Electronic Cigarette Vape Exposure Exacerbates Post-Ischemic Outcomes in Female but Not in Male Rats.

BACKGROUND: Nicotine-containing electronic cigarette (EC) vaping has become popular worldwide, and our understanding of the effects of vaping on stroke outcomes is elusive. Using a rat model of transient middle cerebral artery occlusion, the current exploratory study aims to evaluate the sex-dependent effects of EC exposure on brain energy metabolism and stroke outcomes. METHODS: Adult Sprague-Dawley rats of both sexes were randomly assigned to air/EC vapor (5% nicotine Juul pods) exposure for 16 nights, followed by randomization into 3 cohorts. The first cohort underwent exposure to air/EC preceding randomization to transient middle cerebral artery occlusion (90 minutes) or sham surgery, followed by survival for 21 days. During the survival period, rats underwent sensorimotor and Morris water maze testing. Subsequently, brains were collected for histopathology. A second cohort was exposed to air/EC after which brains were collected for unbiased metabolomics analysis. The third cohort of animals was exposed to air/EC and received transient middle cerebral artery occlusion/sham surgery, and brain tissue was collected 24 hours later for biochemical analysis. RESULTS: In females, EC significantly increased (P<0.05) infarct volumes by 94% as compared with air-exposed rats, 165±50 mm3 in EC-exposed rats, and 85±29 mm3 in air-exposed rats, respectively, while in males such a difference was not apparent. Morris water maze data showed significant deficits in spatial learning and working memory in the EC sham or transient middle cerebral artery occlusion groups compared with the respective air groups in rats of both sexes (P<0.05). Thirty-two metabolites of carbohydrate, glycolysis, tricarboxylic acid cycle, and lipid metabolism were significantly altered (P≤0.05) due to EC, 23 of which were specific for females. Steady-state protein levels of hexokinase significantly decreased (P<0.05) in EC-exposed females; however, these changes were not seen in males. CONCLUSIONS: Even brief EC exposure over 2 weeks impacts brain energy metabolism, exacerbates infarction, and worsens poststroke cognitive deficits in working memory more in female than male rats.

Resveratrol Preconditioning Mitigates Ischemia-Induced Septal Cholinergic Cell Loss and Memory Impairments.

BACKGROUND: Cholinergic cells originating from the nuclei of the basal forebrain (BF) are critical for supporting various memory processes, yet BF cholinergic cell viability has not been explored in the context of focal cerebral ischemia. In the present study, we examined cell survival within several BF nuclei in rodents following transient middle cerebral artery occlusion. We tested the hypothesis that a previously established neuroprotective therapy-resveratrol preconditioning-would rescue BF cell loss, deficits in cholinergic-related memory performance, and hippocampal synaptic dysfunction after focal cerebral ischemia. METHODS: Adult (2-3-month old) male Sprague-Dawley rats or wild-type C57Bl/6J mice were injected intraperitoneally with a single dose of resveratrol or vehicle and subjected to transient middle cerebral artery occlusion using the intraluminal suture method 2 days later. Histopathological, behavioral, and electrophysiological outcomes were measured 1-week post-reperfusion. Animals with reduction in cerebral blood flow <30% of baseline were excluded. RESULTS: Cholinergic cell loss was observed in the medial septal nucleus and diagonal band of Broca following transient middle cerebral artery occlusion. This effect was prevented by resveratrol preconditioning, which also ameliorated transient middle cerebral artery occlusion-induced deficits in cognitive performance and hippocampal long-term potentiation. CONCLUSIONS: We demonstrate for the first time that focal cerebral ischemia induces cholinergic cell death within memory-relevant nuclei of the BF. The preservation of cholinergic cell viability may provide a mechanism by which resveratrol preconditioning improves memory performance and preserves functionality of memory-processing brain structures after focal cerebral ischemia.

Oral contraceptives and stroke: Foes or friends.

Incidents of strokes are increased in young women relative to young men, suggesting that oral contraceptive (OC) use is one of the causes of stroke among young women. Long-term exposures to the varying combinations of estrogen and progestogen found in OCs affect blood clotting, lipid and lipoprotein metabolism, endothelial function, and de novo synthesis of neurosteroids, especially brain-derived 17ß-estradiol. The latter is essential for neuroprotection, memory, sexual differentiation, synaptic transmission, and behavior. Deleterious effects of OCs may be exacerbated due to comorbidities like polycystic ovary syndrome, sickle cell anemia, COVID-19, exposures to endocrine disrupting chemicals, and conventional or electronic cigarette smoking. The goal of the current review is to revisit the available literature regarding the impact of OC use on stroke, to explain possible underlying mechanisms, and to identify gaps in our understanding to promote future research to reduce and cure stroke in OC users.

