Ketamine Anesthesia Research Articles

Perspectives on Excited Delirium and Ketamine

Perspectives on Excited Delirium and Ketamine

Poisson-distributed noise induces cortical γ-activity: explanation of γ-enhancement by anaesthetics ketamine and propofol

Additive noise is known to affect the stability of nonlinear systems. To understand better the role of additive noise in neural systems, we investigate the impact of additive noise on a random neural network of excitatory and inhibitory neurons. Here we hypothesize that the noise originates from the ascending reticular activating system. Coherence resonance in the γ-frequency range emerges for intermediate noise levels while the network exhibits non-coherent activity at low and high noise levels. The analytical study of a corresponding mean-field model system explains the resonance effect by a noise-induced phase transition via a saddle-node bifurcation. An analytical study of the linear mean-field systems response to additive noise reveals that the coherent state exhibits a quasi-cycle in the γ-frequency range whose spectral properties are tuned by the additive noise. To illustrate the importance of the work, we show that the quasi-cycle explains γ-enhancement under impact of the anaesthetics ketamine and propofol as a destabilizing effect of the coherent state.

Neuroprotective Effect of Monosialotetrahexosylganglioside (GM1) on Patients with Parkinson’s Disease Anesthetized by Ketamine under Denoising Algorithm-Based Ultrasound Image Diagnosis

This study was to investigate the value of ultrasound technology based on the bilateral filtering noise elimination algorithm in evaluating the neuroprotective effect of monosialoganglioside in ketamine-anesthetized Parkinson’s disease patients. The research subjects were 75 patients with Parkinson’s disease admitted to the hospital. The patients were randomly divided into three groups according to different treatment methods: A (GM1 + ketamine anesthesia group), B (conventional treatment + ketamine anesthesia group), and C (GM1 + nonketamine anesthesia group), with 25 patients in each group. Twenty-five healthy people with similar general data in the three groups (groups A, B, and C) were also selected as the control group (group D). All patients underwent ultrasonography, and ultrasound images were processed using the bilateral filter noise elimination. Structural similarity (SSIM), mean absolute error (MAE), and peak signal to noise ratio (PSNR) were used to evaluate the treatment effect. Plasma phospholipids, the third part of the PD unified score scale, Montreal cognitive assessment scale, and other indicators were analyzed and compared among the four groups. The bilateral filtering image noise was effectively suppressed, and the edge details were kept well. Some of the weak edges and texture information in the image were eliminated, the visual effect was ideal, and the accuracy of the edges of the picture remained good. The serotonin lipid level in group A was greatly lower than the serum phospholipid level in group B after GM1 treatment (6.55 VS 7.84, P < 0.05 ). Compared with that before treatment, the serotonin lipid level of group A patients decreased after the treatment, and the difference was considerable (7.46 VS 6.55, P < 0.05 ). In short, GM1 had a protective effect on the nerves of patients with Parkinson’s disease anesthetized by ketamine.

Protective effect of thymoquinone in preventing trauma-related damage: an experimental study

Background Secondary injury is a potentially modifiable factor of outcome in traumatic brain injury. This study aimed to investigate thymoquinone's effects on trauma-induced neuronal damage. Methods Eighteen adult female Sprague–Dawley rats were assigned into three groups following ketamine and xylazine anaesthesia (n = 6): Control, Trauma, Trauma + Thymoquinone. First dose of thymoquinone was administered three hours after the trauma. Results The trauma group showed significant oedema, vascular congestion, and ischaemia. Also, caspase-3 activity and malondialdehyde content of brain tissue was significantly increased, and Na,K-ATPase activity and glutathione levels were significantly reduced. Thymoquinone significantly reduced oedema, vascular congestion, ischaemia, and caspase-3 activity compared with the trauma group. While Na,K-ATPase activity and glutathione levels was similar to the Control group, malondialdehyde content was similar to the trauma group. Conclusions This study showed that low dose thymoquinone exhibited a neuroprotective effect following severe traumatic brain injury, if administered within three hours of injury. Similar levels of glutathione and malondialdehyde suggest no antioxidant effect. Significant reduction in oedema and ischaemia in the neuron cells and partially preserved activity of Na,K-ATPase suggest that thymoquinone protects mitochondrial functions and energy levels of the neuronal cells following severe traumatic brain injury.

Targeting the motor cortex to restore walking after incomplete spinal cord injury.

