Norepinephrine Concentrations Research Articles

Renal denervation improves cardiac function independently of afterload and restores myocardial norepinephrine levels in a rodent heart failure model

Renal nerves play a critical role in cardiorenal interactions. Renal denervation (RDN) improved survival in some experimental heart failure (HF) models. It is not known whether these favorable effects are indirect, explainable by a decrease in vascular afterload, or diminished neurohumoral response in the kidneys, or whether RDN procedure per se has direct myocardial effects in the failing heart. To elucidate mechanisms how RDN affects failing heart, we studied load-independent indexes of ventricular function, gene markers of myocardial remodeling, and cardiac sympathetic signaling in HF, induced by chronic volume overload (aorto-caval fistula, ACF) of Ren2 transgenic rats. Volume overload by ACF led to left ventricular (LV) hypertrophy and dysfunction, myocardial remodeling (upregulated Nppa, MYH 7/6 genes), increased renal and circulating norepinephrine (NE), reduced myocardial NE content, increased monoaminoxidase A (MAO-A), ROS production and decreased tyrosine hydroxylase (+) nerve staining. RDN in HF animals decreased congestion in the lungs and the liver, improved load-independent cardiac function (Ees, PRSW, Ees/Ea ratio), without affecting arterial elastance or LV pressure, reduced adverse myocardial remodeling (Myh 7/6, collagen I/III ratio), decreased myocardial MAO-A and inhibited renal neprilysin activity. RDN increased myocardial expression of acetylcholinesterase (Ache) and muscarinic receptors (Chrm2), decreased circulating and renal NE, but increased myocardial NE content, restoring so autonomic control of the heart. These changes likely explain improvements in survival after RDN in this model. The results suggest that RDN has remote, load-independent and favorable intrinsic myocardial effects in the failing heart. RDN therefore could be a useful therapeutic strategy in HF.

Abstract WP187: Association of Renin Angiotensin Aldosterone Blockade and Hypotension After Carotid Artery Stenting

Background: Persistent hypotension after carotid artery stenting (CAS) can lead to adverse outcomes, prolong length of stay (LOS), and increase hospital costs. As catecholamine plays a critical role in blood pressure (BP) regulation, we aimed to determine the relationship between the use of renin-angiotensin-aldosterone inhibitor (RASI) drugs and post-CAS hypotension. Methods: A multicenter prospective study of patients with extracranial internal carotid artery stenosis and history of hypertension requiring CAS at two hospitals in China between January 2020 to May 2023. BP was recorded at frequent intervals for at least 24 hours post-CAS. Blood catecholamine concentrations were assessed in the morning of, and day immediately after, CAS in a subset of patients. Persistent hypotension was defined as systolic BP <90 mmHg or requiring vasopressor treatment for at least 6 hours. Logistic regression models assessed differences in the rates of post-CAS hypotension between RASI and non-RASI patients with adjustment for known confounding variables. Findings: There were 329 patients included: 160 in the RASI group and 169 in the non-RASI group. The RASI group had a higher rate of persistent hypotension (relative risk 1.52, P=0.031). The RASI group showed a greater decline in norepinephrine concentration after CAS compared with the non-RASI group (P=0.008). Patients with persistent post-CAS hypotension showed a similar decline in norepinephrine concentration (P=0.004) when compared with patients without persistent hypotension. Persistent hypotension prolonged LOS (P=0.014). Conclusion: Prior use of RASI for the treatment of hypertension is associated with persistent hypotension after CAS. A relation between decline of norepinephrine after stenting and persistent hypotension supports the role of catecholamine in BP control.

The acute effects of pre- and mid-exercise carbohydrate ingestion on the immunoregulatory stress hormone release in experienced endurance athletes-a systematic review.

