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Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT Receptor Activation via NO Pathway.International Journal of Molecular... Jan 2023Renal vasculature, which is highly innervated by sympathetic fibers, contributes to cardiovascular homeostasis. This renal sympathetic outflow is inhibited by 5-HT in...
Renal vasculature, which is highly innervated by sympathetic fibers, contributes to cardiovascular homeostasis. This renal sympathetic outflow is inhibited by 5-HT in normoglycaemic rats. Considering that diabetes induces cardiovascular complications, we aimed to determine whether diabetic state modifies noradrenergic input at renal level and its serotonergic modulation in rats. Alloxan diabetic rats were anaesthetized (pentobarbital; 60 mg/kg i.p.) and prepared for in situ autoperfusion of the left kidney to continuously measure systemic blood pressure (SBP), heart rate (HR), and renal perfusion pressure (RPP). Electrical stimulation of renal sympathetic outflow induces frequency-dependent increases (Δ) in RPP (23.9 ± 2.1, 59.5 ± 1.9, and 80.5 ± 3.5 mm Hg at 2, 4, and 6 Hz, respectively), which were higher than in normoglycaemic rats, without modifying HR or SBP. Intraarterial bolus of 5-HT and 5-CT (5-HT agonist) reduced electrically induced ΔRPP. Only L-694,247 (5-HT agonist) reproduced 5-CT inhibition on sympathetic-induced vasoconstrictions, whereas it did not modify exogenous noradrenaline-induced ΔRPP. 5-CT inhibition was exclusively abolished by i.v. bolus of LY310762 (5-HT antagonist). An inhibitor of guanylyl cyclase, ODQ (i.v.), completely reversed the L-694,247 inhibitory effect. In conclusion, diabetes induces an enhancement in sympathetic-induced vasopressor responses at the renal level. Prejunctional 5-HT receptors, via the nitric oxide pathway, inhibit noradrenergic-induced vasoconstrictions in diabetic rats.
Topics: Rats; Animals; Serotonin; Rats, Wistar; Receptor, Serotonin, 5-HT1D; Diabetes Mellitus, Experimental; Kidney; Norepinephrine; Sympathetic Nervous System; Electric Stimulation; Blood Pressure
PubMed: 36674892
DOI: 10.3390/ijms24021378 -
Neurocritical Care Aug 2021Multimodality neurologic monitoring (MMM) is an emerging technique for management of traumatic brain injury (TBI). An increasing array of MMM-derived biomarkers now...
BACKGROUND/OBJECTIVE
Multimodality neurologic monitoring (MMM) is an emerging technique for management of traumatic brain injury (TBI). An increasing array of MMM-derived biomarkers now exist that are associated with injury severity and functional outcomes after TBI. A standardized MMM reporting process has not been well described, and a paucity of evidence exists relating MMM reporting in TBI management with functional outcomes or adverse events.
METHODS
Prospective implementation of standardized MMM reporting at a single pediatric intensive care unit (PICU) is described that included monitoring of intracranial pressure (ICP), cerebral oxygenation and electroencephalography (EEG). The incidence of clinical decisions made using MMM reporting is described, including timing of neuroimaging, ICP monitoring discontinuation, use of paralytic, hyperosmolar and pentobarbital therapies, neurosurgical interventions, ventilator and CPP adjustments and neurologic prognostication discussions. Retrospective analysis was performed on the association of MMM reporting with initial Glasgow Coma Scale (GCS) and Pediatric Risk of Mortality III (PRISM III) scores, duration of total hospitalization and PICU hospitalization, duration of mechanical ventilation and invasive ICP monitoring, inpatient complications, time with ICP > 20 mmHg, time with cerebral perfusion pressure (CPP) < 40 mmHg and 12-month Glasgow Outcome Scale-Extended Pediatrics (GOSE-Peds) scores. Association of outcomes with MMM reporting was investigated using the Wilcoxon rank-sum test or Fisher's exact test, as appropriate.
