Early-life propofol exposure does not affect later-life GABAergic inhibition, seizure induction, or social behavior.

The early developing brain is especially vulnerable to anesthesia, which can result in long lasting functional changes. We examined the effects of early-life propofol on adult excitatory-inhibitory balance and behavior. Postnatal day 7 male mice were exposed to propofol (250 mg/kg i.p.) and anesthesia was maintained for 2 h; control mice were given the same volume of isotonic saline and treated identically. The behavior and electrophysiology experiments were conducted when the mice were adults. We found that a 2-h neonatal propofol exposure did not significantly reduce paired pulse inhibition, alter the effect of muscimol (3 µM) to inhibit field excitatory postsynaptic potentials or alter the effect of bicuculline (100 µM) to increase the population spike in the CA1 region of hippocampal slices from adult mice. Neonatal propofol did not alter the evoked seizure response to pentylenetetrazol in adult mice. Neonatal propofol did not affect anxiety, as measured in the open field apparatus, depression-like behavior, as measured by the forced swim test, or social interactions with novel mice, in either the three-chamber or reciprocal social tests. These results were different from those with neonatal sevoflurane which demonstrated reduced adult GABAergic inhibition, increased seizure susceptibility and reduced social interaction. Even though sevoflurane and propofol both prominently enhance GABA inhibition, they have unique properties that alter the long-term effects of early-life exposure. These results indicate that clinical studies grouping several general anesthetic agents in a single group should be interpreted with great caution when examining long-term effects.

Risk factors for postoperative thrombosis-related complications in patients undergoing malignant brain tumor resection: a retrospective cohort study.

Introduction: Patients with malignant brain tumors frequently exhibit hypercoagulation and are at a high risk of postoperative thrombosis-related complications. However, the risk factors for postoperative thrombosis-related complications remain unclear. Methods: In this retrospective, observational study, we consecutively enrolled elective patients undergoing resection of malignant brain tumors from 26 November 2018 to 30 September 2021. The primary objective of the study was to identify risk factors for a composite of three major adverse events including postoperative lower limb deep venous thrombosis, pulmonary embolism, and cerebral ischemia. Results: A total of 456 patients were enrolled in this study, where 112 (24.6%) patients had postoperative thrombosis-related complications, 84 (18.4%) with lower limb deep venous thrombosis, 0 (0.0%) with pulmonary embolism, and 42 (9.2%) with cerebral ischemia. In a multivariate model, age more than 60 years (OR: 3.98, 95% CI: 2.30-6.88, P < 0.001), preoperative abnormal APTT (OR: 2.81, 95% CI: 1.06-7.42, P = 0.037), operation duration longer than 5 h (OR: 2.36, 95% CI: 1.34-4.16, P = 0.003), and admission to ICU (OR: 2.49, 95% CI: 1.21-5.12, P = 0.013) were independent risk factors of the postoperative deep vein thrombosis. Intraoperative plasma transfusion (OR: 6.85, 95% CI: 2.73-17.18, P < 0.001) was associated with significantly increased odds of deep vein thrombosis. Conclusion: Patients with craniocerebral malignant tumors have a high incidence of postoperative thrombosis-related complications. There is an increase in the odds of postoperative lower limb deep venous thrombosis in patients; over 60 years old, with preoperative abnormal APTT, undergoing surgeries longer than 5-h, admission to ICU, or receiving intraoperative plasma infusion. Fresh frozen plasma infusion should be used more cautiously, especially in patients with a high risk of thrombosis.

Ultrasound-guided superficial cervical plexus block reduces opioid consumption in patients undergoing craniotomy via suboccipital retrosigmoid approach: a randomized controlled trial.