In times of physical stress, the body orchestrates a multisystemic regulatory response. The hormones epinephrine and norepinephrine play a role in the immediate regulation chain, while cortisol is involved in delayed regulation. The release of those stress hormones in response to exercise has previously been reported to elicit diverse immune reactions. The aim of this systematic review was to examine and present the acute effects of immediate pre- and mid-exercise carbohydrate ingestion on cortisol, epinephrine and norepinephrine levels in experienced endurance athletes. A systematic literature search was conducted using PubMed, Cochrane Library and Web of Science in accordance with PRISMA guidelines up to February 2023. Randomized controlled trials in English or German language were included if baseline and at least two follow-up measures of blood plasma or serum of chosen stress hormones (cortisol, epinephrine, norepinephrine) were collected in response to prolonged continuous endurance activity. Eligibility furthermore required an acute carbohydrate ingestion of at least 30 g of carbohydrates per hour no more than 30 min before start of the exercise, as well as a placebo-controlled study design. Eleven studies of moderate to high quality were included in this review. Carbohydrate ingestion of at least 30 g per hour was able to attenuate rises in cortisol concentration in majority of the included studies. Epinephrine levels were considerably lower with ingestion of carbohydrates compared to placebo in all studies. Norepinephrine concentrations were largely unaffected by acute carbohydrate feeding. Pre- and mid-exercise ingestion of carbohydrates seems an effective dietary strategy to attenuate rises in cortisol and epinephrine levels and, thus, an effective countermeasure for endurance exercise-induced increases in stress hormone levels.

Norepinephrine induces anoikis resistance in high-grade serous ovarian cancer precursor cells.

High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to stess-induced sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause. Importantly, NE exacerbates advanced HGSC progression. However, little is known about the role of NE in early disease pathogenesis. Here, we investigated the role of NE in instigating anchorage independence and micrometastasis of preneoplastic lesions from the fallopian tube epithelium (FTE) to the ovary, an essential step in HGSC onset. We found that in the presence of NE, FTE cell lines were able to survive in ultra-low-attachment (ULA) culture in a β-adrenergic receptor-dependent (β-AR-dependent) manner. Importantly, spheroid formation and cell viability conferred by treatment with physiological sources of NE were abrogated using the β-AR blocker propranolol. We have also identified that NE-mediated anoikis resistance may be attributable to downregulation of colony-stimulating factor 2. These findings provide mechanistic insight and identify targets that may be regulated by ovary-derived NE in early HGSC.

Lysophosphatidic acid contributes to myocardial ischemia/reperfusion injury by activating TRPV1 in spinal cord.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that plays a crucial role in cardiovascular diseases. Here, we question whether LPA contributes to myocardial ischemia/reperfusion (I/R) injury by acting on transient receptor potential vanilloid 1 (TRPV1) in spinal cord. By ligating the left coronary artery to establish an in vivo I/R mouse model, we observed a 1.57-fold increase in LPA level in the cerebrospinal fluid (CSF). The I/R-elevated CSF LPA levels were reduced by HA130, an LPA synthesis inhibitor, compared to vehicle treatment (4.74 ± 0.34 vs. 6.46 ± 0.94μg/mL, p = 0.0014). Myocardial infarct size was reduced by HA130 treatment compared to the vehicle group (26 ± 8% vs. 46 ± 8%, p = 0.0001). To block the interaction of LPA with TRPV1 at the K710 site, we generated a K710N knock-in mouse model. The TRPV1K710N mice were resistant to LPA-induced myocardial injury, showing a smaller infarct size relative to TRPV1WT mice (28 ± 4% vs. 60 ± 7%, p < 0.0001). Additionally, a sequence-specific TRPV1 peptide targeting the K710 region produced similar protective effects against LPA-induced myocardial injury. Blocking the K710 region through K710N mutation or TRPV1 peptide resulted in reduced neuropeptides release and decreased activity of cardiac sensory neurons, leading to a decrease in cardiac norepinephrine concentration and the restoration of intramyocardial pro-survival signaling, namely protein kinase B/extracellular regulated kinase/glycogen synthase kinase-3β pathway. These findings suggest that the elevation of CSF LPA is strongly associated with myocardial I/R injury. Moreover, inhibiting the interaction of LPA with TRPV1 by blocking the K710 region uncovers a novel strategy for preventing myocardial ischemic injury.

