Does general anesthesia affect neurodevelopment in infants and children?

BMJ ◽

10.1136/bmj.l6459 ◽

2019 ◽

pp. l6459 ◽

Cited By ~ 13

Author(s):

Mary Ellen McCann ◽

Sulpicio G Soriano

Keyword(s):

General Anesthesia ◽

Pediatric Anesthesia ◽

Neuronal Cell ◽

Abnormal Development ◽

In Vivo Studies ◽

General Anesthetics ◽

Neurocognitive Deficits ◽

General Anesthetic

AbstractGeneral anesthesia has been unequivocally linked to abnormal development of the central nervous system, leading to neurocognitive impairments in laboratory models. In vitro and in vivo studies have consistently shown that exposure to GABA agonists (eg, volatile anesthetics, midazolam, and propofol) or NMDA antagonists (eg, ketamine, isoflurane, and nitrous oxide) produces dose dependent and developmental age dependent effects on various neuronal transmission systems. Exposure to these drugs increases neuronal cell death in juvenile animals including rats, mice, and non-human primates. The possibility of anesthetic induced neurotoxicity occurring in children has led to concerns about the safety of pediatric anesthesia. A spectrum of behavioral changes has been documented after general anesthetic exposure in young children, including emergence delirium, which may be evidence of toxicity. Most clinical studies are retrospective; specifics about medications or monitoring are unavailable and many of the outcomes may not be sensitive to detect small neurocognitive deficits. Some of these retrospective studies have shown an association between anesthesia exposure at a young age and neurocognitive deficits, but others have not. Practitioners and families should be reassured that although general anesthetics have the potential to induce neurotoxicity, very little clinical evidence exists to support this.

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The Potential Neuroprotective Role of Free and Encapsulated Quercetin Mediated by miRNA against Neurological Diseases

Nutrients ◽

10.3390/nu13041318 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1318

Author(s):

Tarek Benameur ◽

Raffaella Soleti ◽

Chiara Porro

Keyword(s):

Inflammatory Responses ◽

Pathological Condition ◽

Neurological Diseases ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

In Vivo Studies ◽

Innovative Drug ◽

Chronic Neuroinflammation

Chronic neuroinflammation is a pathological condition of numerous central nervous system (CNS) diseases such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis and many others. Neuroinflammation is characterized by the microglia activation and concomitant production of pro-inflammatory cytokines leading to an increasing neuronal cell death. The decreased neuroinflammation could be obtained by using natural compounds, including flavonoids known to modulate the inflammatory responses. Among flavonoids, quercetin possess multiple pharmacological applications including anti-inflammatory, antitumoral, antiapoptotic and anti-thrombotic activities, widely demonstrated in both in vitro and in vivo studies. In this review, we describe the recent findings about the neuroprotective action of quercetin by acting with different mechanisms on the microglial cells of CNS. The ability of quercetin to influence microRNA expression represents an interesting skill in the regulation of inflammation, differentiation, proliferation, apoptosis and immune responses. Moreover, in order to enhance quercetin bioavailability and capacity to target the brain, we discuss an innovative drug delivery system. In summary, this review highlighted an important application of quercetin in the modulation of neuroinflammation and prevention of neurological disorders.

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In vitro neuroprotective activities of two distinct probiotic consortia

Beneficial Microbes ◽

10.3920/bm2018.0105 ◽

2019 ◽

Vol 10 (4) ◽

pp. 437-447 ◽

Cited By ~ 2

Author(s):

D.R. Michael ◽

T.S. Davies ◽

K.E. Loxley ◽

M.D. Allen ◽

M.A. Good ◽

...

Keyword(s):