Targeting the motor cortex to restore walking after incomplete spinal cord injury.

The concentration of MMP-9 and the effects of intravenous anaesthetics on the efficacy of electroconvulsive therapy in patients with drug-resistant depression

Abstract Introduction: This study attempts to assess the concentration of intracellular matrix metalloproteinase (MMP-9) before and after the treatment of depressive episodes with ECT therapy and also to correlate the concentration of this enzyme with the use of commonly used general anaesthetics. Materials and methods: The study group comprised of 37 patients hospitalized in the Department of Adult Psychiatry in Poznan, with a diagnosis of episodes of drug-resistant depression during the course of bipolar and unipolar affective disorders, and who were being treated using electroconvulsive therapy. For the purpose of inducing anaesthesia during the procedure propofol was used in 10 cases, thiopental in 9 cases. Propofol was alternated with ketamine in a further 10 cases and thiopental was alternated with ketamine in another 9 cases. In order to assess the intensity of depression symptoms, the 17 point Hamilton depression scale was used, immediately before commencing ECT therapy, and one day after its completion. The serum concentration of MMP-9 was determined before and after the series of ECT treatments. In order to assess the serum concentration of MMP-9, an ELISA immunoenzymatic method was applied. Results: In this study, a significant reduction of MMP-9 concentration was noted after therapy, relative to the starting concentration, in the serum of patients suffering from depressive episodes resulting from either unipolar or bipolar affective disorders. These results correlated with improved psychiatric state, as assessed by the Hamilton scale. A significantly lower MMP-9 concentration was noted in the serum of patients given alternating thiopental and ketamine anaesthesia. Conclusions: This study suggests the importance of the enzyme as a biological marker for the effective treatment of depression. Furthermore, the choice of general anaesthetic applied during ECT also plays a role.

A Single Low Dose of Dexmedetomidine Efficiently Attenuates Esketamine-Induced Overactive Behaviors and Neuronal Hyperactivities in Mice.

Introduction: Esketamine (Esk) (S(+)-ketamine) is now used as an alternative to its racemic mixture, i. e., ketamine in anesthesia. Esk demonstrated more powerful potency and rapid recovery in anesthesia and less psychotomimetic side effects comparing with ketamine, but Esk could still induce psychological side effects in patients. This study was to investigate whether dexmedetomidine (Dex) can attenuate the Esk-induced neuronal hyperactivities in Kunming mice.Methods: Dexmedetomidine 0.25, 0.5, and 1 mg/kg accompanied with Esk 50 mg/kg were administrated on Kunming mice to assess the anesthesia quality for 1 h. The indicators, such as time to action, duration of agitation, duration of ataxia, duration of loss pedal withdrawal reaction (PWR), duration of catalepsy, duration of righting reflex (RR) loss, duration of sedation, were recorded for 1 h after intraperitoneal administration. The c-Fos expression in the brain was detected by immunohistochemistry and Western Blot after 1 h of administration. Considering the length of recovery time for more than 1 h in Dex and Dex with Esk groups, other mice were repeatedly used to evaluate recovery time from the administration to emerge from anesthesia.Results: Dexmedetomidine dose-dependently increased recovery time when administrated with Esk or alone. Dex combined with Esk efficiently attenuated the duration of agitation, ataxia, and catalepsy. Dex synergically improved the anesthesia of Esk by increasing the duration of sedation, loss of RR, and loss of PWR. Esk induced the high expression of c-Fos in the cerebral cortex, hippocampus, thalamus, amygdala, hypothalamus, and cerebellum 1 h after administration. Western Blot results indicated that Dex at doses of 0.25, 0.5, and 1 mg/kg could significantly alleviate the Esk-induced c-Fos expression in the mice brain.Conclusion: Dexmedetomidine ranged from 0.25 to 1 mg/kg could improve the anesthesia quality and decreased the neuronal hyperactivities and the overactive behaviors when combined with Esk. However, Dex dose-dependently increased the recovery time from anesthesia. It demonstrated that a small dose of Dex 0.25 mg/kg could be sufficient to attenuate Esk-induced psychotomimetic side effects without extension of recovery time in Kunming mice.

