal hippocampus were evaluated for A[Formula: see text]1-42 expression via western blot in Tg rats only. Analyses of A[Formula: see text]1-42 expression revealed age-dependent increases in all 3 regions critical to spatial learning and memory. Measures of physiological health, including heart, uterine, and body weights, revealed unique age-specific outcomes for female Tg rats, with the 9-month timepoint identified as critical for further research within the trajectory of AD-like behavior, physiology, and pathology.


Asunto(s)
Enfermedad de Alzheimer , Animales , Modelos Animales de Enfermedad , Femenino , Aprendizaje por Laberinto , Trastornos de la Memoria , Ratas , Ratas Transgénicas
8.
eNeuro ; 9(3)2022.
Artículo en Inglés | MEDLINE | ID: mdl-35697512

RESUMEN

Women report greater cigarette cravings during the menstrual cycle phase with higher circulating levels of 17ß-estradiol (E2), which is metabolized to estrone (E1). Both E2 and E1 bind to estrogen receptors (ERs), which have been highly studied in the breast, uterus, and ovary. Recent studies have found that ERs are also located on GABAergic medium spiny neurons (MSNs) within the nucleus accumbens core (NAcore). Glutamatergic plasticity in NAcore MSNs is altered following nicotine use; however, it is unknown whether estrogens impact this neurobiological consequence. To test the effect of estrogen on nicotine use, we ovariectomized (OVX) female rats that then underwent nicotine self-administration acquisition and compared them to ovary-intact (sham) rats. The OVX animals then received either sesame oil (vehicle), E2, or E1+E2 supplementation for 4 or 20 d before nicotine sessions. While both ovary-intact and OVX females readily discriminated levers, OVX females consumed less nicotine than sham females. Further, neither E2 nor E1+E2 increased nicotine consumption back to sham levels following OVX, regardless of the duration of the treatment. OVX also rendered NAcore MSNs in a potentiated state following nicotine self-administration, which was reversed by 4 d of systemic E2 treatment. Finally, we found that E2 and E1+E2 increased ERα mRNA in the NAcore, but nicotine suppressed this regardless of hormone treatment. Together, these results show that estrogens regulate nicotine neurobiology, but additional factors may be required to restore nicotine consumption to ovary-intact levels.


Asunto(s)
Estrógenos , Nicotina , Animales , Estradiol , Femenino , Humanos , Nicotina/farmacología , Ovariectomía , Ratas , Receptores de Estrógenos/metabolismo
9.
Front Neurosci ; 16: 885321, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35692432

RESUMEN

Oral contraceptives and hormone therapies require a progestogen component to prevent ovulation, curtail uterine hyperplasia, and reduce gynecological cancer risk. Diverse classes of synthetic progestogens, called progestins, are used as natural progesterone alternatives due to progesterone's low oral bioavailability. Progesterone and several synthetic analogs can negatively impact cognition and reverse some neuroprotective estrogen effects. Here, we investigate drospirenone, a spironolactone-derived progestin, which has unique pharmacological properties compared to other clinically-available progestins and natural progesterone, for its impact on spatial memory, anxiety-like behavior, and brain regions crucial to these cognitive tasks. Experiment 1 assessed three drospirenone doses in young adult, ovariectomized rats, and found that a moderate drospirenone dose benefited spatial memory. Experiment 2 investigated this moderate drospirenone dose with and without concomitant ethinyl estradiol (EE) treatment, the most common synthetic estrogen in oral contraceptives. Results demonstrate that the addition of EE to drospirenone administration reversed the beneficial working memory effects of drospirenone. The hippocampus, entorhinal cortex, and perirhinal cortex were then probed for proteins known to elicit estrogen- and progestin- mediated effects on learning and memory, including glutamate decarboxylase (GAD)65, GAD67, and insulin-like growth factor receptor protein expression, using western blot. EE increased GAD expression in the perirhinal cortex. Taken together, results underscore the necessity to consider the distinct cognitive and neural impacts of clinically-available synthetic estrogen and progesterone analogs, and why they produce unique cognitive profiles when administered together compared to those observed when each hormone is administered separately.