Cell Model ◽

Neuronal Cell ◽

In Vivo Studies ◽

Intact Cells ◽

Bacterial Consortia ◽

Differentiated Cells ◽

Genes Encoding ◽

Induced Apoptosis

Neurodegeneration has been linked to changes in the gut microbiota and this study compares the neuroprotective capability of two bacterial consortia, known as Lab4 and Lab4b, using the established SH-SY5Y neuronal cell model. Firstly, varying total antioxidant capacities (TAC) were identified in the intact cells from each consortia and their secreted metabolites, referred to as conditioned media (CM). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Crystal Violet (CV) assays of cell viability revealed that Lab4 CM and Lab4b CM could induce similar levels of proliferation in SH-SY5Y cells and, despite divergent TAC, possessed a comparable ability to protect undifferentiated and retinoic acid-differentiated cells from the cytotoxic actions of rotenone and undifferentiated cells from the cytotoxic actions of 1-methyl-4-phenylpyridinium iodide (MPP+). Lab4 CM and Lab4b CM also had the ability to attenuate rotenone-induced apoptosis and necrosis with Lab4b inducing the greater effect. Both consortia showed an analogous ability to attenuate intracellular reactive oxygen species accumulation in SH-SY5Y cells although the differential upregulation of genes encoding glutathione reductase and superoxide dismutase by Lab4 CM and Lab4b CM, respectively, implicates the involvement of consortia-specific antioxidative mechanisms of action. This study implicates Lab4 and Lab4b as potential neuroprotective agents and justifies their inclusion in further in vivo studies.

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Halothane-induced synaptic depression at both in vivo and in vitro reconstructed synapses between identified Lymnaea neurons

Journal of Neurophysiology ◽

10.1152/jn.1995.74.6.2604 ◽

1995 ◽

Vol 74 (6) ◽

pp. 2604-2613 ◽

Cited By ~ 16

Author(s):

G. E. Spencer ◽

N. I. Syed ◽

K. Lukowiak ◽

W. Winlow

Keyword(s):

Synaptic Transmission ◽

Lymnaea Stagnalis ◽

Cell Types ◽

Inhibitory Synapses ◽

General Anesthetics ◽

General Anesthetic ◽

Presynaptic Neuron ◽

Novel Approach

1. In the present study we tested the ability of the general anesthetic, halothane, to affect synaptic transmission at in vivo and in vitro reconstructed peptidergic synapses between identified neurons of Lymnaea stagnalis. 2. An identified respiratory interneuron, visceral dorsal 4 (VD4), innervates a number of postsynaptic cells in the central ring ganglia of Lymnaea. Because VD4 has previously been shown to exhibit immunoreactivity for FMRFamide-related peptides, it was hypothesized that these peptides may be utilized by VD4 during synaptic transmission. In the intact, isolated CNS of Lymnaea, we have identified novel connections between VD4 and the pedal A (PeA) cells. We demonstrate that VD4 makes inhibitory connections with the PeA neurons, in particular PeA4, and that these synaptic responses are mimicked by exogenous application of FMRFamide. 3. The synaptic transmission between VD4 and the PeA cells in an intact, isolated CNS preparation was completely blocked in 2%, but not 1% halothanc. Interestingly, the postsynaptic responses (PeA) to exogenous FMRFamide were maintained in the presence of both 1 and 2% halothane. 4. To determine the specificity of the observed responses and to determine the precise synaptic site of anesthetic action, we reconstructed the VD4/PeA synapses in vitro. After isolation from their respective ganglia, both cell types extended processes and established neuritic contact. We demonstrated that not only did the presynaptic neuron reestablish the appropriate inhibitory synapses with the PeA neurons, but that the PeA cells also maintained their responsiveness to exogenous FMRFamide. 5. Superfusion of the in vitro synaptically connected VD4 and PeA cells with 2% halothane completely abolished the synaptic transmission between these cells. However, even higher concentrations of 4% halothane failed to block the responsiveness of the PeA neurons to exogenous FMRFamide. Moreover, both 1 and 2% halothane enhanced the duration of the postsynaptic response to exogenously applied FMRFamide. These data suggest that the halothane-induced depression of synaptic transmission most likely occurred at the presynaptic level. 6. This study provides the first direct evidence that peptidergic transmission in the nervous system may also be susceptible to the actions of general anesthetics. In addition, we utilized a novel approach of in vitro reconstructed synapses for studying the effects of general anesthetics on monosynaptic transmission in the absence of other synaptic influences.