Ketamine induces EEG oscillations that may aid anesthetic state but not dissociation monitoring

ObjectiveKetamine is an anesthetic drug associated with dissociation. Decreased electroencephalogram alpha (8–13 Hz) and low-beta (13–20 Hz) oscillation power have been associated with ketamine-induced dissociation. We aimed to characterize surface electroencephalogram signatures that may serve as biomarkers for dissociation. MethodsWe analyzed data from a single-site, open-label, high-density surface electroencephalogram study of ketamine anesthesia (2 mg/kg, n = 15). We assessed dissociation longitudinally using the Clinician Administered Dissociation States Scale (CADSS) and administered midazolam to attenuate dissociation and enable causal inference. We analyzed electroencephalogram power and global coherence with multitaper spectral methods. Mixed effects models were used to assess whether power and global coherence signatures of ketamine could be developed into dissociation-specific biomarkers. ResultsCompared to baseline, ketamine unresponsiveness was associated with increased frontal power between 0.5 to 9.3 Hz, 12.2 to 16.6 Hz, and 24.4 to 50 Hz. As subjects transitioned into a responsive but dissociated state (mean CADSS ± SD, 22.1 ± 17), there was a decrease in power between 0.5 to 10.3 Hz and 11.7 to 50 Hz. Midazolam reduced dissociation scores (14.3 ± 11.6), decreased power between 4.4 to 11.7 Hz and increased power between 14.2 to 50 Hz. Our mixed-effects model demonstrated a quadratic relationship between time and CADSS scores. When models (frontal power, occipital power, global coherence) were reanalyzed with midazolam and electroencephalogram features as covariates, only midazolam was retained. ConclusionsKetamine is associated with structured electroencephalogram power and global coherence signatures that may enable principled anesthetic state but not dissociation monitoring. SignificanceA neurophysiological biomarker for dissociation may lead to a better understanding of neuropsychiatric disorders.

Safety and Efficacy of Ketamine-Fentanyl-Dexmedetomidine-Induced Anesthesia and Analgesia in Neonatal and Aged Rats.

The efficiency of many anesthetic regimens is controversial, with side effects especially in the vulnerable children and old population. The study aimed to evaluate the safety and efficacy of low-dose combination of ketamine, fentanyl, and dexmedetomidine (KFD) for anesthesia and analgesia in the neonatal and elderly rats. KFD rapidly induced anesthesia and analgesia in either postnatal days 6 (P6) or 13 months (13M) old rats. Meanwhile, KFD administration had no adverse effects on the cardiovascular and respiratory systems. Compared with control group, there were no distinct morphologic changes in kidney, liver, and brain in KFD group. Moreover, administration of KFD had no influence on hepatic and renal function in rats of both ages. Furthermore, there was no obvious difference in cognitive function between control and KFD groups. These results indicated that the administration of KFD combination offered safe and efficient anesthesia. Collectively, our results suggest the potential implication of the KFD combination in anesthesia management.

Evaluation of Clinico-physiological Effects of Ketamine Alone and in Combination with Dexmedetomidine or Butorphanol in Atropinized Dogs

Background: Ketamine is rarely used alone because of its association with poor muscle relaxation, tachycardia, catalepsy or muscle rigidity and therefore commonly used in combination with alpha 2 agonist or opioid to minimize the untoward effects. The aim of the present anaesthetic study was to evaluate the clinico-physiological effects of ketamine alone and in combination with dexmedetomidine or butorphanol for inducing adequate anaesthesia in dogs. Methods: The present anaesthetic study was conducted on 18 (eighteen) healthy dogs of either sex and randomly divided into three groups (K, DK and BK) with six animals in each group. Atropine sulphate @ 0.04 mg/ kg was administered intramuscularly 15 minutes prior to anaesthetic study to all the animals. In group K, ketamine HCl alone was administered @ 5 mg/kg by slow i/v and kept as control. In group DK and BK, after administration of atropine sulphate 15 minutes later dexmedetomidine @ 10 µg/kg i/m and butorphanol @ 0.2 mg/kg i/m were administered respectively. Ten minutes later ketamine HCl was administered @ 5 mg/kg slowly intravenously in both group DK and BK to induce surgical stage of general anaesthesia. The following clinical parameters were recorded viz., onset of sedation, onset of anaesthesia, degree of analgesia, extent of muscle relaxation, duration of anaesthesia and complete recovery. The physiological parameters (rectal temperature, heart rate and respiratory rate) were recorded before anaesthetic study at 0 min. and at 10 minutes after preanaesthetic administration and then at 10, 20, 40, 60, 90, 120 and 180 minutes after ketamine anaesthesia. All the data were analyzed using SPSS v 15.0 statistics software program and presented as mean±Standard Error. Result: The onset of sedation was quicker in group DK followed by group K and BK. Duration of anaesthesia and complete recovery in group DK was significantly (p less than 0.01) longer than in group K and BK. The degree of analgesia was excellent in group DK and good in group K and BK. The extent of muscle relaxation was excellent in group DK, good in group BK and was poor in group K. The physiological parameters showed transient changes which compensated and remained within normal range during the observation period. The above anaesthetic study suggests that ketamine in combination with dexmedetomidine or butorphanol can be safely used for inducing adequate anaesthesia in dogs. However, dexmedetomidine-ketamine can be used safely for longer duration of surgical procedures in dogs.