RESULTS
Eighty-five children with TBI underwent MMM over 6 years, among which 18 underwent daily MMM reporting over a 21-month period. Clinical decision-making influenced by MMM reporting included timing of neuroimaging (100.0%), ICP monitoring discontinuation (100.0%), timing of extubation trials of surviving patients (100.0%), body repositioning (11.1%), paralytic therapy (16.7%), hyperosmolar therapy (22.2%), pentobarbital therapy (33.3%), provocative cerebral autoregulation testing (16.7%), adjustments in CPP thresholds (16.7%), adjustments in PaCO2 thresholds (11.1%), neurosurgical interventions (16.7%) and neurologic prognostication discussions (11.1%). The implementation of MMM reporting was associated with a reduction in ICP monitoring duration (p = 0.0017) and mechanical ventilator duration (p = 0.0018). No significant differences were observed in initial GCS or PRISM III scores, total hospitalization length, PICU hospitalization length, total complications, time with ICP > 20 mmHg, time with CPP < 40 mmHg, use of tier 2 therapy, or 12-month GOS-E Peds scores.
CONCLUSION
Implementation of MMM reporting in pediatric TBI management is feasible and can be impactful in tailoring clinical decisions. Prospective work is needed to understand the impact of MMM and MMM reporting systems on functional outcomes and clinical care efficacy.
Topics: Brain Injuries, Traumatic; Child; Humans; Intracranial Pressure; Monitoring, Physiologic; Pediatrics; Prospective Studies; Retrospective Studies
PubMed: 33791948
DOI: 10.1007/s12028-021-01190-8 -
Molecular Neurobiology Sep 2023Epilepsy is a severe neurological condition affecting 50-65 million individuals worldwide that can lead to brain damage. Nevertheless, the etiology of epilepsy remains...
Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis.
Epilepsy is a severe neurological condition affecting 50-65 million individuals worldwide that can lead to brain damage. Nevertheless, the etiology of epilepsy remains poorly understood. Meta-analyses of genome-wide association studies involving 15,212 epilepsy cases and 29,677 controls of the ILAE Consortium cohort were used to conduct transcriptome-wide association studies (TWAS) and protein-wide association studies (PWAS). Furthermore, a protein-protein interaction (PPI) network was generated using the STRING database, and significant epilepsy-susceptible genes were verified using chip data. Chemical-related gene set enrichment analysis (CGSEA) was performed to determine novel drug targets for epilepsy. TWAS analysis identified 21,170 genes, of which 58 were significant (TWAS < 0.05) in ten brain regions, and 16 differentially expressed genes were verified based on mRNA expression profiles. The PWAS identified 2249 genes, of which 2 were significant (PWAS < 0.05). Through chemical-gene set enrichment analysis, 287 environmental chemicals associated with epilepsy were identified. We identified five significant genes (WIPF1, IQSEC1, JAM2, ICAM3, and ZNF143) that had causal relationships with epilepsy. CGSEA identified 159 chemicals that were significantly correlated with epilepsy (P < 0.05), such as pentobarbital, ketone bodies, and polychlorinated biphenyl. In summary, we performed TWAS, PWAS (for genetic factors), and CGSEA (for environmental factors) analyses and identified several epilepsy-associated genes and chemicals. The results of this study will contribute to our understanding of genetic and environmental factors for epilepsy and may predict novel drug targets.
Topics: Humans; Transcriptome; Gene Expression Profiling; Genome-Wide Association Study; Brain; Epilepsy; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Cytoskeletal Proteins; Intracellular Signaling Peptides and Proteins; Trans-Activators
PubMed: 37246165
DOI: 10.1007/s12035-023-03382-z -
Pharmaceutical Biology Dec 2022Paeonol (PAE) is the main phytochemical from . Its main pharmacological effects are anti-inflammatory and antioxidant, but its cardioprotective effect is unclear.