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Enhanced Thalamic Spillover Inhibition during Non–rapid-eye-movement Sleep Triggers an Electrocortical Signature of Anesthetic Hypnosis

Anesthesiology ◽

10.1097/aln.0000000000001307 ◽

2016 ◽

Vol 125 (5) ◽

pp. 964-978 ◽

Cited By ~ 5

Author(s):

Lia Mesbah-Oskui ◽

Richard L. Horner

Keyword(s):

Eye Movement ◽

Rem Sleep ◽

Aminobutyric Acid ◽

Rapid Eye Movement ◽

General Anesthetics ◽

General Anesthetic ◽

Brain Wave ◽

Electrocortical Activity

Abstract Background Alterations in thalamic γ-aminobutyric acid–mediated signaling are thought to underlie the increased frontal α-β frequency electrocortical activity that signals anesthetic-induced loss of consciousness with γ-aminobutyric acid receptor type A (GABAAR)–targeting general anesthetics. The general anesthetic etomidate elicits phasic extrasynaptic GABAAR activation (“spillover” inhibition) at thalamocortical neurons in vitro. We hypothesize that this action of etomidate at the thalamus is sufficient to trigger an increase in frontal α-β frequency electrocortical activity and that this effect of etomidate is fully recapitulated by enhanced thalamic spillover inhibition in vivo. Methods We recorded electrocortical activity and sleep–wake behavior in freely behaving wild-type (n = 33) and extrasynaptic δ-subunit–containing GABAAR knockout mice (n = 9) during bilateral microperfusion of the thalamus with etomidate and/or other pharmacologic agents that influence GABAAR or T-type Ca2+ channel activity. Results Microperfusion of etomidate into the thalamus elicited an increase in α-β frequency electrocortical activity that occurred only during non–rapid-eye-movement (REM) sleep (11.0 ± 11.8% and 16.0 ± 14.2% greater 8 to 12- and 12 to 30-Hz power, respectively; mean ± SD; both P < 0.031) and was not affected by blockade of thalamic T-type Ca2+ channels. Etomidate at the thalamus also increased spindle-like oscillations during non-REM sleep (4.5 ± 2.4 spindle per minute with etomidate vs. 3.2 ± 1.7 at baseline; P = 0.002). These effects of etomidate were fully recapitulated by enhanced thalamic extrasynaptic GABAAR-mediated spillover inhibition. Conclusions These findings identify how a prototypic GABAAR-targeting general anesthetic agent can elicit the characteristic brain wave pattern associated with anesthetic hypnosis when acting at the thalamus by promoting spillover inhibition and the necessity of a preexisting non-REM mode of activity in the thalamus to generate this effect.

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General Anesthetic Isoflurane Modulates Inositol 1,4,5-Trisphosphate Receptor Calcium Channel Opening

Anesthesiology ◽

10.1097/aln.0000000000000316 ◽

2014 ◽

Vol 121 (3) ◽

pp. 528-537 ◽

Cited By ~ 21

Author(s):

J. Donald Joseph ◽

Yi Peng ◽

Don-On Daniel Mak ◽

King-Ho Cheung ◽

Horia Vais ◽

...

Keyword(s):

Single Channel ◽

General Anesthetics ◽

General Anesthetic ◽

Minimal Alveolar Concentration ◽

Open Probability ◽

Recombinant Type ◽

Inositol 1,4,5 Trisphosphate ◽

Trisphosphate Receptor

Abstract Background: Pharmacological evidence suggests that inhalational general anesthetics induce neurodegeneration in vitro and in vivo through overactivation of inositol trisphosphate receptor (InsP3R) Ca2+-release channels, but it is not clear whether these effects are due to direct modulation of channel activity by the anesthetics. Methods: Using single-channel patch clamp electrophysiology, the authors examined the gating of rat recombinant type 3 InsP3R (InsP3R-3) Ca2+-release channels in isolated nuclei (N = 3 to 15) from chicken lymphocytes modulated by isoflurane at clinically relevant concentrations in the absence and presence of physiological levels of the agonist inositol 1,4,5-trisphosphate (InsP3). The authors also examined the effects of isoflurane on InsP3R-mediated Ca2+ release from the endoplasmic reticulum and changes in intracellular Ca2+ concentration ([Ca2+]i). Results: Clinically relevant concentrations (approximately 1 minimal alveolar concentration) of the commonly used general anesthetic, isoflurane, activated InsP3R-3 channels with open probability similar to channels activated by 1 µM InsP3 (Po ≈ 0.2). This isoflurane modulation of InsP3R-3 Po depended biphasically on [Ca2+]i. Combination of isoflurane with subsaturating levels of InsP3 in patch pipettes resulted in at least two-fold augmentations of InsP3R-3 channel Po compared with InsP3 alone. These effects were not noted in the presence of saturating [InsP3]. Application of isoflurane to DT40 cells resulted in a 30% amplification of InsP3R-mediated [Ca2+]i oscillations, whereas InsP3-induced increase in [Ca2+]i and cleaved caspase-3 activity were enhanced by approximately 2.5-fold. Conclusion: These results suggest that the InsP3R may be a direct molecular target of isoflurane and plays a role in the mechanisms of anesthetic-mediated pharmacological or neurotoxic effects.