Neonatal Anesthesia by Ketamine in Neonatal Rats Inhibits the Proliferation and Differentiation of Hippocampal Neural Stem Cells and Decreases Neurocognitive Function in Adulthood via Inhibition of the Notch1 Signaling Pathway.

The Notch signaling pathway plays an important role in the regulation of neurogenesis. The objective of this study was to investigate whether the Notch signaling pathway was involved in the neurogenesis impairment and long-term neurocognitive dysfunction caused by neonatal exposure to ketamine. On postnatal day 7 (PND-7), male Sprague-Dawley (SD) rats were intraperitoneally injected with 40mg/kg ketamine four consecutive times (40mg/kg × 4) at 1-h intervals. Notch ligand Jagged1 (0.5mg/kg) and lentivirus overexpressing the Notch1 intracellular domain (LV-NICD1) were microinjected into the hippocampal dentate gyrus (DG) 1h or 4days before ketamine administration, respectively. The expression of Notch1 signaling pathway-related proteins was detected by Western blotting 24h after ketamine administration. The proliferation and differentiation of the neural stem cells (NSCs) in the hippocampal DG were evaluated by double immunofluorescence staining 24h after treatment. Moreover, changes in hippocampus-dependent spatial memory of 2-month-old rats were investigated with the Morris water maze test. Ketamine anesthesia in neonatal rats decreased the expression levels of Jagged1, Notch1, NICD1, and hairy enhancer of split 1 (Hes1); inhibited the proliferation and astrocytic differentiation of NSCs; and promoted the differentiation of neurons. Neonatal exposure to ketamine caused deficits in hippocampus-dependent spatial reference memory tasks in 2-month-old rats. Microinjection of Jagged1 or LV-NICD1 reversed the inhibitory effect of ketamine on the expression of Notch1-related proteins in the hippocampal DG, attenuated the ketamine-mediated decrease in NSC proliferation and differentiation, and improved the cognitive function of 2-month-old rats after neonatal exposure to ketamine. These results suggest that neonatal exposure to ketamine in rats inhibits the proliferation and differentiation of hippocampal NSCs and impairs neurocognitive function in adulthood. The Notch1 signaling pathway may be involved in the impairment of hippocampus-dependent learning and memory during adulthood caused by neonatal exposure to ketamine. These findings contribute to further understanding the neurotoxicity induced by neonatal exposure to ketamine and the underlying mechanisms.

Ketamine Induces Ferroptosis of Liver Cancer Cells by Targeting lncRNA PVT1/miR-214-3p/GPX4.

BackgroundLiver cancer ranks the top four malignant cancer type worldwide, which needs effective and safe treatment. Ferroptosis is a novel form of regulated cell death driven by iron-dependent lipid peroxidation and has been regarded as a promising therapeutic target for cancers. In this work, we aimed to study the effects of anesthetic ketamine on proliferation and ferroptosis of liver cancer.MethodsCell viability and proliferation were detected by cell counting kit 8 (CCK-8), colony formation, and 5-ethynyl-2′-deoxyuridine (EdU) assay. Ferroptosis was determined by levels of Fe2+, lipid reactive oxygen species (ROS), and malondialdehyde (MDA). RNA levels of lncPVT1, miR-214-3p, and glutathione peroxidase 4 (GPX4) were checked by real-time PCR assay. Clinical liver tumor samples were collected to detect the levels of long noncoding RNA lncPVT1, miR-214-3p, and GPX4, and their correlation was evaluated by Pearson comparison test. Luciferase reporter gene assay and RNA pulldown were conducted to determine the binding between lncPVT1, miR-214-3p, and GPX4 3ʹUTR.ResultsKetamine significantly suppressed viability and proliferation of liver cancer cells both in vitro and in vivo, as well as stimulated ferroptosis, along with decreased expression of lncPVT1 and GPX4. LncPVT1 directly interacted with miR-214-3p to impede its role as a sponge of GPX4. Depletion of lncPVT1 accelerated the ferroptosis of live cancer cells, whereas miR-214-3p inhibition and GPX4 overexpression reversed this effect. Ketamine-induced cell growth suppression and ferroptosis were also suppressed by miR-214-3p inhibition and GPX4 overexpression.ConclusionIn this work, we determined that ketamine suppressed viability of liver cancer cells and induced ferroptosis and identified the possible regulatory mechanism of lncPVT1/miR-214-3p/GPX4 axis.

