Neural assemblies coordinated by cortical waves are associated with waking and hallucinatory brain states.

The relationship between sensory stimuli and perceptions is brain-state dependent: in wakefulness, suprathreshold stimuli evoke perceptions; under anesthesia, perceptions are abolished; and during dreaming and in dissociated states, percepts are internally generated. Here, we exploit this state dependence to identify brain activity associated with internally generated or stimulus-evoked perceptions. In awake mice, visual stimuli phase reset spontaneous cortical waves to elicit 3-6 Hz feedback traveling waves. These stimulus-evoked waves traverse the cortex and entrain visual and parietal neurons. Under anesthesia as well as during ketamine-induced dissociation, visual stimuli do not disrupt spontaneous waves. Uniquely, in the dissociated state, spontaneous waves traverse the cortex caudally and entrain visual and parietal neurons, akin to stimulus-evoked waves in wakefulness. Thus, coordinated neuronal assemblies orchestrated by traveling cortical waves emerge in states in which perception can manifest. The awake state is privileged in that this coordination is reliably elicited by external visual stimuli.

Comparison Between the Protective Effect of Isoflurane and Propofol on Myocardium During Coronary Artery Bypass Grafting: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Intravenous non-volatile anaesthetics like propofol are commonly used in cardiac surgeries across several countries. Volatile anaesthetics like isoflurane may help in protecting the myocardium and minimize ischaemia-reperfusion injury. Hence, we did this review to compare the cardioprotective effect of isoflurane and propofol among patients undergoing coronary artery bypass grafting (CABG). METHODS: We conducted a search in the databases Medical Literature Analysis and Retrieval System Online (or MEDLINE), Embase, PubMed Central®, ScienceDirect, Google Scholar, and Cochrane Library from inception until April 2021. We carried out a meta-analysis with random-effects model and reported pooled risk ratio (RR) or standardized mean difference (SMD) with 95% confidence interval (CI) depending on the type of outcome. RESULTS: We analysed 13 studies including 808 participants. Almost all were low-quality studies. For cardiac index, the pooled SMD was 0.14 (95% CI: -0.22 to 0.50); for cardiac troponin I, pooled SMD was 0.10 (95% CI: -0.28 to 0.48). For mortality, the RR was 3.00 (95% CI: 0.32 to 28.43); for MI, pooled RR was 1.58 (95% CI: 0.59 to 4.20); and for inotropic drug use, pooled RR was 1.04 (95% CI: 0.90 to 1.21). For length of intensive care unit stay, the pooled SMD was 0.13 (95% CI: -0.29 to 0.55), while pooled SMD for mechanical ventilation time was -0.02 (95% CI: -0.54 to 0.51). CONCLUSION: Isoflurane did not have significant cardioprotective effect compared to propofol following CABG. Hence, the anaesthetists need to check some viable alternatives to manage these patients and reduce the rate of postoperative complications.

Isoflurane pretreatment protects against myocardial ischemia/reperfusion injury via mediating lncRNA CASC15/miR-542-3p axis.

The protective effect of isoflurane on cardiomyocyte ischemia/reperfusion injury (I/RI) was explored in hypoxia and reoxygenation (H/R) induced cardiomyocyte injury model. In terms of mechanism, the participation of long non-coding RNA CASC15/microR-542-3p axis was further discussed. H9c2 cells received H/R treatment to mimic myocardial I/RI. RT-qPCR was performed to quantify mRNA levels. Cell viability and apoptosis were evaluated after isoflurane pretreatment and cell transfection. ELISA was performed to measure the concentrations of inflammatory/oxidative stress-related cytokines (TNF-α, IL-6, MDA, SOD). The target relationship between CASC12 and miR-542-3p was determined via dual-luciferase reporter assay. Isoflurane pretreatment alleviated H/R-induced cell viability suppression and cell apoptosis promotion, which was accompanied by CASC15 downregulation. CASC15 overexpression abolished the influence of isoflurane on cardiomyocytes' viability and apoptosis. H/R-induced excessive release of TNF-α and IL-6 was hold down by isoflurane, which was re-activated after CASC15 overexpression. The concentration changes of both MDA and SOD by isoflurane were reversed by CASC15 overexpression. CASC15 functioned as miR-542-3p sponger, and miR-542-3p overexpression attenuated the effect of isoflurane and CASC15 on H/R-induced cardiac I/RI. Isoflurane pretreatment was beneficial for the alleviation of cardiac I/RI by inhibiting oxidative stress and myocardial inflammatory response. CASC15/miR-542-3p axis was required for isoflurane to exhibit its protective activity against cardiac I/RI.