Lasting mesothalamic dopamine imbalance and altered exploratory behavior in rats after a mild neonatal hypoxic event.

Adversities during the perinatal period can decrease oxygen supply to the fetal brain, leading to various hypoxic brain injuries, which can compromise the regularity of brain development in different aspects. To examine the catecholaminergic contribution to the link between an early-life hypoxic insult and adolescent behavioral aberrations, we used a previously established rat model of perinatal hypoxia but altered the hypobaric to normobaric conditions. Exploratory and social behavior and learning abilities were tested in 70 rats of both sexes at adolescent age. Inherent vertical locomotion, sensory-motor functions and spatial learning abilities were explored in a subset of animals to clarify the background of altered exploratory behavior. Finally, the concentrations of dopamine (DA) and noradrenaline in midbrain and pons, and the relative expression of genes for DA receptors D1 and D2, and their down-stream targets (DA- and cAMP-regulated phosphoprotein, Mr 32 kDa, the regulatory subunit of protein kinase A, and inhibitor-5 of protein phosphatase 1) in the hippocampus and thalamus were investigated in 31 rats. A lesser extent of alterations in exploratory and cognitive aspects of behavior in the present study suggests that normobaric conditions mitigate the hypoxic injury compared to the one obtained under hypobaric conditions. Increased exploratory rearing was the most prominent consequence, with impaired spatial learning in the background. In affected rats, increased midbrain/pons DA content, as well as mRNA levels for DA receptors and their down-stream elements in the thalamus, but not the hippocampus, were found. We can conclude that a mild hypoxic event induced long-lasting disbalances in mesothalamic DA signaling, contributing to the observed behavioral alterations. The thalamus was thereby indicated as another structure, besides the well-established striatum, involved in mediating hypoxic effects on behavior through DA signaling.

The Effects of the Dietary Inclusion of By-Products Obtained after the Extraction of Vitamin B2 from Fermented Soybean on the Performance and Meat Quality of Growing–Finishing Pigs

The by-products obtained after the extraction of vitamin B2 from fermented soybean (VBP), primarily consisting of soybean meal, soybean oil, vitamin B2, and Bacillus subtilis, may serve as a cost-effective and recycled resource in animal feed. This research aimed to assess the impact of VBP on the growth performance, nutrient utilization, blood parameters, and meat quality of pigs in the growing–finishing phase. In this 16-week feeding experiment, 140 pigs of mixed breed [Duroc × (Landrace × Yorkshire)] were used, with an initial average body weight of 26.05 ± 1.32 kg. The pigs were assigned randomly to one of four dietary groups, each consisting of five pigs, with two gilts and three barrows per pen, and a total of seven repetitions per treatment. The animals were fed different levels of by-products after vitamin B2 extraction (0, 10, 20, and 30 g/kg as the CON, VBP10, VBP20, and VBP30 dietary groups, respectively) in a three-phase feeding trial (wk. 0–4, 4–8, and 8–13). When higher levels of VBP were added as supplements, the outcomes indicated that there were no notable variations (p &gt; 0.05) in growth performance and nutrient digestibility among the treatment groups throughout the trial. In phase II (4–8 weeks), the inclusion of VBP in the diets showed a reduction (p = 0.011; with linear and quadratic effects, p = 0.003) in serum norepinephrine concentration. The sensory evaluation of meat color was linearly improved (p = 0.043) in pigs fed with graded levels of VBP supplementation. The percentage of lean meat showed a significant improvement (p = 0.016) with the gradual levels of VBP supplementation. The addition of 30 g/kg (on an as-fed basis) of vitamin B2 by-products in the diet can simultaneously mitigate the negative impacts of acute stress without compromising growth performance and enhance the percentage of lean meat. These findings suggest that VBP could be a viable and economical alternative to corn and soybean meal and partially replace it in pig feed.