Cannabis sativa and/or melatonin do not alter brain lipid but alter oxidative mechanisms in female rats

BackgroundLipid profile and redox status play a role in brain (dys)functions. Cannabinoid and melatonergic systems operate in the brain and contribute to brain (patho)physiology, but their roles in the modulation of brain lipid and redox status are not well-known. We studied the effect of ethanol extract of Cannabis sativa (CS) and/or melatonin (M) on the lipid profile and anti-oxidant system of the rat brain.MethodsWe randomly divided twenty-four (24) female Wistar rats into 4 groups (n = 6 rats each). Group 1 (control) received distilled water mixed with DMSO. Groups II–IV received CS (2 mg/kg), M (4 mg/kg), and co-administration of CS and M (CS + M) respectively via oral gavage between 8:00 am and 10:00 am once daily for 14 days. Animals underwent 12-h fasting after the last day of treatment and sacrificed under ketamine anesthesia (20 mg/kg; i.m). The brain tissues were excised and homogenized for assay of the concentrations of the total cholesterol (TC), triacylglycerol (TG), high-density lipoprotein cholesterol (HDL-C), nitric oxide (NO), malondialdehyde (MDA), and the activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and acetylcholinesterase (AChE). One-way analysis of variance (ANOVA) was used to compare means across groups, followed by the least significant difference (LSD) post-hoc test.ResultsCS and/or M did not affect the lipid profile parameters. However, CS increased the G6PD (from 15.58 ± 1.09 to 21.02 ± 1.45 U/L; p = 0.047), GPx (from 10.47 ± 0.86 to 17.71 ± 1.04 U/L; p = 0.019), and SOD (from 0.81 ± 0.02 to 0.90 ± 0.01 μM; p = 0.007), but decreased NO (from 9.40 ± 0.51 to 6.75 ± 0.21 μM; p = 0.010) and had no effect on MDA (p = 0.905), CAT (p = 0.831), GR (p = 0.639), and AChE (p = 0.571) in comparison with the control group. M augmented the increase in G6PD (from 21.02 ± 1.45 U/L to 27.18 ± 1.81 U/L; p = 0.032) and decrease in NO (from 6.75 ± 0.21 to 4.86 ± 0.13 μM; p = 0.034) but abolished the increase in GPx (from 17.71 ± 1.04 to 8.59 ± 2.06 U/L; p = 0.006) and SOD (from 0.90 ± 0.01 to 0.70 ± 0.00 μM; p = 0.000) elicited by CS in the rat brain in comparison with the CS group.ConclusionsCS and M do not alter brain lipid profile. Our data support the contention that CS elicits an anti-oxidative effect on the brain tissue and that CS + M elicits a pro-oxidant effect in rat brain.

Quantitative analysis of human brain microdialysate for target site pharmacokinetics of major anesthetics ketamine, midazolam and propofol

Brain microdialysis samples of intensive care patients treated with the essential anesthetics ketamine, midazolam and propofol were investigated. Importantly, despite decades of clinical use, comprehensive human cerebral pharmacokinetic data of these drugs is still missing.To encounter this apparent lack of knowledge, we combined cerebral microdialysis with leading-edge analytical instrumentation to monitor the neurochemistry of living human patients. For the quantitative analysis, high performing analytical approaches were developed that can handle minute sample volumes and possible ultralow target analyte levels. The developed methods provided detection limits below 100 ng L−1 for all target analytes and high precision (below 4% RSD intraday). Methods were linear between LODs and 100 μg L−1 for ketamine, 75 μg L−1 for midazolam and 10 μg L−1 for propofol respectively, with coefficients of determination R2≥ 0.999. Further, being aware of the error-prone and demanding translation of microdialysis levels to interstitial concentrations, in vitro approaches for recovery testing of microdialysis probes as well as internal normalization approaches were conducted.Thus, we herein report the first cerebral pharmacokinetic data of ketamine, midazolam and propofol determined in microdialysis samples of 15 neurointensive care patients. We could prove blood-brain barrier penetration of all of the investigated anesthetics and could correlate applied dosages and actual brain exposition of ketamine.However, we emphasize the need of an expanded prospective study including individual microdialysis recovery testing as well as matched serum and/or cerebrospinal fluid collection for a more comprehensive cerebral pharmacokinetic understanding.