Xenoestrogens impact brain estrogen receptor signaling during the female lifespan: A precursor to neurological disease?

Xenoestrogens, foreign synthetic chemicals mimicking estrogens, are lurking in our surroundings. Climate change may alter their toxicity and bioavailability. Since xenoestrogens have extremely high lipid solubility and are structurally similar to natural endogenous estrogens, they can bind to estrogen receptors (ERs) -alpha (ER-α) and -beta (ER-ß). Scientific evidence accumulated over the past decades have suggested that natural 17ß-estradiol (E2; a potent estrogen), via activation of its receptors, plays a pivotal role in regulation of brain development, differentiation, metabolism, synaptic plasticity, neuroprotection, cognition, anxiety, body temperature, feeding and sexual behavior. In the brain, ER-ß is predominantly expressed in the various regions, including cerebral cortex and hippocampus, that have been shown to play a key role in cognition. Therefore, disturbances in function of ER-ß mediated E2 signaling by xenoestrogens can lead to deleterious effects that potentiate a variety of neurological diseases starting from prenatal to post-menopause in women. The goal of this review is to identify the possible neurological effects of xenoestrogens that can alter estrogen receptor-mediated signaling in the brain during different stages of the female lifespan.

Traumatic brain injury in women across lifespan.

Traumatic brain injury (TBI) is a leading cause of death and disability and a global public health challenge. Every year more than 50 million people suffer a TBI, and it is estimated that 50% of the global population will experience at least one TBI in their lifetime. TBI affects both men and women of all ages, however there is a male bias in TBI research as women have frequently been left out of the literature despite irrefutable evidence of male and female dimorphism in several posttraumatic measures. Women uniquely experience distinct life stages marked by levels of endogenous circulating sex hormones, as well as by physiological changes that are nonexistent in men. In addition to generalized sex-specific differences, a woman's susceptibility, neurological outcomes, and treatment success may vary considerably depending upon when in her lifespan she incurred a traumatic insult. How women impacted by TBI might differ from other women as a factor of age and physiology is not well understood. Furthermore, there is a gap in the knowledge of what happens when TBI occurs in the presence of certain sex-specific and sex-nonspecific variables, such as during pregnancy, with oral contraceptive use, in athletics, in cases of addiction and nicotine consumption, during perimenopause, postmenopause, in frailty, among others. Parsing out how hormone-dependent and hormone-independent lifespan variables may influence physiological, neurodegenerative, and functional outcomes will greatly contribute to future investigative studies and direct therapeutic strategies. The goal of this review is to aggregate the knowledge of prevalence, prognosis, comorbid risk, and response of women incurring TBI at differing phases of lifespan. We strive to illuminate commonalities and disparities among female populations, and to pose important questions to highlight gaps in the field in order to further the endeavor of targeted treatment interventions in a patient-specific manner.

The Impact of Nicotine along with Oral Contraceptive Exposure on Brain Fatty Acid Metabolism in Female Rats.

Smoking-derived nicotine (N) and oral contraceptive (OC) synergistically exacerbate ischemic brain damage in females, and the underlying mechanisms remain elusive. In a previous study, we showed that N + OC exposure altered brain glucose metabolism in females. Since lipid metabolism complements glycolysis, the current study aims to examine the metabolic fingerprint of fatty acids in the brain of female rats exposed to N+/-OC. Adolescent and adult Sprague-Dawley female rats were randomly (n = 8 per group) exposed to either saline or N (4.5 mg/kg) +/-OC (combined OC or placebo delivered via oral gavage) for 16-21 days. Following exposure, brain tissue was harvested for unbiased metabolomic analysis (performed by Metabolon Inc., Morrisville, NC, USA) and the metabolomic profile changes were complemented with Western blot analysis of key enzymes in the lipid pathway. Metabolomic data showed significant accumulation of fatty acids and phosphatidylcholine (PC) metabolites in the brain. Adolescent, more so than adult females, exposed to N + OC showed significant increases in carnitine-conjugated fatty acid metabolites compared to saline control animals. These changes in fatty acyl carnitines were accompanied by an increase in a subset of free fatty acids, suggesting elevated fatty acid ß-oxidation in the mitochondria to meet energy demand. In support, ß-hydroxybutyrate was significantly lower in N + OC exposure groups in adolescent animals, implying a complete shunting of acetyl CoA for energy production via the TCA cycle. The reported changes in fatty acids and PC metabolism due to N + OC could inhibit post-translational palmitoylation of membrane proteins and synaptic vesicle formation, respectively, thus exacerbating ischemic brain damage in female rats.