Effects of tasipimidine premedication with and without methadone and dexmedetomidine on cardiovascular variables during propofol-isoflurane anaesthesia in Beagle dogs.

OBJECTIVE: To evaluate cardiovascular effects of oral tasipimidine on propofol-isoflurane anaesthesia with or without methadone and dexmedetomidine at equianaesthetic levels. STUDY DESIGN: Prospective, placebo-controlled, blinded, experimental trial. ANIMALS: A group of seven adult Beagle dogs weighing (mean ± standard deviation) 12.4 ± 2.6 kg and a mean age of 20.6 ± 1 months. METHODS: The dogs underwent four treatments 60 minutes before induction of anaesthesia with propofol. PP: placebo orally and placebo (NaCl 0.9%) intravenously (IV); TP: tasipimidine 30 µg kg-1 orally and placebo IV; TMP: tasipimidine 30 µg kg-1 orally and methadone 0.2 mg kg-1 IV; and TMPD: tasipimidine 30 µg kg-1 orally with methadone 0.2 mg kg-1 and dexmedetomidine 1 µg kg-1 IV followed by 1 µg kg-1 hour-1. Isoflurane in oxygen was maintained for 120 minutes at 1.2 individual minimum alveolar concentration preventing motor movement. Cardiac output (CO), tissue blood flow (tbf), tissue oxygen saturation (stO2) and relative haemoglobin content were determined. Arterial and mixed venous blood gases, arterial and pulmonary artery pressures and heart rate (HR) were measured at baseline; 60 minutes after oral premedication; 5 minutes after IV premedication; 15, 30, 60, 90 and 120 minutes after propofol injection; and 30 minutes after switching the vaporiser off. Data were analysed by two-way anova for repeated measures; p < 0.05. RESULTS: Tasipimidine induced a significant 20-30% reduction in HR and CO with decreases in MAP (10-15%), tbf (40%) and stO2 (43%). Blood pressure and oxygenation variables were mainly influenced by propofol-isoflurane-oxygen anaesthesia, preceded by short-lived alterations related to IV methadone and dexmedetomidine. CONCLUSIONS AND CLINICAL RELEVANCE: Tasipimidine induced mild to moderate cardiovascular depression. It can be incorporated into a common anaesthetic protocol without detrimental effects in healthy dogs, when anaesthetics are administered to effect and cardiorespiratory function is monitored.

Genotype- and sex-specific changes in vital parameters during isoflurane anesthesia in a mouse model of Alzheimer's disease.

Background: The prevalence of neurodegenerative diseases is increasing as is life expectancy with Alzheimer's disease accounting for two-thirds of dementia cases globally. Whether general anesthesia and surgery worsen cognitive decline is still a matter of debate and most likely depending on the interplay of various influencing factors. In order to account for this complexity, Alzheimer's disease animal models have been developed. The Tg2576 model of Alzheimer's disease is a well-established mouse model exhibiting amyloidopathy and age-dependent sex-specific differences in Alzheimer's disease symptomology. Yet, data on anesthesia in this mouse model is scarce and a systematic comparison of vital parameters during anesthesia with wild-type animals is missing. In order to investigate the safety of general anesthesia and changes in vital parameters during general anesthesia in Tg2576 mice, we did a secondary analysis of vital parameters collected during general anesthesia in aged Tg2576 mice. Methods: After governmental approval (General Administration of the Free State of Bavaria, file number: 55.2-1-54-2532-149-11) 60 mice at 10-12 months of age were exposed to isoflurane (1.6 Vol%) for 120 min, data of 58 mice was analyzed. During general anesthesia, heart rate, respiratory rate, temperature, isoflurane concentration and fraction of inspired oxygen were monitored and collected. Data were analyzed using univariate and multivariate linear mixed regression models. Results: During general anesthesia, heart rate decreased in a sex-specific manner. Respiratory rate decreased and body temperature increased dependent on genotype. However, the changes were limited and all vital parameters stayed within physiological limits. Conclusion: Isoflurane anesthesia in the Tg2576 mouse model is safe and does not seem to influence experimental results by interacting with vital parameters. The present study provides information on appropriate anesthesia in order to advance research on anesthesia and AD and could contribute to improving laboratory animal welfare.