Fluorescent Probes Based on Ag NPs@N/GQDs and Molecularly Imprinted Polymer for Sensitive Detection of Noradrenaline in Bananas.

Fluorescence intensity and selective recognition ability are crucial factors in determining the analytical techniques for fluorescent probes. In this study, a core-shell fluorescent material, composed of silver nanoparticles@nitrogen-doped graphene quantum dots (Ag NPs@N/GQDs), was synthesised using mango leaves as the raw material through a thermal cracking method, resulting in strong fluorescence luminescence intensity. By employing noradrenaline as a template molecule and using a surface molecular imprinting technique, a molecularly imprinted membrane (MIP) was formed on the surface of the fluorescent material, that was subsequently eluted to obtain a highly specific, fluorescent probe capable of recognising noradrenaline. The probe captured various concentrations of noradrenaline using the MIP, which decreased the fluorescence intensity. Then a method for detecting trace amounts of noradrenaline was established. This method exhibited a linear range from 0.5 -700pM with a detection limit of 0.154pM. The proposed method was implemented in banana samples. Satisfactory recoveries were confirmed at four different concentrations. The method presented a relative standard deviation (RSD) of less than 5.0%.

Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases.

In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals. Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac 18F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed. Nine participants had low initial myocardial 18F-dopamine-derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 had normal radioactivity. At 7 years of follow-up, 8 of 9 with low initial radioactivity and 1 of 11 with normal radioactivity were diagnosed with a central LBD (LBD+) (P = 0.0009 by Fisher's exact test). Conversely, all 9 LBD+ participants had low 18F-dopamine-derived radioactivity before or at the time of diagnosis of a central LBD, whereas among 25 participants without a central LBD only 1 (4%) had persistently low radioactivity (P < 0.0001 by Fisher's exact test). Cardiac 18F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not. gov NCT00775853. Division of Intramural Research, NIH, NINDS.

An ex vivo method to evaluate vasoactivity induced by hemoglobin-based oxygen carriers in resistance vessels.

Red blood cell substitutes offer a solution to the problem of blood shortage and side effects of blood transfusion. Hemoglobin-based oxygen carriers (HBOCs) are one of the promising substitutes for red blood cells. Vasoactivity, which refers to the side effect of HBOCs that causes vasoconstriction and subsequent hypertension, limits the clinical application of HBOCs. In this study, an ex vivo method for the evaluation of vasoactivity induced by HBOCs was established based on isolated rat mesenteric artery vessels and the DMT120CP system. The DMT120CP system, equipped with a flowmeter, permits the control of intravascular pressure, pressure gradient, and flow conditions with high accuracy, simulating the physiological conditions for isolated vessels. The concentration of noradrenaline was optimized to 1 × 10-6∼3 × 10-6M. PEGylated bovine hemoglobin (PEG-bHb) was synthesized and perfused into the vessel for vasoactivity evaluation, with bHb as the positive control and PSS buffer solution as the negative control. PEG-bHb showed a hydration diameter of 15.5 ± 1.4nm and a P50 value of 6.99mmHg. PEG-bHb exhibited a colloid osmotic pressure of 64.1mmHg and a viscosity of 1.73 cp at 40mg/mL. The established vasoactivity evaluation method showed significant differences in samples (bHb or PEG-bHb) with different vasoactivity properties. The vasoconstriction percentage induced by PEG-bHb samples synthesized in different batches showed coefficients of variation less than 5%, indicating good applicability and repeatability. The established evaluation method can be applied to study the vasoactivity induction and elimination strategies, promoting the clinical application of HBOCs.