Ketamine Produces a Long-Lasting Enhancement of CA1 Neuron Excitability.

Ketamine is a clinical anesthetic and antidepressant. Although ketamine is a known NMDA receptor antagonist, the mechanisms contributing to antidepression are unclear. This present study examined the loci and duration of ketamine’s actions, and the involvement of NMDA receptors. Local field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant and anesthetic concentrations. Effects of NMDA receptor antagonists APV and MK-801, GABA receptor antagonist bicuculline, and a potassium channel blocker TEA were also studied. Ketamine decreased population spike amplitudes during application, but a long-lasting increase in amplitudes was seen during washout. Bicuculline reversed the acute effects of ketamine, but the washout increase was not altered. This long-term increase was statistically significant, sustained for >2 h, and involved postsynaptic mechanisms. A similar effect was produced by MK-801, but was only partially evident with APV, demonstrating the importance of the NMDA receptor ion channel block. TEA also produced a lasting excitability increase, indicating a possible involvement of potassium channel block. This is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anesthesia, while increased excitatory transmission contributes to its antidepressant effects.

Neuroprotective Effects of Dexmedetomidine on the Ketamine-Induced Disruption of the Proliferation and Differentiation of Developing Neural Stem Cells in the Subventricular Zone.

Background: Ketamine disrupts the proliferation and differentiation of developing neural stem cells (NSCs). Therefore, the safe use of ketamine in pediatric anesthesia has been an issue of increasing concern among anesthesiologists and children's parents. Dexmedetomidine (DEX) is widely used in sedation as an antianxiety agent and for analgesia. DEX has recently been shown to provide neuroprotection against anesthetic-induced neurotoxicity in the developing brain. The aim of this in vivo study was to investigate whether DEX exerted neuroprotective effects on the proliferation and differentiation of NSCs in the subventricular zone (SVZ) following neonatal ketamine exposure.Methods: Postnatal day 7 (PND-7) male Sprague-Dawley rats were equally divided into the following five groups: control group (n = 8), ketamine group (n = 8), 1 μg/kg DEX+ketamine group (n = 8), 5 μg/kg DEX+ketamine group (n = 8) and 10 μg/kg DEX+ketamine group (n = 8). Immediately after treatment, rats received a single intraperitoneal injection of BrdU, and the proliferation and differentiation of NSCs in the SVZ were assessed using immunostaining at 24 h after the BrdU injection. In the olfactory behavioral tests, rats in each group were raised until 2 months old, and the buried food test and olfactory memory test were performed.Results: The proliferation of NSCs and astrocytic differentiation in the SVZ were significantly inhibited at 24 h after repeated ketamine exposure in the neonatal period, and neuronal differentiation was markedly increased. Furthermore, pretreatment with moderately high (5 μg/kg) or high doses (10 μg/kg) of DEX reversed ketamine-induced disturbances in the proliferation and differentiation of NSCs. In the behavior tests, repeated neonatal ketamine exposure induced olfactory cognitive dysfunction in the adult stage, and moderately high and high doses of DEX reversed the olfactory cognitive dysfunction induced by ketamine.Conclusions: Based on the present findings, pretreatment with a moderately high (5 μg/kg) or high dose (10 μg/kg) of DEX may alleviate the developmental neurogenesis disorder in the SVZ at 24 h after repeated ketamine exposure and improve olfactory cognitive dysfunction in adulthood.

Excitation of Putative Glutamatergic Neurons in the Rat Parabrachial Nucleus Region Reduces Delta Power during Dexmedetomidine but not Ketamine Anesthesia.