Isoflurane, like sepsis, decreases CYP1A2 liver enzyme activity in intensive care patients: a clinical study and network model.

PURPOSE: Liver function of intensive care patients is routinely monitored by static blood pathology. For specific indications, liver specific cytochrome activity may be measured by the commercially available maximum liver function capacity (LiMAx) test via quantification of the cytochrome P450 1A2 (CYP1A2) dependent C-methacetin metabolism. Sedation with the volatile anesthetic isoflurane was suspected to abrogate the correlation of LiMAx test with global liver function. We hypothesized that isoflurane has a CYP1A2-activity and LiMAx test result decreasing effect. METHODS: In this monocentric, observational clinical study previously liver healthy intensive care patients, scheduled to be changed from propofol to isoflurane sedation, were enrolled. LiMAx testing was done before, during and after termination of isoflurane sedation. RESULTS: The mean LiMAx value decreased during isoflurane sedation. Septic patients (n = 11) exhibited lower LiMAx values compared to non-septic patients (n = 11) at all time points. LiMAx values decreased with isoflurane from 140 ± 82 to 30 ± 34 µg kg-1 h-1 in the septic group and from 253 ± 92 to 147 ± 131 µg kg-1 h-1 in the non-septic group while laboratory markers did not imply significant hepatic impairment. Lactate increased during isoflurane inhalation without clinical consequence. CONCLUSION: Sepsis and isoflurane have independently demonstrated an effect on reducing the hepatic CYP1A2-activity. A network model was constructed that could explain the mechanism through the influence of isoflurane on hypoxia inducible factor (HIF-1α) by upregulation of the hypoxia-inducible pathway and the downregulation of CYP1A2-activity via the ligand-inducible pathway. Thus, the increased anaerobic metabolism may result in lactate accumulation. The influence of isoflurane sedation on the validated correlation of global liver function with CYP1A2-activity measured by LiMAx testing needs to be investigated in more detail.

Simultaneous two-photon imaging and wireless EEG recording in mice.

Background: In vivo two-photon imaging is a reliable method with high spatial resolution that allows observation of individual neuron and dendritic activity longitudinally. Neurons in local brain regions can be influenced by global brain states such as levels of arousal and attention that change over relatively short time scales, such as minutes. As such, the scientific rigor of investigating regional neuronal activities could be enhanced by considering the global brain state. New method: In order to assess the global brain state during in vivo two-photon imaging, CBRAIN (collective brain research platform aided by illuminating neural activity), a wireless EEG collecting and labeling device, was controlled by the same computer of two-photon microscope. In an experiment to explore neuronal responses to isoflurane anesthesia through two-photon imaging, we investigated whether the response of individual cells correlated with concurrent EEG changes induced by anesthesia. Results: In two-photon imaging, calcium activities of the excitatory neurons in the primary somatosensory cortex disappeared in about 30s after to the initiation of isoflurane anesthesia. The simultaneously recorded EEG showed various transitional activity for about 7 min from the initiation of anesthesia and continued with burst and suppression alternating pattern thereafter. As such, there was a dissociation between excitatory neuron activity of the primary somatosensory cortex and the global brain activity under anesthesia. Comparison with existing methods: Existing methods to combine two-photon and EEG recording used wired EEG recording. In this study, wireless EEG was used in conjunction with two-photon imaging, facilitated by CBRAIN. More importantly, built-in algorithms of the CBRAIN can automatically detect brain state such as sleep. The codes used for EEG classification are easy to use, with no prior experience required. Conclusion: Simultaneous recording of wireless EEG and two-photon imaging provides a practical way to capture individual neuronal activities with respect to global brain state in an experimental set-up.

Intraoperative Isoflurane End-Tidal Concentration during Infusion of Fentanyl, Tramadol, or Fentanyl-Tramadol Combination in Cats.