Assessment of the neuroprotective effect of green synthesized iron oxide nanoparticles capped with curcumin against a rat model of Parkinson's disease.

The current study aims to investigate the protective effect of iron oxide nanoparticles capped with curcumin (FeONPs-Cur) against motor impairment and neurochemical changes in a rat model of Parkinson's disease (PD) induced by reserpine. Rats were grouped into control, PD model induced by reserpine, and PD model treated with FeONPs-Cur (8 rats/group). The open field test was used to assess motor activity. The concentration of dopamine (DA), norepinephrine (NE), serotonin (5-HT), lipid peroxidation (MDA), reduced glutathione (GSH), and nitric oxide (NO), and the activities of Na+,K+,ATPase, acetylcholinesterase (AchE), and monoamine oxidase (MAO) were determined in the midbrain and striatum. Data were analyzed by ANOVA at P-value<0.05. The PD model exhibited a decrease in motor activity. In the midbrain and striatum of the PD model, DA, NE, and 5-HT levels decreased significantly (P-value<0.05). However, an increase in MAO, NO, and MDA was observed. GSH, AchE and Na+,K+,ATPase decreased significantly in the two brain areas. FeONPs-Cur prevented the decline of dopamine and norepinephrine and reduced oxidative stress in both areas. It also prevented the increased MAO activity in the two areas and the inhibited activity of AchE and Na+,K+,ATPase in the midbrain. These changes were associated with improvements in motor activity. The present data indicate that FeONPs-Cur could prevent the motor deficits induced in the PD rat model by restoring dopamine and norepinephrine in the midbrain and striatum. The antioxidant activity of FeONPs-Cur contributed to its protective effect. These effects nominate FeONPs-Cur as an antiparkinsonian candidate.

Lumbar epidural analgesia and sciatic and femoral peripheral nerve blocks attenuate the stress-induced response in patients during the early postoperative period following total knee replacement

Invasive surgical procedures cause immune system downregulation by inducing a profound proinflammatory response. Establishing the most effective type of postoperative analgesia is crucial to maintain the equilibrium of the immune system. The purpose of this research was to evaluate the influence of epidural analgesia, peripheral nerve blockade as well as systemic analgesia on stress response in patients during the early postoperative period following total knee replacement. In total, 60 patients undergoing total knee replacement were allocated into three groups (n = 20, per group) in this prospective randomized study. Group 1, Group 2 and Group 3 received epidural analgesia, sciatic and femoral peripheral nerve blocks and systemic analgesia, respectively. Intensity of pain was measured at rest and upon movement. Blood samples were collected at baseline (T0), immediately before (T1) and after (T2) surgery, and 24 (T3) and 72 (T4) h postoperatively. The absolute number of leukocytes, concentrations of catecholamine, cortisol and C-reactive protein were determined. Patients in Group 1 and Group 2 exhibited lower pain scores than Group 3. Concentrations of cortisol and norepinephrine, but not epinephrine, were significantly lower in Group 1 and Group 2 at T2 than in Group 3. Significantly lower interleukin-1β concentrations were observed in Group 1 and Group 2 at T3 and T4 than in Group 3. Interleukin-6 concentrations were minor in Group 1 and Group 2 at T2 than in Group 3. Lumbar epidural analgesia and sciatic and femoral peripheral nerve blocks are effective analgesic techniques that reduce the acute inflammatory stress response in patients during the early postoperative period following total knee replacement.

In vivo imaging reveals a synchronized correlation among neurotransmitter dynamics during propofol and sevoflurane anesthesia.