Red Cell Microparticles Suppress Hematoma Growth Following Intracerebral Hemorrhage in Chronic Nicotine-Exposed Rats.

Spontaneous intracerebral hemorrhage (sICH) is a disabling stroke sub-type, and tobacco use is a prominent risk factor for sICH. We showed that chronic nicotine exposure enhances bleeding post-sICH. Reduction of hematoma growth is a promising effective therapy for sICH in smoking subjects. Red-blood-cell-derived microparticles (RMPs) are hemostatic agents that limit hematoma expansion following sICH in naïve rats. Considering the importance of testing the efficacy of experimental drugs in animal models with a risk factor for a disease, we tested RMP efficacy and the therapeutic time window in limiting hematoma growth post-sICH in rats exposed to nicotine. Young rats were chronically treated with nicotine using osmotic pumps. sICH was induced in rats using an injection of collagenase in the right striatum. Vehicle/RMPs were administered intravenously. Hematoma volume and neurological impairment were quantified ≈24 h after sICH. Hematoma volumes in male and female nicotine-exposed rats that were treated with RMPs at 2 h post-sICH were significantly lower by 26 and 31% when compared to their respective control groups. RMP therapy was able to limit hematoma volume when administered up to 4.5 h post-sICH in animals of both sexes. Therefore, RMPs may limit hematoma growth in sICH patients exposed to tobacco use.

Osteocalcin, ovarian senescence, and brain health.

Menopause, an inevitable event in a woman's life, significantly increases risk of bone resorption and diseases such as Alzheimer's, vascular dementia, cardiac arrest, and stroke. The sole role of bones, as traditionally regarded, is to provide structural support for skeletal muscles and allow for ambulation, however this concept is becoming quickly outdated. New literature has emerged that suggests the bone cell-derived hormone osteocalcin (OCN) plays a pivotal role in cognition. OCN levels are correlated with bone mass density and bone turnover, and thus are strongly influenced by the changes associated with menopause. The goal of the current review is to discuss potential gaps in our knowledge of OCN and cognition, discrepancies in methods of OCN quantification, and therapies to enhance circulating OCN. A discussion on implementing exercise or low frequency vibration interventions at the menopausal transition to reduce risk and severity of neurological diseases and associated cognitive decline is included.

The peri-menopause in a woman's life: a systemic inflammatory phase that enables later neurodegenerative disease.

The peri-menopause or menopausal transition-the time period that surrounds the final years of a woman's reproductive life-is associated with profound reproductive and hormonal changes in a woman's body and exponentially increases a woman's risk of cerebral ischemia and Alzheimer's disease. Although our understanding of the exact timeline or definition of peri-menopause is limited, it is clear that there are two stages to the peri-menopause. These are the early menopausal transition, where menstrual cycles are mostly regular, with relatively few interruptions, and the late transition, where amenorrhea becomes more prolonged and lasts for at least 60 days, up to the final menstrual period. Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-ß). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-ß-mediated mechanisms.

Whole Body Vibration Therapy after Ischemia Reduces Brain Damage in Reproductively Senescent Female Rats.

A risk of ischemic stroke increases exponentially after menopause. Even a mild-ischemic stroke can result in increased frailty. Frailty is a state of increased vulnerability to adverse outcomes, which subsequently increases risk of cerebrovascular events and severe cognitive decline, particularly after menopause. Several interventions to reduce frailty and subsequent risk of stroke and cognitive decline have been proposed in laboratory animals and patients. One of them is whole body vibration (WBV). WBV improves cerebral function and cognitive ability that deteriorates with increased frailty. The goal of the current study is to test the efficacy of WBV in reducing post-ischemic stroke frailty and brain damage in reproductively senescent female rats. Reproductively senescent Sprague-Dawley female rats were exposed to transient middle cerebral artery occlusion (tMCAO) and were randomly assigned to either WBV or no-WBV groups. Animals placed in the WBV group underwent 30 days of WBV (40 Hz) treatment performed twice daily for 15 min each session, 5 days each week. The motor functions of animals belonging to both groups were tested intermittently and at the end of the treatment period. Brains were then harvested for inflammatory markers and histopathological analysis. The results demonstrate a significant reduction in inflammatory markers and infarct volume with significant increases in brain-derived neurotrophic factor and improvement in functional activity after tMCAO in middle-aged female rats that were treated with WBV as compared to the no-WBV group. Our results may facilitate a faster translation of the WBV intervention for improved outcome after stroke, particularly among frail women.