The aim of this study was to evaluate the end-tidal concentration of isoflurane required, clinical parameters, intraoperative antinociceptive effect, and postoperative analgesia in cats undergoing ovariohysterectomy, receiving fentanyl, tramadol, or fentanyl/tramadol. Sixty-six cats in three groups, were premedicated with dexmedetomidine and infused with one of the following treatments: fentanyl, tramadol, or fentanyl/tramadol combination. Anesthesia was induced with alfaxolone and maintained with isoflurane, titrated to keep heart rate, respiratory rate and systolic arterial pressure within target values recorded at endotracheal intubation. An intraoperative cumulative scale was performed. Postoperatively, a short form of the Glasgow Composite Measure Pain Scale Feline was used at 2, 12, and 24 h. The groups were similar for age, weight, dose of dexmedetomidine, and alfaxalone administered. A greater reduction in the end-tidal isoflurane fraction was observed with the combined fentanyl/tramadol infusion than with either fentanyl or tramadol alone. No differences in the end-tidal isoflurane fraction were found between fentanyl or tramadol alone. Hemodynamic stability associated with minimal cardiopulmonary changes, low response to noxious intraoperative stimulation, and low postoperative pain scores were also observed with the fentanyl/tramadol combination. The fentanyl/tramadol combination provided a reduction in the end-tidal isoflurane fraction compared with fentanyl or tramadol alone.

Isoflurane preconditioning induced genomic changes in mouse cortex.

Background: Altered patterns of genetic expression induced by isoflurane preconditioning in mouse brain have not yet been investigated. The aim of our pilot study is to examine the temporal sequence of changes in the transcriptome of mouse brain cortex produced by isoflurane preconditioning. Methods: Twelve-wk-old wild-type (C57BL/6J) male mice were randomly assigned for the experiments. Mice were exposed to isoflurane 2% in air for 1 h and brains were harvested at the following time points-immediately (0 h), and at 6, 12, 24, 36, 48, and 72 h after isoflurane exposure. A separate cohort of mice were exposed to three doses of isoflurane on days 1, 2, and 3 and brains were harvested after the third exposure. The NanoString mouse neuropathology panel was used to analyse isoflurane-induced gene expression in the cortex. The neuropathology panel included 760 genes covering pathways involved in neurodegeneration and other nervous system diseases, and 10 internal reference genes for data normalisation. Results: Genes involving several pathways were upregulated and downregulated by isoflurane preconditioning. Interestingly, a biphasic response was noted, meaning, an early expression of genes (until 6 h), followed by a transient pause (until 24 h), and a second wave of genomic response beginning at 36 h of isoflurane exposure was noted. Conclusions: Isoflurane preconditioning induces significant alterations in the genes involved in neurodegeneration and other nervous system disorders in a temporal sequence. These data could aid in the identification of molecular mechanisms behind isoflurane preconditioning-induced neuroprotection in various central nervous system diseases.

The role of astrocytic γ-aminobutyric acid in the action of inhalational anesthetics.

BACKGROUND: Inhalational anesthetics target the inhibitory extrasynaptic γ-aminobutyric acid type A (GABAA) receptors. Both neuronal and glial GABA mediate tonic inhibition of the extrasynaptic GABAA receptors. However, the role of glial GABA during inhalational anesthesia remains unclear. This study aimed to evaluate whether astrocytic GABA contributes to the action of different inhalational anesthetics. METHODS: Gene knockout of monoamine oxidase B (MAOB) was used to reduce astrocytic GABA levels in mice. The hypnotic and immobilizing effects of isoflurane, sevoflurane, and desflurane were assessed by evaluating the loss of righting reflex (LORR) and tail-pinch withdrawal response (LTWR) in MAOB knockout and wild-type mice. Minimum alveolar concentration (MAC) for LORR, time to LORR, MAC for LTWR and time to LTWR of isoflurane, sevoflurane, and desflurane were assessed. RESULTS: Time to LORR and time to LTWR with isoflurane were significantly longer in MAOB knockout mice than in wild-type mice (P < 0.001 and P = 0.032, respectively). Time to LORR with 0.8 MAC of sevoflurane was significantly longer in MAOB knockout mice than in wild-type mice (P < 0.001), but not with 1.0 MAC of sevoflurane (P=0.217). MAC for LTWR was significantly higher in MAOB knockout mice exposed to sevoflurane (P < 0.001). With desflurane, MAOB knockout mice had a significantly higher MAC for LORR (P = 0.003) and higher MAC for LTWR (P < 0.001) than wild-type mice. CONCLUSIONS: MAOB knockout mice showed reduced sensitivity to the hypnotic and immobilizing effects of isoflurane, sevoflurane, and desflurane. Behavioral tests revealed that the hypnotic and immobilizing effects of inhalational anesthetics would be mediated by astrocytic GABA.