10.
Front Cell Infect Microbiol ; 11: 702628, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34660336

RESUMEN

Menopause in human females and subsequent ovarian hormone deficiency, particularly concerning 17ß-estradiol (E2), increase the risk for metabolic dysfunctions associated with obesity, diabetes type 2, cardiovascular diseases, and dementia. Several studies indicate that these disorders are also strongly associated with compositional changes in the intestinal microbiota; however, how E2 deficiency and hormone therapy affect the gut microbial community is not well understood. Using a rat model, we aimed to evaluate how ovariectomy (OVX) and subsequent E2 administration drive changes in metabolic health and the gut microbial community, as well as potential associations with learning and memory. Findings indicated that OVX-induced ovarian hormone deficiency and E2 treatment had significant impacts on several health-affecting parameters, including (a) the abundance of some intestinal bacterial taxa (e.g., Bifidobacteriaceae and Porphyromonadaceae), (b) the abundance of microbial short-chain fatty acids (SCFAs) (e.g., isobutyrate), (c) weight/BMI, and (d) high-demand spatial working memory following surgical menopause. Furthermore, exploratory correlations among intestinal bacteria abundance, cognition, and BMI underscored the putative influence of surgical menopause and E2 administration on gut-brain interactions. Collectively, this study showed that surgical menopause is associated with physiological and behavioral changes, and that E2-linked compositional changes in the intestinal microbiota might contribute to some of its related negative health consequences. Overall, this study provides novel insights into interactions among endocrine and gastrointestinal systems in the post-menopausal life stage that collectively alter the risk for the development and progression of cardiovascular, metabolic, and dementia-related diseases.


Asunto(s)
Microbioma Gastrointestinal , Animales , Estrógenos , Femenino , Menopausia , Obesidad , Ratas , Memoria Espacial
11.
Front Aging Neurosci ; 13: 734173, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34539388

RESUMEN

A major obstacle to progress in understanding the etiology of normative and pathological human brain aging is the availability of suitable animal models for experimentation. The present article will highlight our current knowledge regarding human brain aging and neurodegeneration, specifically in the context of Alzheimer's disease (AD). Additionally, it will examine the use of the rhesus macaque monkey as a pragmatic translational animal model in which to study underlying causal mechanisms. Specifically, the discussion will focus on behavioral and protein-level brain changes that occur within the central nervous system (CNS) of aged monkeys, and compare them to the changes observed in humans during clinically normative aging and in AD.

12.
J Neuroendocrinol ; 33(9): e13002, 2021 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-34378820

RESUMEN

Menopause has been linked to changes in memory. Oestrogen-containing hormone therapy is prescribed to treat menopause-related symptoms and can ameliorate memory changes, although the parameters impacting oestrogen-related memory efficacy are unclear. Cognitive experience and practice have been shown to be neuroprotective and to improve learning and memory during ageing, with the type of task playing a role in subsequent cognitive outcomes. Whether task complexity matters, and whether these outcomes interact with menopause and oestrogen status, remains unknown. To investigate this, we used a rat model of surgical menopause to systematically assess whether maze task complexity, as well as order of task presentation, impacts spatial learning and memory during middle age when rats received vehicle, low-17ß-oestradiol (E2 ) or high-E2 treatment. The direction, and even presence, of the effects of prior maze experience differed depending on the E2 dose. Surgical menopause without E2 treatment yielded the least benefit, as prior maze experience did not have a substantial effect on subsequent task performance for vehicle treated rats regardless of task demand level during the first exposure to maze experience or final testing. High-dose E2 yielded a variable benefit, and low-dose E2 produced the greatest benefit. Specifically, low-dose E2 broadly enhanced learning and memory in surgically menopausal rats that had prior experience on another task, regardless of the complexity level of this prior experience. These results demonstrate that E2 dose influences the impact of prior cognitive experience on learning and memory during ageing, and highlights the importance of prior cognitive experience in subsequent learning and memory outcomes.