Parabrachial nucleus excitation reduces cortical delta oscillation (0.5 to 4 Hz) power and recovery time associated with anesthetics that enhance γ-aminobutyric acid type A receptor action. The effects of parabrachial nucleus excitation on anesthetics with other molecular targets, such as dexmedetomidine and ketamine, remain unknown. The hypothesis was that parabrachial nucleus excitation would cause arousal during dexmedetomidine and ketamine anesthesia. Designer Receptors Exclusively Activated by Designer Drugs were used to excite calcium/calmodulin-dependent protein kinase 2α-positive neurons in the parabrachial nucleus region of adult male rats without anesthesia (nine rats), with dexmedetomidine (low dose: 0.3 µg · kg-1 · min-1 for 45 min, eight rats; high dose: 4.5 µg · kg-1 · min-1 for 10 min, seven rats), or with ketamine (low dose: 2 mg · kg-1 · min-1 for 30 min, seven rats; high dose: 4 mg · kg-1 · min-1 for 15 min, eight rats). For control experiments (same rats and treatments), the Designer Receptors Exclusively Activated by Designer Drugs were not excited. The electroencephalogram and anesthesia recovery times were recorded and analyzed. Parabrachial nucleus excitation reduced delta power in the prefrontal electroencephalogram with low-dose dexmedetomidine for the 150-min analyzed period, excepting two brief periods (peak median bootstrapped difference [clozapine-N-oxide - saline] during dexmedetomidine infusion = -6.06 [99% CI = -12.36 to -1.48] dB, P = 0.007). However, parabrachial nucleus excitation was less effective at reducing delta power with high-dose dexmedetomidine and low- and high-dose ketamine (peak median bootstrapped differences during high-dose [dexmedetomidine, ketamine] infusions = [-1.93, -0.87] dB, 99% CI = [-4.16 to -0.56, -1.62 to -0.18] dB, P = [0.006, 0.019]; low-dose ketamine had no statistically significant decreases during the infusion). Recovery time differences with parabrachial nucleus excitation were not statistically significant for dexmedetomidine (median difference for [low, high] dose = [1.63, 11.01] min, 95% CI = [-20.06 to 14.14, -20.84 to 23.67] min, P = [0.945, 0.297]) nor low-dose ketamine (median difference = 12.82 [95% CI: -3.20 to 39.58] min, P = 0.109) but were significantly longer for high-dose ketamine (median difference = 11.38 [95% CI: 1.81 to 24.67] min, P = 0.016). These results suggest that the effectiveness of parabrachial nucleus excitation to change the neurophysiologic and behavioral effects of anesthesia depends on the anesthetic's molecular target.

BIOCHEMICAL PARAMETERS CHANGES OF JAW BONE REMODELING IN EXPERIMENTAL ANIMALS UNDER THE INFLUENCE OF THE SUGGESTED PASTE, INTENDED FOR LOCAL TREATMENT OF CHRONIC GRANULATING PERIODONTITIS OF PERMANENT TEETH IN CHILDREN

The aim of the research was to study in an experiment on rats the biochemical parameters of the jaw bone remodeling under the influence of the developed paste, intended for the local treatment of chronic granulating periodontitis of permanent teeth in children.
 The experimental research was performed on 36 young rats (males) of the Wistar line (130-150g body weight), which were kept in the vivarium. The animals were divided into 2 groups: an experimental and a control one - 18 rats each. They were operated in sterile conditions under ketamine anesthesia. After applying the alcohol to the skin, a scalpel was used to make an incision along the lower edge of the mandible in the area of the canines and a longitudinal incision of the buccal muscle, then access to the bone was bluntly created. Using a sharp dental probe, a bone defect was modeled, in which the animals of the experimental group were injected with a paste based on comfrey tincture and calcium hydroxide. The control group was operated without the application of paste, the bone defect healed under a blood clot. The surgical wound was sutured in layers with polyamide thread and treated with 1% alcohol solution of diamond green.
 Blood sampling in experimental animals of both groups (6 rats each) was performed on 7th, 14th and 28th day after surgery. Animals were removed from the experiment by decapitation under ketamine anesthesia. Experimental animals were operated on and removed from the experiment during one day, under the same conditions.
 Determination of the amount of calcium and inorganic phosphorus in the blood serum of rats was carried out using standard kits of research by "SIMKO Ltd” company, Lviv. The activity of acidic and alkaline phosphatases in the serum was determined using kits of research by BIO-Ld-TEST company, Lachem (Czech Republic) and "Simbj Ltd", Lviv, respectively. In order to determine these parameters in the serum of normal rats, we took blood from 6 healthy young animals that did not participate in the experiment and were on the diet of the vivarium.
 The research found out that in the healing of artificial bone defects in the lower jaws of rats of the experimental group there were significant fluctuations in calcium and phosphorus levels and changes in the activity of acid phosphatase and alkaline phosphatase in the serum. The amount of Ca and P in the blood of rats decreased sufficiently. Alkaline phosphatase activity increased in both groups on the 7th and 14th day of the experiment, but the difference between the indicators in the groups was 38.35% (p <0.05) and 13.16% (p <0, 01) respectively. This was probably due to the rapid remission of inflammation at the site of surgery in the experimental group, as the paste we developed, which was used to fill a bone defect in this group of animals, has anti-inflammatory properties. Subsequent changes in alkaline phosphatase activity occurred similarly in both groups. This testified to the intensification of bone remodeling processes, as well as bone regeneration and mineralization under the influence of the paste we have developed.
 Our biochemical researches of the blood of experimental animals confirmed the previously obtained results of morphological and densitometric studies and showed that the recovery of bone wounds of the lower jaws of rats occurs almost equally in the experimental and control groups, and paste based on comfrey tincture and calcium hydroxide promotes bone regeneration at the site of the defect and stimulates osteosynthesis.