CONTEXT
Paeonol (PAE) is the main phytochemical from . Its main pharmacological effects are anti-inflammatory and antioxidant, but its cardioprotective effect is unclear.
OBJECTIVE
The study investigates the effects and underlying mechanisms of PAE on transverse aortic constriction (TAC)-induced heart failure (HF) in mice.
MATERIALS AND METHODS
C57BL/6 mice were randomly divided into five groups: sham, TAC, PAE10 (TAC + PAE 10 mg/kg), PAE20 (TAC + PAE 20 mg/kg) and PAE 50 (TAC + PAE 50 mg/kg). Paeonol was intragastrically administered to mice for 4 weeks. Mice were anaesthetized with pentobarbital sodium and underwent cardiac echocardiography using echocardiography system. Serum levels of atrial natriuretic peptide (ANP), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Myocardial apoptosis was detected with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining. Haematoxylin-eosin (H&E) and Masson's staining were used for histopathological evaluation. Western and quantitative real-time PCR (qRT-PCR) were performed to detect levels of apoptosis and fibrosis-related proteins.
RESULTS
Echocardiography showed PAE improved cardiac function (LVEF: TAC, 52.3±6.8%; PAE20, 65.8±3.6%; PAE50, 71.4±2.5%) and H&E staining showed PAE alleviated myocardial injury (TAC: 1170.3 ± 134.6 μm; PAE50: 576.0 ± 53.5 μm). Western and qRT-PCR results showed that PAE down-regulated the levels of ANP, BNP and α-MHC. In addition, TUNEL and western results showed PAE significantly inhibited apoptosis. Masson and western results showed PAE inhibited cardiac hypertrophy. Western results showed the ERK1/2/JNK pathway could be inhibited by PAE.
DISCUSSION AND CONCLUSIONS
Paeonol regulates ERK1/2/JNK to improve cardiac function, which provides theoretical support for the extensive clinical treatment of HF.
Topics: Acetophenones; Animals; Aorta; Apoptosis; Cardiomegaly; Cardiotonic Agents; Constriction, Pathologic; Disease Models, Animal; Heart Failure; MAP Kinase Signaling System; Male; Mice; Mice, Inbred C57BL; Signal Transduction
PubMed: 35249458
DOI: 10.1080/13880209.2022.2040543 -
Annals of Palliative Medicine Apr 2021L-theanine (L-THE), a natural amino acid found in green tea, has been shown to improve anxiety and sleep. Neumentix proprietary spearmint extract (PSE), which is...
BACKGROUND
L-theanine (L-THE), a natural amino acid found in green tea, has been shown to improve anxiety and sleep. Neumentix proprietary spearmint extract (PSE), which is commonly found in beverage flavoring a pharmaceutical, also has a wide range of health benefits, including cognitive performance improvement.
METHODS
Four experiments tested the effects of L-THE and PSE on sleep: a direct sleeping test, pentobarbital-induced sleeping test, sub-hypnotic pentobarbital-induced sleeping test, and sodium barbital-induced sleeping test. Presence of neurotransmitters in brain tissue was detected by liquid chromatography mass spectroscopy (HP LC-MS) during these studies.
RESULTS
Pentobarbital-induced sleeping and sodium barbital-induced sleeping tests examined the potential effect of L-THE/PSE mixture on synergistic sleep, while neurotransmitter levels in the brain were determined by the high performance liquid chromatography/mass spectroscopy (HPLC/MS) method. L-THE and L-THE/PSE mixture showed increased sleep duration and shortened sleep latency when co-administrated with pentobarbital or sodium barbital. The mixture also increased sleeping rate when co-administrated with the pentobarbital at sub-hypnotic dose. Additionally, the L-THE, PSE and L-THE/PSE mixture significantly increased the concentrations of acetylcholine (Ach), γ-aminobutyric acid (GABA), and decreased the concentration of serotonin (5-HT) in the brain.