13.
Front Behav Neurosci ; 15: 696838, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34366807

RESUMEN

A variety of U.S. Food and Drug Administration-approved hormone therapy options are currently used to successfully alleviate unwanted symptoms associated with the changing endogenous hormonal milieu that occurs in midlife with menopause. Depending on the primary indication for treatment, different hormone therapy formulations are utilized, including estrogen-only, progestogen-only, or combined estrogen plus progestogen options. There is little known about how these formulations, or their unique pharmacodynamics, impact neurobiological processes. Seemingly disparate pre-clinical and clinical findings regarding the cognitive effects of hormone therapies, such as the negative effects associated with conjugated equine estrogens and medroxyprogesterone acetate vs. naturally circulating 17ß-estradiol (E2) and progesterone, signal a critical need to further investigate the neuro-cognitive impact of hormone therapy formulations. Here, utilizing a rat model of transitional menopause, we administered either E2, progesterone, levonorgestrel, or combinations of E2 with progesterone or with levonorgestrel daily to follicle-depleted, middle-aged rats. A battery of assessments, including spatial memory, anxiety-like behaviors, and depressive-like behaviors, as well as endocrine status and ovarian follicle complement, were evaluated. Results indicate divergent outcomes for memory, anxiety, and depression, as well as unique physiological profiles, that were dependent upon the hormone regimen administered. Overall, the combination hormone treatments had the most consistently favorable profile for the domains evaluated in rats that had undergone experimentally induced transitional menopause and remained ovary-intact. The collective results underscore the importance of investigating variations in hormone therapy formulation as well as the menopause background upon which these formulations are delivered.

14.
Neuropharmacology ; 198: 108756, 2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34416269

RESUMEN

Women have more difficulty maintaining smoking cessation than men, and experience greater withdrawal symptomatology as well as higher prevalence of relapse. Further, currently available treatments for smoking cessation, such as the nicotine patch and varenicline, have been shown to be less effective in women. Fluctuations in ovarian hormones across the menstrual cycle can affect craving and smoking relapse propensity. In addition, many women who smoke use some form of oral contraceptives, which most often contain ethinyl estradiol (EE), a synthetic, orally bio-available estrogen that is currently prescribed to women chronically and has been shown to alter smoking reward in women. The current study examined the impact of 17ß-estradiol (E2), the prominent endogenous form of the steroid hormone estrogen, as well as EE, on nicotine self-administration, demand, and reinstatement following ovariectomy (OVX) or sham surgery. OVX vehicle-treated female rats consumed less nicotine, had lower intensity of demand, and reinstated less compared to sham vehicle-treated female rats. OVX-E2 and OVX-EE treatment groups showed a rebound of nicotine intake later in training, and Q0 levels of consumption were partially rescued in both groups. Further, E2 but not EE reversed the abolishment of reinstated nicotine seeking induced by OVX. Taken together, these results demonstrate that natural and synthetic estrogens play a critical role in mediating the neurobehavioral effects of nicotine, and future studies are essential for our understanding of how synthetic hormones contained within oral contraceptives interact with smoking.