General anesthesia is widely applied in clinical practice. However, the precise mechanism of loss of consciousness induced by general anesthetics remains unknown. Here, we measured the dynamics of five neurotransmitters, including γ-aminobutyric acid, glutamate, norepinephrine, acetylcholine, and dopamine, in the medial prefrontal cortex and primary visual cortex of C57BL/6 mice through in vivo fiber photometry and genetically encoded neurotransmitter sensors under anesthesia to reveal the mechanism of general anesthesia from a neurotransmitter perspective. Results revealed that the concentrations of γ-aminobutyric acid, glutamate, norepinephrine, and acetylcholine increased in the cortex during propofol-induced loss of consciousness. Dopamine levels did not change following the hypnotic dose of propofol but increased significantly following surgical doses of propofol anesthesia. Notably, the concentrations of the five neurotransmitters generally decreased during sevoflurane-induced loss of consciousness. Furthermore, the neurotransmitter dynamic networks were not synchronized in the non-anesthesia groups but were highly synchronized in the anesthetic groups. These findings suggest that neurotransmitter dynamic network synchronization may cause anesthetic-induced loss of consciousness.

Regulation of noradrenaline synthesis, uptake, and degradation in the left ventricle by fatty acid amide hydrolase (FAAH) inhibitor URB597 in the chronic unpredictable stress model of depression

Depression has been linked to the dysfunction of the autonomic nervous system, which may cause dysregulation of the cardiovascular system. One promising therapeutic strategy for treating different diseases is inhibiting the enzyme fatty acid amide hydrolase (FAAH), which increases the availability of endogenous cannabinoids. We examined the effect of chronic FAAH inhibition with URB597 treatment on the noradrenaline (NA) content, synthesis, transport, and degradation in the left ventricle of female and male rats exposed to chronic unpredictable stress (CUS). CUS decreased the levels of both NA and dopamine-?-hydroxylase (DBH) protein in male rats and decreased NA transporter (NET) protein levels in female rats while elevating monoamine oxidase A (MAO-A) in both sexes. Intraperitoneal URB597 application led to increased expression of DBH in stressed males, as well as elevated NET protein levels and decreased MAO-A protein levels in the left ventricle of stressed rats of both sexes. URB597 treatment may have a beneficial effect on the cardiovascular system in an animal model of depression with heightened sympathoneural activity.

Viloxazine Increases Extracellular Concentrations of Norepinephrine, Dopamine, and Serotonin in the Rat Prefrontal Cortex at Doses Relevant for the Treatment of Attention-Deficit/Hyperactivity Disorder.

Viloxazine ER (viloxazine extended-release capsules; Qelbree®), a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment, has known activity as a norepinephrine (NE) transporter (NET) inhibitor. In vitro studies have also shown direct pharmacological effects on specific serotonin (5-HT) receptors, but not on the serotonin transporter (SERT). An in vivo microdialysis study in rats showed viloxazine (50 mg/kg i.p.) increased extracellular 5-HT, NE, and dopamine (DA) in the prefrontal cortex (PFC), a key brain region in ADHD pathology. This study evaluated whether these effects occur at clinically relevant concentrations. Microdialysis experiments were conducted in freely-moving, Sprague-Dawley rats (males, 8 weeks). Viloxazine (1, 3, 10, 30 mg/kg) was administered intraperitoneally to establish the dose range in rats at which viloxazine plasma concentrations aligned with those of individuals with ADHD administered therapeutic doses of viloxazine ER. Concentrations of unbound viloxazine, NE, 5-HT, DA, and NE and 5-HT metabolites (3,5-dihydroxyphenylglycol [DHPG] and 5-hydroxyindoleacetic acid [5-HIAA]) were measured in PFC interstitial fluid. After identifying a therapeutically relevant dose (30 mg/kg), the experiment was repeated using 30 and 50 mg/kg viloxazine (as 50 mg/kg increased NE, 5-HT, and DA in prior studies). Viloxazine unbound (free drug) plasma concentrations in rats at 30 mg/kg were comparable to free drug concentrations in individuals with ADHD taking clinically effective doses (based on validated population PK models). Viloxazine 30 mg/kg significantly increased extracellular NE, 5-HT, and DA PFC levels compared to vehicle. Concomitant decreases in DHPG, but not 5-HIAA, support the inhibitory effect of viloxazine on NET but not SERT. At clinically relevant concentrations, viloxazine increases PFC NE, DA, and 5-HT. Prefrontal augmentation of 5-HT does not appear to result from 5-HT reuptake inhibition but may be related to activation of 5-HT neurons. The potential therapeutic role of serotonergic effects in ADHD treatment merits further exploration.