Nicotine Alters Estrogen Receptor-Beta-Regulated Inflammasome Activity and Exacerbates Ischemic Brain Damage in Female Rats.

Smoking is a preventable risk factor for stroke and smoking-derived nicotine exacerbates post-ischemic damage via inhibition of estrogen receptor beta (ER-β) signaling in the brain of female rats. ER-β regulates inflammasome activation in the brain. Therefore, we hypothesized that chronic nicotine exposure activates the inflammasome in the brain, thus exacerbating ischemic brain damage in female rats. To test this hypothesis, adult female Sprague-Dawley rats (6⁻7 months old) were exposed to nicotine (4.5 mg/kg/day) or saline for 16 days. Subsequently, brain tissue was collected for immunoblot analysis. In addition, another set of rats underwent transient middle cerebral artery occlusion (tMCAO; 90 min) with or without nicotine exposure. One month after tMCAO, histopathological analysis revealed a significant increase in infarct volume in the nicotine-treated group (64.24 ± 7.3 mm³; mean ± SEM; n = 6) compared to the saline-treated group (37.12 ± 7.37 mm³; n = 7, p < 0.05). Immunoblot analysis indicated that nicotine increased cortical protein levels of caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC) and pro-inflammatory cytokines interleukin (IL)-1β by 88% (p < 0.05), 48% (p < 0.05) and 149% (p < 0.05), respectively, when compared to the saline-treated group. Next, using an in vitro model of ischemia in organotypic slice cultures, we tested the hypothesis that inhibition of nicotine-induced inflammasome activation improves post-ischemic neuronal survival. Accordingly, slices were exposed to nicotine (100 ng/mL; 14⁻16 days) or saline, followed by treatment with the inflammasome inhibitor isoliquiritigenin (ILG; 24 h) prior to oxygen-glucose deprivation (OGD; 45 min). Quantification of neuronal death demonstrated that inflammasome inhibition significantly decreased nicotine-induced ischemic neuronal death. Overall, this study shows that chronic nicotine exposure exacerbates ischemic brain damage via activation of the inflammasome in the brain of female rats.

Estrogen receptor beta signaling alters cellular inflammasomes activity after global cerebral ischemia in reproductively senescence female rats.

Periodic treatments with estrogen receptor subtype-ß (ER-ß) agonist reduce post-ischemic hippocampal injury in ovariectomized rats. However, the underlying mechanism of how ER-ß agonists protect the brain remains unknown. Global cerebral ischemia activates the innate immune response, and a key component of the innate immune response is the inflammasome. This study tests the hypothesis that ER-ß regulates inflammasome activation in the hippocampus, thus reducing ischemic hippocampal damage in reproductively senescent female rats that received periodic ER-ß agonist treatments. First, we determined the effect of hippocampal ER-ß silencing on the expression of the inflammasome proteins caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), and interleukin (IL)-1ß. Silencing of ER-ß attenuated 17ß-estradiol mediated decrease in caspase 1, ASC, and IL-1ß. Next, we tested the hypothesis that periodic ER-ß agonist treatment reduces inflammasome activation and ischemic damage in reproductively senescent female rats. Periodic ER-ß agonist treatments significantly decreased inflammasome activation and increased post-ischemic live neuronal counts by 32% (p < 0.05) as compared to the vehicle-treated, reproductively senescent rats. Current findings demonstrated that ER-ß activation regulates inflammasome activation and protects the brain from global ischemic damage in reproductively senescent female rats. Further investigation on the role of a periodic ER-ß agonist regimen to reduce the innate immune response in the brain could help reduce the incidence and the impact of global cerebral ischemia in post-menopausal women. We propose that estrogen receptor subtype-ß (ER-ß) activation regulates inflammasome activation and protects the brain from global ischemic damage in reproductively senescent female rats.

Periodic Estrogen Receptor-Beta Activation: A Novel Approach to Prevent Ischemic Brain Damage.