Asunto(s)
Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Congéneres del Estradiol/farmacología , Estradiol/farmacología , Estrógenos/farmacología , Tabaquismo/psicología , Animales , Fumar Cigarrillos/psicología , Señales (Psicología) , Etinilestradiol/farmacología , Femenino , Ovariectomía , Ratas , Ratas Long-Evans , Recurrencia , Recompensa , Autoadministración
15.
Front Behav Neurosci ; 15: 610078, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33643006

RESUMEN

Rodent aging research often utilizes spatial mazes, such as the water radial-arm-maze (WRAM), to evaluate cognition. The WRAM can simultaneously measure spatial working and reference memory, wherein these two memory types are often represented as orthogonal. There is evidence, however, that these two memory forms yield interference at a high working memory load. The current study systematically evaluated whether the presence of a reference memory component impacts handling of an increasing working memory load. Young and aged female rats were tested to assess whether aging impacts this relationship. Cholinergic projections from the basal forebrain to the hippocampus and cortex can affect cognitive outcomes, and are negatively impacted by aging. To evaluate whether age-related changes in working and reference memory profiles are associated with cholinergic functioning, we assessed choline acetyltransferase activity in these behaviorally-tested rats. Results showed that young rats outperformed aged rats on a task testing solely working memory. The addition of a reference memory component deteriorated the ability to handle an increasing working memory load, such that young rats performed similar to their aged counterparts. Aged rats also had challenges when reference memory was present, but in a different context. Specifically, aged rats had difficulty remembering which reference memory arms they had entered within a session, compared to young rats. Further, aged rats that excelled in reference memory also excelled in working memory when working memory demand was high, a relationship not seen in young rats. Relationships between cholinergic activity and maze performance differed by age in direction and brain region, reflecting the complex role that the cholinergic system plays in memory and attentional processes across the female lifespan. Overall, the addition of a reference memory requirement detrimentally impacted the ability to handle working memory information across young and aged timepoints, especially when the working memory challenge was high; these age-related deficits manifested differently with the addition of a reference memory component. This interplay between working and reference memory provides insight into the multiple domains necessary to solve complex cognitive tasks, potentially improving the understanding of complexities of age- and disease- related memory failures and optimizing their respective treatments.

16.
Behav Pharmacol ; 32(2&3): 112-122, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32960852

RESUMEN

Discovery of neural mechanisms underlying neuropsychiatric disorders within the aging and addiction fields has been a main focus of the National Institutes of Health. However, there is a dearth of knowledge regarding the biological interactions of aging and addiction, which may have important influences on progression of disease and treatment outcomes in aging individuals with a history of chronic drug use. Thus, there is a large gap in these fields of research, which has slowed progress in understanding and treating substance use disorders (SUDs) as well as age-related diseases, specifically in women who experience precipitous reproductive cycle transitions during aging. The goal of this review is to highlight overlap of SUDs and age-related processes with a specific focus on menopause and smoking, and identify critical gaps. We have narrowed the focus of the review to smoking, as the majority of findings on hormonal and aging influences on drug use have come from this area of research. Further, we highlight female-specific issues such as transitional menopause and exogenous estrogen use. These issues may impact drug use cessation as well as outcomes with aging and age-related neurodegenerative diseases in women. We first review clinical studies for smoking, normal aging, and pathological aging, and discuss the few aging-related studies taking smoking history into account. Conversely, we highlight the dearth of clinical smoking studies taking age as a biological variable into account. Preclinical and clinical literature show that aging, age-related pathological brain disease, and addiction engage overlapping neural mechanisms. We hypothesize that these putative drivers interact in meaningful ways that may exacerbate disease and hinder successful treatment outcomes in such comorbid populations. We highlight areas where preclinical studies are needed to uncover neural mechanisms in aging and addiction processes. Collectively, this review highlights the need for crosstalk between different fields of research to address medical complexities of older adults, and specifically women, who smoke.