Effects of intracerebral noradrenaline on cognitive decline associated with the loss of occlusal support.

The lack of occlusal support reportedly reduces cognitive function; however, the underlying mechanisms remain unclear. The locus coeruleus, which is located adjacent to the trigeminal mesencephalic nucleus, secretes noradrenaline throughout the brain. In this study, we evaluated the effects of noradrenaline in the hippocampus and cerebral cortex on cognitive decline following tooth extraction in rats. We performed passive avoidance experiments on male Wistar rats with extracted maxillary molars and determined the neuron density in the locus coeruleus and trigeminal mesencephalic nucleus using immunostaining and Nissl staining, respectively. We also assessed noradrenaline concentrations in the hippocampus and cerebral cortex using enzyme-linked immunosorbent assay. In the passive avoidance experiment, the latency in the bright compartment was significantly shorter (P < 0.05) in the extraction group than in the control group. The numbers of cells in the locus coeruleus and trigeminal nucleus were significantly lower (P < 0.05) in the extraction group compared to those in the control group. The noradrenaline levels in the hippocampus and cerebral cortex were also significantly lower (P < 0.05) in the extraction group than those in the control group. The lack of occlusal support associated with tooth extraction reduces the number of cells in the trigeminal mesencephalic nucleus and locus coeruleus, which may reduce the supply of noradrenaline to the cerebral cortex and hippocampus, leading to a decline in cognitive function.

Presynaptic Adrenoceptors.

Presynaptic α2-adrenoceptors are localized on axon terminals of many noradrenergic and non-noradrenergic neurons in the peripheral and central nervous systems. Their activation by exogenous agonists leads to inhibition of the exocytotic release of noradrenaline and other transmitters from the neurons. Most often, the α2A-receptor subtype is involved in this inhibition. The chain of molecular events between receptor occupation and inhibition of the exocytotic release of transmitters has been determined. Physiologically released endogenous noradrenaline elicits retrograde autoinhibition of its own release. Some clonidine-like α2-receptor agonists have been used to treat hypertension. Dexmedetomidine is used for prolonged sedation in the intensive care; It also has a strong analgesic effect. The α2-receptor antagonist mirtazapine increases the noradrenaline concentration in the synaptic cleft by interrupting physiological autoinhibion of release. It belongs to the most effective antidepressive drugs. β2-Adrenoceptors are also localized on axon terminals in the peripheral and central nervous systems. Their activation leads to enhanced transmitter release, however, they are not activated by endogenous adrenaline.

Действие 1-метил-4-(4-фторфенил)- 1,2,3,6-тетрагидропиридина на биохимические показатели сыворотки крови и обмен моноаминов в головном мозге мышей

Changes in biochemical parameters of blood serum and monoamine metabolism in the brain were studied on male white outbred mice subjected to intraperitoneal injections of 1-methyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (MPTP-F). The levels of norepinephrine, dopamine, serotonin and their metabolites — dioxyphenylacetic, homovanilinic and 5-hydroxyindolacetic acids — were neasured by HPLC in the cerebral cortex, hippocampus, olfactory tubercle and striatum of the right and left sides of the brain. The treatement with MPTP-F did not lead to significant changes in the biochemical parameters of blood serum. An increase in the norepinephrine concentration a decrease in the dopamine level in the right striatum were found in animals treated with MPTP-F. No changes were detected in other studied brain areas. It has been suggested that the effect of the neurotoxin MPTP-F is determined by several factors, i. e. the lipophilic properties of the molecule, the quantitative distribution of dopamine neurons between right and left sides of the brain, differences in the linear velocity of blood flow through the right and left carotid arteries and the state of the blood-brain barrier. The results obtained may indicate the prospects of using MPTP-F for modeling the early stage of Parkinson’s disease.