CONCLUSIONS
These data demonstrated that L-THE/PSE mixture regulates sleep disorders via the GABA receptor and neurotransmitter systems.
Topics: Animals; Brain; Glutamates; Mice; Neurotransmitter Agents; Sleep; gamma-Aminobutyric Acid
PubMed: 33966405
DOI: 10.21037/apm-21-663 -
Frontiers in Neuroscience 2020Mayer waves may synchronize overlapping propriobulbar interneuronal microcircuits constituting the respiratory rhythm and pattern generator, sympathetic oscillators, and...
Mayer waves may synchronize overlapping propriobulbar interneuronal microcircuits constituting the respiratory rhythm and pattern generator, sympathetic oscillators, and cardiac vagal preganglionic neurons. Initially described by Sir Sigmund Mayer in the year 1876 in the arterial pressure waveform of anesthetized rabbits, authors have since extensively observed these oscillations in recordings of hemodynamic variables, including arterial pressure waveform, peripheral resistance, and blood flow. Authors would later reveal the presence of these oscillations in sympathetic neural efferent discharge and brainstem and spinal zones corresponding with sympathetic oscillators. Mayer wave central tendency proves highly consistent within, though the specific frequency band varies extensively across, species. Striking resemblance of the Mayer wave central tendency to the species-specific baroreflex resonant frequency has led the majority of investigators to comfortably presume, and generate computational models premised upon, a baroreflex origin of these oscillations. Empirical interrogation of this conjecture has generated variable results and derivative interpretations. Sinoaortic denervation and effector sympathectomy variably reduces or abolishes spectral power contained within the Mayer wave frequency band. Refractorines of Mayer wave generation to barodeafferentation lends credence to the hypothesis these waves are chiefly generated by brainstem propriobulbar and spinal cord propriospinal interneuronal microcircuit oscillators and likely modulated by the baroreflex. The presence of these waves in unitary discharge of medullary lateral tegmental field and rostral ventrolateral medullary neurons (contemporaneously exhibiting fast sympathetic rhythms [2-6 and 10 Hz bands]) in spectral variability in vagotomized pentobarbital-anesthetized and unanesthetized midcollicular (i.e., intercollicular) decerebrate cats supports genesis of Mayer waves by supraspinal sympathetic microcircuit oscillators. Persistence of these waves following high cervical transection in vagotomized unanesthetized midcollicular decerebrate cats would seem to suggest sympathetic microcircuit oscillators generate these waves. The widespread presence of Mayer waves in brainstem sympathetic-related and non-sympathetic-related cells would seem to betray a general tendency of neurons to oscillate at this frequency. We have thus presented an extensive and, hopefully cohesive, discourse evaluating, and evolving the interpretive consideration of, evidence seeking to illumine our understanding of origins of, and insight into mechanisms contributing to, the genesis of Mayer waves. We have predicated our arguments and conjectures in the substance and matter of empirical data, though we have occasionally waxed philosophical beyond these traditional confines in suggesting interpretations exceeding these limits. We believe our synthesis and interpretation of the relevant literature will fruitfully inspire future studies from the perspective of a more intimate appreciation and conceptualization of network mechanisms generating oscillatory variability in neuronal and neural outputs. Our evaluation of Mayer waves informs a novel set of disciplines we term quantum neurophysics extendable to describing subatomic reality. Beyond informing our appreciation of mechanisms generating sympathetic oscillations, Mayer waves may constitute an intrinsic property of neurons extant throughout the cerebrum, brainstem, and spinal cord or reflect an emergent property of interactions between arteriogenic and neuronal oscillations.
PubMed: 32765203
DOI: 10.3389/fnins.2020.00395 -
Annals of Palliative Medicine Oct 2021γ-aminobutyric acid (GABA) is a naturally occurring non-protein amino acid in the nervous system and has a wide range of physiological functions in the body. Walnut...