Asunto(s)
Envejecimiento/fisiología , Conducta Adictiva/epidemiología , Trastornos Relacionados con Sustancias/epidemiología , Factores de Edad , Anciano , Envejecimiento/patología , Animales , Femenino , Humanos , Menopausia/fisiología , Enfermedades Neurodegenerativas/epidemiología , Fumar/epidemiología , Investigación Biomédica Traslacional/organización & administración
17.
J Neurosci ; 41(3): 555-575, 2021 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-33239400

RESUMEN

Neuronal and network-level hyperexcitability is commonly associated with increased levels of amyloid-ß (Aß) and contribute to cognitive deficits associated with Alzheimer's disease (AD). However, the mechanistic complexity underlying the selective loss of basal forebrain cholinergic neurons (BFCNs), a well-recognized characteristic of AD, remains poorly understood. In this study, we tested the hypothesis that the oligomeric form of amyloid-ß (oAß42), interacting with α7-containing nicotinic acetylcholine receptor (nAChR) subtypes, leads to subnucleus-specific alterations in BFCN excitability and impaired cognition. We used single-channel electrophysiology to show that oAß42 activates both homomeric α7- and heteromeric α7ß2-nAChR subtypes while preferentially enhancing α7ß2-nAChR open-dwell times. Organotypic slice cultures were prepared from male and female ChAT-EGFP mice, and current-clamp recordings obtained from BFCNs chronically exposed to pathophysiologically relevant level of oAß42 showed enhanced neuronal intrinsic excitability and action potential firing rates. These resulted from a reduction in action potential afterhyperpolarization and alterations in the maximal rates of voltage change during spike depolarization and repolarization. These effects were observed in BFCNs from the medial septum diagonal band and horizontal diagonal band, but not the nucleus basalis. Last, aged male and female APP/PS1 transgenic mice, genetically null for the ß2 nAChR subunit gene, showed improved spatial reference memory compared with APP/PS1 aged-matched littermates. Combined, these data provide a molecular mechanism supporting a role for α7ß2-nAChR in mediating the effects of oAß42 on excitability of specific populations of cholinergic neurons and provide a framework for understanding the role of α7ß2-nAChR in oAß42-induced cognitive decline.


Asunto(s)
Péptidos beta-Amiloides/genética , Prosencéfalo Basal/fisiopatología , Disfunción Cognitiva/genética , Disfunción Cognitiva/fisiopatología , Sistema Nervioso Parasimpático/fisiopatología , Fragmentos de Péptidos/genética , Transducción de Señal/genética , Receptor Nicotínico de Acetilcolina alfa 7/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Línea Celular , Fenómenos Electrofisiológicos , Femenino , Genotipo , Humanos , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Transgénicos , Neuronas/patología
18.
Pharmaceutics ; 12(12)2020 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-33348722

RESUMEN

Exogenously administered 17ß-estradiol (E2) can improve spatial learning and memory, although E2 also exerts undesired effects on peripheral organs. Clinically, E2 has been solubilized in cyclodextrin for intranasal administration, which enhances brain-specific delivery. Prior work shows that the cyclodextrin structure impacts region-specific brain distribution of intranasally administered small molecules. Here, we investigated (1) cyclodextrin type-specific modulation of intranasal E2 brain distribution, and (2) cognitive and peripheral tissue effects of intranasal E2 in middle-aged ovariectomized rats. First, brain and peripheral organ distribution of intranasally administered, tritiated E2 was measured for E2 solubilized freely or in one of four cyclodextrin formulations. The E2-cyclodextrin formulation with greatest E2 uptake in cognitive brain regions versus uterine horns was then compared to free E2 on learning, memory, and uterine measures. Free E2 improved spatial reference memory, whereas E2-cyclodextrin impaired spatial working memory compared to their respective controls. Both E2 formulations increased uterine horn weights relative to controls, with E2-cyclodextrin resulting in the greatest uterine horn weight, suggesting increased uterine stimulation. Thus, intranasal administration of freely solubilized E2 is a strategic delivery tool that can yield a cognitively beneficial impact of the hormone alongside decreased peripheral effects compared to intranasal administration of cyclodextrin solubilized E2.