INTRODUCTION: The effectiveness of superficial cervical plexus block (SCPB) at decreasing opioid use and improving hemodynamic stability during suboccipital retrosigmoid craniotomy has not been established. The aim of this study is to evaluate the analgesic effect of preoperative ultrasound-guided SCPB for craniotomy via a suboccipital retrosigmoid approach. METHODS: This was a prospective, single-center, randomized, double-blind, parallel-group controlled trial. One hundred and six adult patients undergoing suboccipital retrosigmoid craniotomy were randomly allocated into either the SCPB group (n=53) to receive 10 mL of 0.5% ropivacaine or the control group (n=53) to receive 0.9% normal saline injected into the superficial layer of prevertebral fascia guided by ultrasound. The primary outcome was the cumulative consumption of sufentanil with patient-controlled intravenous analgesia (PCIA) within 24 hours. Secondary outcomes included the overall perioperative consumption of opioids, the area under the curve of the pain score from 1 hour to 48 hours (AUC1-48), intraoperative hemodynamic parameters, and anesthesia depth. RESULTS: The mean PCIA pump cumulative consumption of sufentanil in the first 24 hour postoperative period was significantly lowered by SCPB (5.0 µg vs 9.8 µg, 95% CI: -8.0 to -2.4; p=0.001). The total perioperative consumption of sufentanil (45.0 µg vs 54.5 µg, 95% CI: -14.8 to -4.1; p=0.001) was also significantly decreased by SCPB. The incidence of severe pain within 24 hours was decreased by SCPB (7.5% vs 26.4%, p=0.01). SCPB significantly decreased the AUC1-48 of the pain score. Intraoperative hemodynamic parameters and anesthesia depth were similar between groups (p>0.05). DISCUSSION: SCPB provides effective analgesia in patients undergoing craniotomy and tumor resection via suboccipital retrosigmoid approach. SCPB demonstrates an opioid-sparing effect and allows for the maintenance hemodynamic stability at an appropriate depth of anesthesia. TRIAL REGISTRATION NUMBER: NCT04036812.

Exposure to Sevoflurane, But Not Ketamine, During Early-life Brain Development has Long-Lasting Effects on GABAA Receptor Mediated Inhibitory Neurotransmission.

Understanding the different mechanisms associated with different anesthetic targeted receptors is critical towards identifying accurate long-term outcome measures as a result of early-life anesthetic exposure. We examined changes in GABAA receptor mediated neurotransmission by a predominately GABAA receptor targeted anesthetic, sevoflurane or a predominately NMDA receptor targeted anesthetic, ketamine. Postnatal day 7 male mice were exposed to sevoflurane or ketamine and examined as adults for changes in inhibitory neurotransmission and its associated change in induced seizure activity. Paired pulse stimulation experiment showed that early-life sevoflurane treated mice had significantly less hippocampal CA1 inhibition later in life. There was significantly increased CA1 excitatory output in the sevoflurane treated group compared to the no sevoflurane treated group after the GABA agonist muscimol. Similar to our previously established data for early-life sevoflurane, here we established early-life ketamine administration resulted in neurodevelopmental behavioral changes later in life. However, muscimol did not produce a significant difference on the excitatory CA1 output between early-life ketamine group and saline group. While sevoflurane treated mice showed significantly higher induced seizure intensities and shorter latency periods to reach seizure intensity stage 5 (Racine score) compared with no sevoflurane treated mice, this phenomenon was not observed in the ketamine vs. saline treated groups. Early-life sevoflurane, but not ketamine, exposure reduced GABAergic inhibition and enhanced seizure activity later in life. The results indicate that early-life exposure to different anesthetics lead to distinct long-term effects and their unique pathways require mechanistic studies to understand induced long-lasting changes in the brain.

Neonatal anesthesia exposure impacts brain microRNAs and their associated neurodevelopmental processes.

MicroRNAs (miRNAs), when subjected to environmental stimuli, can exhibit differential expression. As critical regulators of gene expression, differential miRNA expression has been implicated in numerous disorders of the nervous system. In this study, we focused on the effect of a general anesthetic, as an environmental stimulus, on miRNA expression of the developing brain. General anesthetics have potential long-lasting neurotoxic effects on the developing brain, resulting in behavioral changes in adulthood. We first carried out an unbiased profiling approach to examine the effect of single-episode neonatal general anesthetic, sevoflurance (sevo), exposure on miRNA expression of the brain. Neonatal sevo has a significant effect on the expression of specific miRNAs of the whole brain and the hippocampus that is both immediate - directly after neonatal treatment, as well as long-lasting - during adulthood. Functionally, neonatal sevo-associated miRNA gene-targets share potential neurodevelopmental pathways related to axon guidance, DNA transcription, protein phosphorylation and nervous system development. Our understanding on the role of miRNAs provides a putative epigenetic/molecular bridge that links neonatal general anesthetic's effect with its associated functional change.