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Impact of anesthesia and analgesia techniques on glioblastoma progression. A narrative review

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa123 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Ann Privorotskiy ◽

Shreyas P Bhavsar ◽

Frederick F Lang ◽

Jian Hu ◽

Juan P Cata

Keyword(s):

Patient Outcomes ◽

Clinical Studies ◽

Narrative Review ◽

In Vivo Studies ◽

General Anesthetics ◽

Anesthetic Care ◽

Inflammatory Drugs ◽

Cox 2 Inhibitors

Abstract Glioblastoma (GBM) is an aggressive malignant CNS tumor with a median survival of 15 months after diagnosis. Standard therapy for GBM includes surgical resection, radiation, and temozolomide. Recently, anesthetics and analgesics have received attention for their potential involvement in mediating tumor growth. This narrative review investigated whether various members of the 2 aforementioned classes of drugs have a definitive impact on GBM progression by summarizing pertinent in vitro, in vivo, and clinical studies. Recent publications regarding general anesthetics have been inconsistent, showing that they can be pro-tumoral or antitumoral depending on the experimental context. The local anesthetic lidocaine has shown consistent antitumoral effects in vitro. Clinical studies looking at anesthetics have not concluded that their use improves patient outcomes. In vitro and in vivo studies looking at opioid involvement in GBM have demonstrated inconsistent findings regarding whether these drugs are pro-tumoral or antitumoral. Nonsteroidal anti-inflammatory drugs, and specifically COX-2 inhibitors, have shown inconsistent findings across multiple studies looking at whether they are beneficial in halting GBM progression. Until multiple repeatable studies show that anesthetics and analgesics can suppress GBM growth, there is no strong evidence to recommend changes in the anesthetic care of these patients.

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Direct electrophysiological actions of pentobarbital at concentrations achieved during general anesthesia

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1990.259.6.h1743 ◽

1990 ◽

Vol 259 (6) ◽

pp. H1743-H1751 ◽

Cited By ~ 3

Author(s):

S. Nattel ◽

Z. G. Wang ◽

C. Matthews

Keyword(s):

Action Potential ◽

General Anesthesia ◽

Action Potential Duration ◽

Refractory Period ◽

High Performance ◽

In Vivo Studies ◽

Voltage Change ◽

Alpha Chloralose

Pentobarbital and alpha-chloralose are widely used for experimental anesthesia, but their direct electrophysiological actions at anesthetic concentrations are unknown. Trough and peak concentrations measured by high-performance liquid chromatography averaged 27 +/- 3 and 45 +/- 13 mg/l (means +/- SD) for pentobarbital and 41 +/- 15 and 103 +/- 13 mg/l for alpha-chloralose in dogs receiving them for general anesthesia. The direct effects of each agent on papillary muscle action potentials obtained from guinea pigs killed by decapitation were studied in vitro. Pentobarbital increased action potential duration to 95% by 24 +/- 6 and 33 +/- 4% at 25 and 50 mg/l (P less than 0.001 for each), respectively, and caused corresponding increases in effective refractory period. Furthermore, pentobarbital reduced maximum rate of voltage change (Vmax) of phase 0 in a voltage-, rate-, and concentration-dependent fashion, suggesting use-dependent sodium channel blocking actions. The voltage dependence of Vmax was shifted by 3.7 +/- 1.7 (P less than 0.01) and 6.5 +/- 1.8 mV (P less than 0.001) by 25 and 50 mg/l pentobarbital, respectively. In canine ventricular muscle, pentobarbital caused rate- and concentration-dependent decreases in Vmax and increases in action potential duration and refractory period over a concentration range of 5-100 mg/l. alpha-Chloralose was devoid of direct electrophysiological effects in both species. We conclude that pentobarbital has potentially important electrophysiological actions on ventricular tissues at concentrations required for general anesthesia and may confound the results of in vivo studies.

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