Isoflurane treatment for refractory and super-refractory status epilepticus in dogs.

Introduction: Resistant epileptic episodes, such as refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE), are neurological emergencies that require immediate medical treatment. Although inhalational anesthetics, such as isoflurane (ISO), have been proposed as a means of seizure control in dogs, there is currently a lack of both experimental and clinical studies on this subject. Study design: This is a retrospective clinical study. Methods: Records of dogs that received ISO for the management of RSE and SRSE during their intensive care unit (ICU) hospitalization at the Companion Animal Clinic of the Aristotle University of Thessaloniki were included in the present study. The study period spanned from February 2013 to March 2023. Dogs were identified as responders (R) when RSE/SRSE ceased after ISO administration, and the dogs were successfully discharged from the ICU after ISO discontinuation. Dogs were identified as non-responders (NR) when RSE/SRSE ceased after ISO administration, but RSE/SRSE reoccurred after ISO discontinuation. Additional data about the number and time of ISO cycles, the time of ICU hospitalization, the side effects of ISO administration, and an additional administration of antiepileptic drugs (AEDs) and anesthetic drugs were also recorded. Results: A total of 20 dogs with 26 recorded RSE/SRSE episodes and 26 anesthetic cycles with ISO were included in the present study. The clinical termination of seizure activity was achieved 100% (26/26) in all episodes. In 73.1% (19/26) of the episodes, ISO administration resulted in successful RSE/SRSE treatment. Poor outcome was recorded in 26.9% (7/26) of the episodes because RSE/SRSE reoccurred after ISO discontinuation, and the dogs were euthanatized or died due to cardiac arrest. Inspiratory ISO ranged between 0.5 and 4.0%. The median time of the anesthetic cycles with ISO was 12.67 h (4.00-62.00). The median duration of the ICU hospitalization was 48.00 h (24.00-120.00). At least one ISO-related side effect was recorded in 23 out of 26 (88.5%) episodes. Conclusion: To the authors' knowledge, this is the first clinical study that addresses the administration of ISO for RSE/SRSE treatment in dogs. The use of ISO may be beneficial in terminating RSE/SRSE; however, further prospective studies are necessary to confirm this observation.

Comparative brain-wide mapping of ketamine- and isoflurane-activated nuclei and functional networks in the mouse brain.

Ketamine (KET) and isoflurane (ISO) are two widely used general anesthetics, yet their distinct and shared neurophysiological mechanisms remain elusive. In this study, we conducted a comparative analysis of the effects of KET and ISO on c-Fos expression across the mouse brain, utilizing hierarchical clustering and c-Fos-based functional network analysis to evaluate the responses of individual brain regions to each anesthetic. Our findings reveal that KET activates a wide range of brain regions, notably in the cortical and subcortical nuclei involved in sensory, motor, emotional, and reward processing, with the temporal association areas (TEa) as a strong hub, suggesting a top-down mechanism affecting consciousness by primarily targeting higher order cortical networks. In contrast, ISO predominantly influences brain regions in the hypothalamus, impacting neuroendocrine control, autonomic function, and homeostasis, with the locus coeruleus (LC) as a connector hub, indicating a bottom-up mechanism in anesthetic-induced unconsciousness. KET and ISO both activate brain areas involved in sensory processing, memory and cognition, reward and motivation, as well as autonomic and homeostatic control, highlighting their shared effects on various neural pathways. In conclusion, our results highlight the distinct but overlapping effects of KET and ISO, enriching our understanding of the mechanisms underlying general anesthesia.

Anaesthetic-sparing effect of the anxiolytic drug tasipimidine in Beagle dogs.