In women, the risk for cerebral ischemia climbs rapidly after menopause. At menopause, production of ovarian hormones; i.e., progesterone and estrogen, slowly diminishes. Estrogen has been suggested to confer natural protection to premenopausal women from ischemic stroke and some of its debilitating consequences. This notion is also strongly supported by laboratory studies showing that a continuous chronic 17ß-estradiol (E2; a potent estrogen) regimen protects brain from ischemic injury. However, concerns regarding the safety of the continuous intake of E2 were raised by the failed translation to the clinic. Recent studies demonstrated that repetitive periodic E2 pretreatments, in contrast to continuous E2 treatment, provided neuroprotection against cerebral ischemia in ovariectomized rats. Periodic E2 pretreatment protects hippocampal neurons through activation of estrogen receptor subtype beta (ER-ß). Apart from neuroprotection, periodic activation of ER-ß in ovariectomized rats significantly improves hippocampus-dependent learning and memory. Difficulties in learning and memory loss are the major consequence of ischemic brain damage. Periodic ER-ß agonist pretreatment may provide pharmacological access to a protective state against ischemic stroke and its debilitating consequences. The use of ER-ß-selective agonists constitutes a safer target for future research than ER-α agonist or E2, inasmuch as it lacks the ability to stimulate the proliferation of breast or endometrial tissue. In this review, we highlight ER-ß signaling as a guide for future translational research to reduce cognitive decline and cerebral ischemia incidents/impact in post-menopausal women, while avoiding the side effects produced by chronic E2 treatment.

A Perspective on Hormonal Contraception Usage in Central Nervous System Injury.

Naturally occurring life stages in women are associated with changes in the milieu of endogenous ovarian hormones. Women of childbearing age may be exposed to exogenous ovarian hormone(s) because of their use of varying combinations of estrogen and progesterone hormones-containing oral contraceptives (OC; also known as "the pill"). If women have central nervous system (CNS) injury such as spinal cord injury (SCI) and traumatic brain injury (TBI) during their childbearing age, they are likely to retain their reproductive capabilities and may use OC. Many deleterious side effects of long-term OC use have been reported, such as aberrant blood clotting and endothelial dysfunction that consequently increase the risk of myocardial infarction, venous thromboembolism, and ischemic brain injury. Although controversial, studies have suggested that OC use is associated with neuropsychiatric ramifications, including uncontrollable mood swings and poorer cognitive performance. Our understanding about how the combination of endogenous hormones and OC-conferred exogenous hormones affect outcomes after CNS injuries remains limited. Therefore, understanding the impact of OC use on CNS injury outcomes needs further investigation to reveal underlying mechanisms, promote reporting in clinical or epidemiological studies, and raise awareness of possible compounded consequences. The goal of the current review is to discuss the impacts of CNS injury on endogenous ovarian hormones and vice-versa, as well as the putative consequences of exogenous ovarian hormones (OC) on the CNS to identify potential gaps in our knowledge to consider for future laboratory, epidemiological, and clinical studies.

Impact of menopause-associated frailty on traumatic brain injury.

Navigating menopause involves traversing a complex terrain of hormonal changes that extend far beyond reproductive consequences. Menopausal transition is characterized by a decrease in estradiol-17ß (E2), and the impact of menopause resonates not only in the reproductive system but also through the central nervous system, musculoskeletal, and gastrointestinal domains. As women undergo menopausal transition, they become more susceptible to frailty, amplifying the risk and severity of injuries, including traumatic brain injury (TBI). Menopause triggers a cascade of changes leading to a decline in muscle mass, accompanied by diminished tone and excitability, thereby restricting the availability of irisin, a crucial hormone derived from muscles. Concurrently, bone mass undergoes reduction, culminating in the onset of osteoporosis and altering the dynamics of osteocalcin, a hormone originating from bones. The diminishing levels of E2 during menopause extend their influence on the gut microbiota, resulting in a reduction in the availability of tyrosine, tryptophan, and serotonin metabolites, affecting neurotransmitter synthesis and function. Understanding the interplay between menopause, frailty, E2 decline, and the intricate metabolisms of bone, gut, and muscle is imperative when unraveling the nuances of TBI after menopause. The current review underscores the significance of accounting for menopause-associated frailty in the incidence and consequences of TBI. The review also explores potential mechanisms to enhance gut, bone, and muscle health in menopausal women, aiming to mitigate frailty and improve TBI outcomes.

Post-stroke periodic estrogen receptor-beta agonist improves cognition in aged female rats.