Fasting for 48h induced similar glucose intolerance in both sexes despite greater perceived stress and decreased estradiol levels in females.

The purpose of this study was to compare the effects of fasting for 48 h on the evoked insulin and glucose responses in males and females, and to explore factors such as stress and estrogen levels that might influence these responses. Healthy, nonobese male (n = 14) and female (n = 14) subjects underwent 48-h fasting trial. Changes in glucose tolerance and insulin levels in response to the oral glucose tolerance test, subjectively perceived stress and catecholamine concentrations were measured in all participants. Estrogen levels were also measured in the female participants during the 48-h fast. Glucose area under the curve (AUC) values increased similarly in both sexes after 48-h fasting (P < 0.05), but females displayed a greater rise in insulin AUC values than males (P < 0.05). Fasting increased plasma epinephrine concentrations in both sexes (P < 0.05), whereas plasma norepinephrine concentrations and subjective stress increased only in females (P < 0.05). Plasma 17-β-estradiol concentrations in females decreased after fasting (P < 0.05). Fasting for 48h induced a similar glucose intolerance in females and males, despite decreased 17-β-estradiol levels and greater psychological and physiological stress in females. These differences represent a plausible explanation for the gender-based differences observed in insulin responses. Retrospectively registered on ClinicalTrials.gov(NCT05545943) in September 19, 2022.

Intermittent fasting disrupts hippocampal-dependent memory and norepinephrine content in aged male and female mice

Intermittent fasting (IMF) is associated with many health benefits in animals and humans. Yet, little is known if an IMF diet affects mood and cognitive processing. We have previously identified that IMF in diet-induced obese males increases norepinephrine and dopamine content in the hypothalamus and increases arcuate neuropeptide Y (NPY) gene expression more than in ad libitum control males. This suggests that IMF may improve cognition through activation of the hindbrain norepinephrine neuronal network and reverse the age-dependent decline in NPY expression. Less is known about the association between anxiety and IMF. Although, in humans, IMF during Ramadan may alleviate anxiety. Here, we address the impact of IMF on anxiety-like behavior using the open field test, hippocampal-dependent memory using the Y-maze and spatial object recognition, and hippocampal-independent memory using novel object recognition in middle-aged male and female (12 mo) and aged male and female (18 mo) mice. Using ELISA, we determined norepinephrine (NE) content in the dorsal hippocampus (DH) and prefrontal cortex (PFC). We also investigated gene expression in the arcuate nucleus (ARC), the lateral hypothalamus (LH), and the locus coeruleus (LC). In IMF-treated females at both ages, we observed an improvement in spatial navigation although an impairment in spatial object orientation. IMF-treated females (12 mo) had a reduction and IMF-treated males (12 mo) displayed an improvement in novel object recognition memory. IMF-treated females (18 mo) exhibited anxiolytic-like behavior and increased locomotion. In the DH, IMF-treated males (12 mo) had a greater amount of NE content and IMF-treated males (18 mo) had a reduction. In the ARC, IMF-treated males (12 mo) exhibited an increase in Agrp and Npy and a decrease in Adr1a. In the ARC, IMF-treated males (18 mo) exhibited an increase in Npy and a decrease in Adr1a; females had a trending decrease in Cart. In the LH at 12 months, IMF-treated males had a decrease in Npy5r, Adr1a, and Adr1b; both males and females had a reduction in Npy1r. In the LH, IMF-treated females (18 mo) had a decrease in Hcrt. In the LC at both ages, mice largely exhibited sex effects. Our findings indicate that IMF produces alterations in mood, cognition, DH NE content, and ARC, LH, and LC gene expression depending on sex and age.