OBJECTIVE: To evaluate the effect of oral tasipimidine on dog handling, ease of catheter placement and propofol and isoflurane requirements for anaesthesia. STUDY DESIGN: Placebo-controlled, randomized, blinded, experimental trial. ANIMALS: A group of seven adult Beagle dogs weighing (mean ± standard deviation) 13.1 ± 2.7 kg with a mean age of 18.6 ± 1 months. METHODS: The dogs underwent four treatments before induction of anaesthesia with propofol. PP: placebo orally (PO) 60 minutes before induction of anaesthesia followed by placebo (NaCl 0.9%) intravenously (IV). TP: tasipimidine 30 µg kg-1 (PO) 60 minutes before induction of anaesthesia followed by placebo (NaCl 0.9%) IV. TMP: tasipimidine 30 µg kg-1 PO 60 minutes before induction of anaesthesia followed by methadone 0.2 mg kg-1 IV. TMPD: tasipimidine 30 µg kg-1 PO 60 minutes before induction of anaesthesia followed by methadone 0.2 mg kg-1 and dexmedetomidine 1 µg kg-1 IV followed by a dexmedetomidine constant rate infusion of 1 µg kg-1 hour-1. Sedation, response to catheter placement, intubation quality, time to loss of consciousness, time to intubation, required dose of propofol and minimum alveolar isoflurane concentration preventing motor movement (MACNM) were determined. A mixed-model analysis or the Friedman and Mann-Whitney test were used; p-value < 0.05. RESULTS: Response to catheter placement did not differ between treatments. Tasipimidine alone reduced the propofol dose by 30%. Addition of methadone or methadone and dexmedetomidine reduced the propofol dose by 48% and 50%, respectively. Isoflurane MACNM was reduced by 19% in tasipimidine-medicated dogs, whereas in combination with methadone or methadone and dexmedetomidine, isoflurane MACNM was reduced by 35%. CONCLUSIONS AND CLINICAL RELEVANCE: An anxiolytic dose of tasipimidine induced mild signs of sedation in dogs and reduced propofol and isoflurane requirements to induce and maintain anaesthesia, which needs to be considered in an anaesthetic plan.

The Interaction between Anesthetic Isoflurane and Model-Biomembrane Monolayer Using Simultaneous Quartz Crystal Microbalance (QCM) and Quartz Crystal Impedance (QCI) Methods.

The interaction between anesthetic Isoflurane (Iso) and model-biomembrane on the water surface has been investigated using quartz crystal microbalance (QCM) and quartz crystal impedance (QCI) methods. The model-biomembranes used were dipalmitoyl phosphatidyl choline (DPPC), DPPC-palmitic acid (PA) mixture (DPPC:PA = 8:2), DPPC-Alamethicin (Al) mixture (DPPC:Al = 39:1), and DPPC-ß-Lactoglobulin (ßLG) mixture (DPPC:ßLG = 139:1) monolayers, respectively. The quartz crystal oscillator (QCO) was attached horizontally to each monolayer, and QCM and QCI measurements were performed simultaneously. It was found that Iso hydrate physisorbed on each monolayer/water interface from QCM and changed those interfacial viscosities from QCI. With an increase in Iso concentration, pure DPPC, DPPC-PA mixed, and DPPC-Al mixed monolayers showed a two-step process of Iso hydrate on both physisorption and viscosity, whereas it was a one-step for the DPPC-ßLG mixed monolayer. The viscosity change in the DPPC-ßLG mixed monolayer with the physisorption of Iso hydrate was much larger than that of other monolayers, in spite of the one-step process. From these results, the action mechanism of anesthetics and their relevance to the expression of anesthesia were discussed, based on the "release of interfacial hydrated water" hypothesis on the membrane/water interface.

Xenobiotics Triggering Acute Intermittent Porphyria and Their Effect on Mouse Brain Respiratory Complexes.