Opioid receptor system contributes to the acute and sustained antidepressant-like effects, but not the hyperactivity motor effects of ketamine in mice

In 2000, a subanesthetic dose (0.5 mg/kg i.v.) of the dissociative anesthetic ketamine was reported to have both rapid and robust antidepressant effects in patients diagnosed with major depressive disorder and later, ketamine also was shown to be effective in treatment-resistant depressed patients. However, the mechanisms responsible for ketamine's antidepressant effects remain unclear. In 2018, a clinical study reported that pretreatment with the nonselective opioid antagonist naltrexone attenuated the rapid antidepressant effect of ketamine in depressed patients. The current study investigated the potential role of the opioid receptor system in the acute and sustained antidepressant-like and hyperactive effects of ketamine. Mice were tested in the tail suspension test (TST) and differential-reinforcement-of-low-rate responding (DRL) 72 s task which are behavioral screens for antidepressant-like properties. Additionally, open field locomotor activity also was measured. In all behavioral assays, mice were pretreated with the nonselective opioid receptor antagonist naltrexone or saline prior to ketamine administration. The current study found that ketamine (10 mg/kg) produced acute (30 min) and sustained (24 h) antidepressant-like effects in TST, which were attenuated by pretreatment of 2 mg/kg naltrexone. Ketamine (32 mg/kg) also produced an acute antidepressant-like effect in the DRL 72 s task that was attenuated by pretreatment of 2 mg/kg naltrexone. Finally, ketamine (10 and 32 mg/kg) produced hyperactivity in the open field; however, pretreatment with 2 mg/kg naltrexone failed to block the hyperactivity effects ketamine. These results, along with recent clinical findings, suggest that ketamine's antidepressant effects, but not its hyperactive effects, involve activation of the opioid system.

General Anesthesia Disrupts Complex Cortical Dynamics in Response to Intracranial Electrical Stimulation in Rats

The capacity of human brain to sustain complex cortical dynamics appears to be strongly associated with conscious experience and consistently drops when consciousness fades. For example, several recent studies in humans found a remarkable reduction of the spatiotemporal complexity of cortical responses to local stimulation during dreamless sleep, general anesthesia, and coma. However, this perturbational complexity has never been directly estimated in non-human animals in vivo previously, and the mechanisms that prevent neocortical neurons to engage in complex interactions are still unclear. Here, we quantify the complexity of electroencephalographic (EEG) responses to intracranial electrical stimulation in rats, comparing wakefulness to propofol, sevoflurane, and ketamine anesthesia. The evoked activity changed from highly complex in wakefulness to far simpler with propofol and sevoflurane. The reduced complexity was associated with a suppression of high frequencies that preceded a reduced phase-locking, and disruption of functional connectivity and pattern diversity. We then showed how these parameters dissociate with ketamine and depend on intensity and site of stimulation. Our results support the idea that brief periods of activity-dependent neuronal silence can interrupt complex interactions in neocortical circuits, and open the way for further mechanistic investigations of the neuronal basis for consciousness and loss of consciousness across species.