Women have a higher risk of having an ischemic stroke and increased cognitive decline after stroke as compared to men. The female sex hormone 17ß-estradiol (E2) is a potent neuro- and cognitive-protective agent. Periodic E2 or estrogen receptor subtype-beta (ER-ß) agonist pre-treatments every 48 h before an ischemic episode ameliorated ischemic brain damage in young ovariectomized or reproductively senescent (RS) aged female rats. The current study aims to investigate the efficacy of post-stroke ER-ß agonist treatments in reducing ischemic brain damage and cognitive deficits in RS female rats. Retired breeder (9-10 months) Sprague-Dawley female rats were considered RS after remaining in constant diestrus phase for more than a month. The RS rats were exposed to transient middle cerebral artery occlusion (tMCAO) for 90 min and treated with either ER-ß agonist (beta 2, 3-bis(4-hydroxyphenyl) propionitrile; DPN; 1 mg/kg; s.c.) or DMSO vehicle at 4.5 h after induction of tMCAO. Subsequently, rats were treated with either ER-ß agonist or DMSO vehicle every 48 h for ten injections. Forty-eight hours after the last treatment, animals were tested for contextual fear conditioning to measure post-stroke cognitive outcome. Neurobehavioral testing, infarct volume quantification, and hippocampal neuronal survival were employed to determine severity of stroke. Periodic post-stroke ER-ß agonist treatment reduced infarct volume, improved recovery of cognitive capacity by increasing freezing in contextual fear conditioning, and decreased hippocampal neuronal death in RS female rats. These data suggest that periodic post-stroke ER-ß agonist treatment to reduce stroke severity and improve post-stroke cognitive outcome in menopausal women has potential for future clinical investigation.

Synergistic inhibitory effect of nicotine plus oral contraceptive on mitochondrial complex-IV is mediated by estrogen receptor-ß in female rats.

Chronic nicotine and oral contraceptive (NOC) exposure caused significant loss of hippocampal membrane-bound estrogen receptor-beta (ER-ß) in female rats compared with exposure to nicotine alone. Mitochondrial ER-ß regulates estrogen-mediated mitochondrial structure and function; therefore, investigating the impact of NOC on mitochondrial ER-ß and its function could help delineate the harmful synergism between nicotine and OC. In this study, we tested the hypothesis that NOC-induced loss of mitochondrial ER-ß alters the oxidative phosphorylation system protein levels and mitochondrial respiratory function. This hypothesis was tested in hippocampal mitochondria isolated from female rats exposed to saline, nicotine, OC or NOC for 16 days. NOC decreased the mitochondrial ER-ß protein levels and reduced oxygen consumption and complex IV (CIV) activity by 34% and 26% compared with saline- or nicotine-administered groups, respectively. We also observed significantly low protein levels of all mitochondrial-encoded CIV subunits after NOC as compared with the nicotine or saline groups. Similarly, the silencing of ER-ß reduced the phosphorylation of cyclic-AMP response element binding protein, and also reduced levels of CIV mitochondrial-encoded subunits after estrogen stimulation. Overall, these results suggest that mitochondrial ER-ß loss is responsible for mitochondrial malfunction after NOC.

Nitrite therapy is neuroprotective and safe in cardiac arrest survivors.

Cardiac arrest results in significant mortality after initial resuscitation due in most cases to ischemia-reperfusion induced brain injury and to a lesser degree myocardial dysfunction. Nitrite has previously been shown to protect against reperfusion injury in animal models of focal cerebral and heart ischemia. Nitrite therapy after murine cardiac arrest improved 22 h survival through improvements in myocardial contractility. These improvements accompanied transient mitochondrial inhibition which reduced oxidative injury to the heart. Based on preliminary evidence that nitrite may also protect against ischemic brain injury, we sought to test this hypothesis in a rat model of asphyxia cardiac arrest with prolonged survival (7d). Cardiac arrest resulted in hippocampal CA1 delayed neuronal death well characterized in this and other cardiac arrest models. Nitrite therapy did not alter post-arrest hemodynamics but did result in significant (75%) increases in CA1 neuron survival. This was associated with increases in hippocampal nitrite and S-nitrosothiol levels but not cGMP shortly after therapy. Mitochondrial function 1h after resuscitation trended towards improvement with nitrite therapy. Based on promising preclinical data, the first ever phase I trial of nitrite infusions in human cardiac arrest survivors has been undertaken. We present preliminary data showing low dose nitrite infusion did not result in hypotension or cause methemoglobinemia. Nitrite thus appears safe and effective for clinical translation as a promising therapy against cardiac arrest mediated heart and brain injury.