Heme enzyme dysfunction causes a group of diseases called porphyrias. Particularly, a decrease in porphobilinogen deaminase, involved in the third step of heme biosynthesis, leads to acute intermittent porphyria (AIP). Considering our previous works demonstrating the multiplicity of brain metabolisms affected by porphyrinogenic agents, this study aimed to elucidate whether they cause any alteration on the mitochondrial respiratory chain. The activities of respiratory chain complexes (I to IV) were measured in encephalon mitochondria of CF1 male mice receiving volatile anesthetics: isoflurane (2 mL/kg) and sevoflurane (1.5 mL/kg), ethanol (30%), allylisopropylacetamide (AIA) (350 mg/kg), and barbital (167 mg/kg). Moreover, they were compared versus animals with pathological levels of 5-aminolevulinic acid (ALA, 40 mg/kg). Complex I-III activity was induced by isoflurane and decreased by AIA, ethanol, and ALA. Complex II-III activity was increased by sevoflurane and decreased by isoflurane and AIA. Complex II activity was increased by sevoflurane and barbital and decreased by AIA, ethanol, and ALA. Complex IV activity was increased by barbital and ALA and decreased by sevoflurane. The damage to the respiratory chain by ALA could be reflecting the pathophysiological condition of patients with AIP. Better understanding the broad effect of porphyrinogenic drugs and the mechanisms acting on the onset of AIP is vital in translational medicine.

Long-term isoflurane anesthesia induces cognitive deficits via AQP4 depolarization mediated blunted glymphatic inflammatory proteins clearance.

Perioperative neurocognitive disorders (PND) refer to cognitive deterioration that occurs after surgery or anesthesia. Prolonged isoflurane exposure has potential neurotoxicity and induces PND, but the mechanism is unclear. The glymphatic system clears harmful metabolic waste from the brain. This study sought to unveil the functions of glymphatic system in PND and explore the underlying molecular mechanisms. The PND mice model was established by long term isoflurane anesthesia. The glymphatic function was assessed by multiple in vitro and in vivo methods. An adeno-associated virus was used to overexpress AQP4 and TGN-020 was used to inhibit its function. This research revealed that the glymphatic system was impaired in PND mice and the blunted glymphatic transport was closely associated with the accumulation of inflammatory proteins in the hippocampus. Increasing AQP4 polarization could enhance glymphatic transport and suppresses neuroinflammation, thereby improve cognitive function in the PND model mice. However, a marked impaired glymphatic inflammatory proteins clearance and the more severe cognitive dysfunction were observed when decreasing AQP4 polarization. Therefore, long-term isoflurane anesthesia causes blunted glymphatic system by inducing AQP4 depolarization, enhanced the AQP4 polarization can alleviate the glymphatic system malfunction and reduce the neuroinflammatory response, which may be a potential treatment strategy for PND.

In Vivo Evaluation of Brain [18F]F-FDG Uptake Pattern Under Different Anaesthesia Protocols.

BACKGROUND/AIM: Since the use of anaesthetics has the drawback of altering radiotracer distribution, preclinical positron emission tomography (PET) imaging findings of anaesthetised animals must be carefully handled. This study aimed at assessing the cerebral [18F]F-FDG uptake pattern in healthy Wistar rats under four different anaesthesia protocols using microPET/magnetic resonance imaging (MRI) examinations. MATERIALS AND METHODS: Post-injection of 15±1.2 MBq of [18F]F-FDG, either while awake or during the isoflurane-induced incubation phase was applied. Prior to microPET/MRI imaging, one group of the rats was subjected to forane-only anaesthesia while the other group was anaesthetised with the co-administration of forane and dexmedetomidine/Dexdor® Results: While as for the whole brain it was the addition of dexmedetomidine/Dexdor® to the anaesthesia protocol that generated the differences between the radiotracer concentrations of the investigated groups, regarding the cortex, the [18F]F-FDG accumulation was rather affected by the way of incubation. To ensure the most consistent and highest uptake, forane-induced anaesthesia coupled with an awake uptake condition seemed to be most suitable method of anaesthetisation for cerebral metabolic assessment. Diminished whole brain and cortical tracer accumulation detected upon dexmedetomidine/Dexdor® administration highlights the significance of the mechanism of action of different anaesthetics on radiotracer pharmacokinetics. CONCLUSION: Overall, the standardization of PET protocols is of utmost importance to avoid the confounding factors derived from anaesthesia.

Central Artery Hemodynamics in Angiotensin II-Induced Hypertension and Effects of Anesthesia.