BACKGROUND
γ-aminobutyric acid (GABA) is a naturally occurring non-protein amino acid in the nervous system and has a wide range of physiological functions in the body. Walnut peptide (WP) contains high levels of arginine, aspartic acid, and glutamate, and has been shown to improve cognitive deficits and memory impairment in mice, while restoring antioxidant enzyme levels and reducing brain inflammatory mediators.
METHODS
This study investigated the effects of GABA and WP, either alone or in combination, on sleep disturbances in mice. The pentobarbital-prolonged sleep test, pentobarbital-threshold sleep test, and barbital-induced sleep test were conducted to assess the effects of GABA and WP on sleep quality by gavage for 30 days as follows: GABA (102.25 mg/kg), WP (102.25 mg/kg), GABA (33.95, 102.25, 306.75 mg/kg)/WP (102.25 mg/kg) mixture. Furthermore, neurotransmitter tests were performed using mice brain tissue to investigate the possible mechanisms of GABA and WP on sleep status.
RESULTS
The results showed that the combined use of GABA and WP significantly increased sleep duration compared with single administration of either WP or GABA. Increasing doses of GABA in mice treated with combined GABA and WP elevated the sleep rate to 50.00%, 64.28%, and 64.28%, respectively, compared to mice treated with GABA alone (35.71%) or mice treated with WP alone (28.57%). In mice that received a combination of GABA and WP orally, the latency time was significantly decreased after 30 days compared to control mice (P<0.05). Additionally, in mice treated with GABA, WP, or the combination of GABA and WP, the concentrations of GABA and acetylcholine (Ach) in the brain were significantly elevated and the concentration of serotonin (5-HT) was decreased compared to untreated mice.
CONCLUSIONS
These results demonstrated that the combined administration of GABA and WP could prolong the sleep duration, increase sleep rate, and shorten the sleep latency more effectively than the administration of either GABA or WP alone. The mechanisms of action may be related to the regulation of neurotransmitters in the brain tissue by the combination of GABA and WP.
Topics: Animals; Juglans; Mice; Pentobarbital; Peptides; Sleep; gamma-Aminobutyric Acid
PubMed: 34763469
DOI: 10.21037/apm-21-2798 -
Neuropsychopharmacology : Official... Jan 2023Neurosteroids that positively modulate GABA receptors are among a growing list of rapidly acting antidepressants, including ketamine and psychedelics. To develop...
Neurosteroids that positively modulate GABA receptors are among a growing list of rapidly acting antidepressants, including ketamine and psychedelics. To develop increasingly specific treatments with fewer side effects, we explored the possibility of EEG signatures in mice, which could serve as a cross-species screening tool. There are few studies of the impact of non-sedative doses of rapid antidepressants on EEG in either rodents or humans. Here we hypothesize that EEG features may separate a rapid antidepressant neurosteroid, allopregnanolone, from other GABA positive modulators, pentobarbital and diazepam. Further, we compared the actions GABA modulators with those of ketamine, an NMDA antagonist and prototype rapid antidepressant. We examined EEG spectra during active exploration at two cortical locations and examined cross-regional and cross-frequency interactions. We found that at comparable doses, the effects of allopregnanolone, despite purported selectivity for certain GABAR subtypes, was indistinguishable from pentobarbital during active waking exploration. The actions of diazepam had recognizable common features with allopregnanolone and pentobarbital but was also distinct, consistent with subunit selectivity of benzodiazepines. Finally, ketamine exhibited no distinguishing overlap with allopregnanolone in the parameters examined. Our results suggest that rapid antidepressants with different molecular substrates may remain separated at the level of large-scale ensemble activity, but the studies leave open the possibility of commonalities in more discrete circuits and/or in the context of a dysfunctional brain.