19.
Horm Behav ; 126: 104854, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32949557

RESUMEN

17ß-estradiol (E2)-containing hormone therapy is a safe, effective way to alleviate unwanted menopause symptoms. Preclinical research has focused upon the role of E2 in learning and memory using a surgically menopausal rodent model whereby the ovaries are removed. Given that most women retain their reproductive tract and undergo a natural menopause transition, it is necessary to understand how exogenous E2 impacts a structurally intact, but follicle-deplete, system. In the current study, 8 month old female rats were administered the ovatoxin 4-vinylcyclohexene diepoxide (VCD), which accelerates ovarian follicular depletion, to model the human menopause transition. After follicular depletion, at 11 months old, rats were administered Vehicle or tonic E2 treatment for 12 days prior to behavioral evaluation on spatial working and reference memory tasks. Results demonstrated that E2 had both enhancing and impairing effects on taxed working memory depending upon the learning or retention phases of the water radial-arm maze, with no impact on reference memory. Relationships between memory scores and circulating estrogen levels were specific to follicle-depleted rats without E2 treatment. Collectively, findings demonstrate the complexity of E2 administration in a follicle-depleted background, with cognitive effects specific to working memory; furthermore, E2 administration altered circulating hormonal milieu and relationships between hormone profiles and memory. In sum, menopausal etiology impacts the parameters of E2 effects on cognition, complementing prior work with other estrogen compounds. Deciphering estrogenic actions in a system wherein the reproductive tract remains intact with follicle-depleted ovaries, thus modeling the majority or menopausal women, is critical for translational perspectives.


Asunto(s)
Envejecimiento/efectos de los fármacos , Estradiol/farmacología , Memoria/efectos de los fármacos , Reserva Ovárica/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , Envejecimiento/fisiología , Envejecimiento/psicología , Animales , Cognición/efectos de los fármacos , Ciclohexenos , Femenino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Menopausia/efectos de los fármacos , Menopausia/psicología , Modelos Animales , Folículo Ovárico/citología , Folículo Ovárico/efectos de los fármacos , Ovario/citología , Ovario/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Compuestos de Vinilo
20.
Addict Biol ; 25(1): e12711, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-30734439

RESUMEN

Women report greater craving during certain phases of the menstrual cycle. As well, research indicates that pharmacotherapies for smoking may be less efficacious in women compared with men, which may be due to interactions with natural fluctuations in ovarian hormone levels. N-Acetylcysteine (NAC) is a glutamatergic compound that has shown some efficacy in treating substance use disorders and aids in the prevention of relapse. However, it is unclear whether NAC has sex-specific effectiveness for nicotine relapse treatment. Given that NAC has shown promise to reduce nicotine reinstatement in preclinical models using male rats, the exploration of potential sex differences in the efficacy of NAC is warranted. Using a rat model, we first investigated the ability of NAC treatment (100 mg/kg, ip) during nicotine withdrawal with extinction training to reduce cue-induced nicotine seeking in male and female rats. Next, we assessed whether NAC's effects were estrous cycle-dependent for female rats. Results show that following NAC treatment during extinction, reinstatement of nicotine seeking was significantly decreased in males but not females, indicating a sex-specific effect of NAC. Furthermore, for females, both vehicle- and NAC-treated groups significantly reinstated nicotine-seeking behavior compared with extinction, regardless of estrous cycle phase. These results suggest that NAC is inefficacious in reducing nicotine relapse in females regardless of estrous cycle phase at the dose evaluated here. These collective findings could have important clinical implications for use and efficacy of NAC as a pharmacotherapy for freely cycling women smokers.


Asunto(s)
Acetilcisteína/farmacología , Señales (Psicología) , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Tabaquismo/tratamiento farmacológico , Animales , Ansia/efectos de los fármacos , Modelos Animales de Enfermedad , Ciclo Estral , Extinción Psicológica , Femenino , Depuradores de Radicales Libres/farmacología , Masculino , Nicotina , Ratas , Ratas Sprague-Dawley , Factores Sexuales , Síndrome de Abstinencia a Sustancias/fisiopatología , Tabaquismo/fisiopatología
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