Systemic hypertension is a strong risk factor for cardiovascular, neurovascular, and renovascular diseases. Central artery stiffness is both an initiator and indicator of hypertension, thus revealing a critical relationship between the wall mechanics and hemodynamics. Mice have emerged as a critical animal model for studying effects of hypertension and much has been learned. Regardless of the specific mouse model, data on changes in cardiac function and hemodynamics are necessarily measured under anesthesia. Here, we present a new experimental-computational workflow to estimate awake cardiovascular conditions from anesthetized data, which was then used to quantify effects of chronic angiotensin II-induced hypertension relative to normotension in wild-type mice. We found that isoflurane anesthesia had a greater impact on depressing hemodynamics in angiotensin II-infused mice than in controls, which led to unexpected results when comparing anesthetized results between the two groups of mice. Through comparison of the awake simulations, however, in vivo relevant effects of angiotensin II-infusion on global and regional vascular structure, properties, and hemodynamics were found to be qualitatively consistent with expectations. Specifically, we found an increased in vivo vascular stiffness in the descending thoracic aorta and suprarenal abdominal aorta, leading to increases in pulse pressure in the distal aorta. These insights allow characterization of the impact of regionally varying vascular remodeling on hemodynamics and mouse-to-mouse variations due to induced hypertension.

Neuroprotective effect of erythropoietin on anesthesia-induced neurotoxicity through the modulation of autophagy in Caenorhabditis elegans.

Background: The anti-oxidative, anti-inflammatory, and anti-apoptotic effects of erythropoietin may provide neuroprotective effects. Erythropoietin also modulates autophagy signaling that may play a role in anesthesia-induced neurotoxicity (AIN). Herein, we investigated whether AIN can be attenuated by the neuroprotective effect of erythropoietin in the Caenorhabditis elegans (C. elegans). Methods: Synchronized worms were divided into the control, Iso, EPO, and EPO-Iso groups. The chemotaxis index (CI) was evaluated when they reached the young adult stage. The lgg-1::GFP-positive puncta per seam cell were used to determine the autophagic events. The erythropoietin-mediated pathway of autophagy was determined by measuring the genetic expression level of let-363, bec-1, atg-7, atg-5, and lgg-3. Results: Increased lgg-1::GFP puncta were observed in the Iso, EPO, and EPO-Iso groups. In the Iso group, only the let-363 level decreased significantly as compared to that in the control group (P = 0.009). bec-1 (P < 0.001), atg-5 (P = 0.012), and lgg-3 (P < 0.001) were expressed significantly more in the EPO-Iso group than in the Iso groups. Repeated isoflurane exposure during development decreased the CI. Erythropoietin could restore the decreased CI by isoflurane significantly in the EPO-Iso group. Conclusion: Erythropoietin showed neuroprotective effects against AIN and modulated the autophagic pathway in C. elegans. This experimental evidence of erythropoietin-related neuroprotection against AIN may be correlated with the induced autophagic degradation process that was sufficient for handling enhanced autophagy induction in erythropoietin-treated worms.

Post-Anesthesia Cognitive Dysfunction in Mice Is Associated with an Age-Related Increase in Neuronal Intracellular [Ca2+]-Neuroprotective Effect of Reducing Intracellular [Ca2+]: In Vivo and In Vitro Studies.

Background: Postoperative cognitive dysfunction (POCD) is a common disorder after general anesthesia in elderly patients, the precise mechanisms of which remain unclear. Methods: We investigated the effect of isoflurane with or without dantrolene pretreatment on intracellular calcium concentration ([Ca2+]i), reactive oxygen species (ROS) production, cellular lactate dehydrogenase (LDH) leak, calpain activity, and cognitive function using the Morris water maze test of young (3 months), middle-aged (12-13 months), and aged (24-25 months) C57BL6/J mice. Results: Aged cortical and hippocampal neurons showed chronically elevated [Ca2+]i compared to young neurons. Furthermore, aged hippocampal neurons exhibited higher ROS production, increased LDH leak, and elevated calpain activity. Exposure to isoflurane exacerbated these markers in aged neurons, contributing to increased cognitive deficits in aged mice. Dantrolene pretreatment reduced [Ca2+]i for all age groups and prevented or significantly mitigated the effects of isoflurane on [Ca2+]i, ROS production, LDH leak, and calpain activity in aged neurons. Dantrolene also normalized or improved age-associated cognitive deficits and mitigated the cognitive deficits caused by isoflurane. Conclusions: These findings suggest that isoflurane-induced cytotoxicity and cognitive decline in aging are linked to disruptions in neuronal intracellular processes, highlighting the reduction of [Ca2+]i as a potential therapeutic intervention.