Topics: Humans; Mice; Animals; Pregnanolone; Ketamine; Pentobarbital; Receptors, GABA-A; Diazepam; Neurosteroids; Antidepressive Agents; gamma-Aminobutyric Acid; Electroencephalography
PubMed: 36168047
DOI: 10.1038/s41386-022-01450-x -
International Journal of Experimental... Feb 2021This study aims to compare the influence of different anaesthesia methods on the mechanisms involved in the development of hepatoblastoma (HB). HB rabbit models were...
This study aims to compare the influence of different anaesthesia methods on the mechanisms involved in the development of hepatoblastoma (HB). HB rabbit models were constructed and divided into three groups: disoprofol, pentobarbital sodium and HB groups. After anaesthesia, rabbit blood was collected from the tail vein. Haematological analysis (platelets) and an ELISA was used to measure the thrombopoietin (TPO) and 5-hydroxytryptamine (5-HT). Flow cytometry was used to determine expression of P-selectin and PAF. The expression of 5-HTR2B, PCNA, vWF, P70s6k, 4E-BP1, mTOR and FRAP was determined in the tumour itself or in vascular tissues obtained from the rabbits. The platelet content in the disoprofol group. The content or expression of TPO, 5-HT, P-selectin, PAF, 5-HTR2B, PCNA, vWF, P70s6k, 4E-BP1, mTOR and FRAP was significantly higher in the disoprofol group compared to pentobarbital sodium and HB groups. Expression of these molecules was much higher in the pentobarbital sodium group compared with the HB group. These findings suggest that disoprofol anaesthesia can promote HB development via the mTOR/p70S6K1 and FRAP signalling pathway.
Topics: Animals; Hepatoblastoma; Hypnotics and Sedatives; Liver Neoplasms; Pentobarbital; Platelet Activation; Propofol; Rabbits; Signal Transduction
PubMed: 33410572
DOI: 10.1111/iep.12378 -
BMC Anesthesiology Dec 2021To determine the hypnotic and analgesic effects of brimonidine, and evaluate its efficacy and safety for general anesthesia. Potentiation of pentobarbital sleeping time...
BACKGROUND
To determine the hypnotic and analgesic effects of brimonidine, and evaluate its efficacy and safety for general anesthesia. Potentiation of pentobarbital sleeping time following brimonidine administration was observed in mice, as was the analgesic activity of brimonidine.
METHODS
The median effective dose (ED) and lethal dose (LD) of intraperitoneally injected brimonidine were determined in hypnotized mice. In addition, the LD of intravenously injected brimonidine, and ED of intravenously, intramuscularly, and intrarectally injected brimonidine in hypnotized rabbits were determined. Finally, the synergistic anesthetic effect of brimonidine and chloral hydrate was evaluated in rabbits.
RESULTS
Intraperitoneal injection of 10 mg/kg brimonidine enhanced the hypnotic effect of a threshold dose of pentobarbital. Intraperitoneally injected brimonidine produced dose-related analgesic effects in mice. The ED of intraperitoneally administered brimonidine in hypnotized mice was 75.7 mg/kg and the LD was 379 mg/kg. ED values of intravenous, intramuscular, and intrarectal brimonidine for hypnosis in rabbits were 5.2 mg/kg, 8.8 mg/kg, and 8.7 mg/kg, respectively; the LD of intravenous brimonidine was 146 mg/kg. Combined intravenous administration of 0.6 mg/kg brimonidine and 0.03 g/kg chloral hydrate had a synergistic anesthetic effect.
CONCLUSIONS
Brimonidine elicited hypnotic and analgesic effects after systemic administration and exhibited safety. Moreover, brimonidine enhanced the effects of other types of narcotics when combined.
Topics: Adrenergic alpha-2 Receptor Agonists; Anesthesia, General; Animals; Brimonidine Tartrate; Dose-Response Relationship, Drug; Mice; Rabbits
PubMed: 34861822
DOI: 10.1186/s12871-021-01516-1