Sevoflurane Blocks the Induction of Long-term Potentiation When Present during, but Not When Present Only before, the High-frequency Stimulation.

BACKGROUND: This study tests the hypothesis that sevoflurane blocks long-term potentiation only if it is present during the high-frequency stimulation that induces long-term potentiation. METHODS: Long-term potentiation, an electrophysiologic correlate of memory, was induced by high-frequency stimulation and measured as a persistent increase in the field excitatory postsynaptic potential slope in the CA1 region. RESULTS: Long-term potentiation was induced in the no sevoflurane group (171 ± 58% vs. 96 ± 11%; n = 13, mean ± SD); when sevoflurane (4%) was present during the high-frequency stimulation, long-term potentiation was blocked (92 ± 22% vs. 99 ± 7%, n = 6). While sevoflurane reduced the size of the field excitatory postsynaptic potential to single test stimuli by 59 ± 17%, it did not significantly reduce the size of the field excitatory postsynaptic potentials during the 100 Hz high-frequency stimulation. If sevoflurane was removed from the artificial cerebrospinal fluid superfusing the slices 10 min before the high-frequency stimulation, then long-term potentiation was induced (185 ± 48%, n = 7); this was not different from long-term potentiation in the no sevoflurane slices (171 ± 58). Sevoflurane before, but not during, ⊖-burst stimulation, a physiologic stimulus, did not block the induction of long-term potentiation (151 ± 37% vs. 161 ± 34%, n = 7). CONCLUSIONS: Sevoflurane blocks long-term potentiation formation if present during the high-frequency stimulation; this blockage of long-term potentiation does not persist if sevoflurane is discontinued before the high-frequency stimulation. These results may explain why short periods of insufficient sevoflurane anesthesia may lead to recall of painful or traumatic events during surgery.

Early-life single-episode sevoflurane exposure impairs social behavior and cognition later in life.

BACKGROUND: Single-episode anesthetic exposure is the most prevalent surgery-related incidence among young children in the United States. Although numerous studies have used animals to model the effects of neonatal anesthetics on behavioral changes later on in life, our understanding of the functional consequences to the developing brain in a comprehensive and clinically relevant manner is unclear. METHODS: The volatile anesthetic, sevoflurane (sevo) was administered to C57BL6 postnatal day 7 (P7) mice in a 40% oxygen and 60% nitrogen gas mixture. In order to examine the effects of sevo alone on the developing brain in a clinically relevant manner, mice were exposed to an average of 2.38 ± 0.11% sevo for 2 h. No sevo (control) mice were treated in an identical manner without sevo exposure. Mice were examined for cognition and neuropsychiatric-like behavioral changes at 1-5 months of age. RESULTS: Using the active place avoidance (APA) test and the novel object recognition (NOR) test, we demonstrated that P7 sevo-treated mice showed a deficit in learning and memory both during periadolescence and adulthood. We then employed a battery of neuropsychiatric-like behavioral tests to examine social interaction, communication, and repetitive behavior. Interestingly, compared to the no-sevo-treated group, sevo-treated mice showed significant reductions in the time interacting with a novel mouse (push-crawl and following), time and interaction in a chamber with a novel mouse, and time sniffing a novel social odor. CONCLUSIONS: Our study established that single-episode, 2-h sevo treatment during early life impairs cognition later on in life. With this approach, we also observed neuropsychiatric-like behavior changes such as social interaction deficits in the sevo-treated mice. This study elucidated the effects of a clinically relevant single-episode sevo application, given during the neonatal period, on neurodevelopmental behavioral changes later on in life.

Lidocaine Reduces Acute Postoperative Pain After Supratentorial Tumor Surgery in the PACU: A Secondary Finding From a Randomized, Controlled Trial.

BACKGROUND: Perioperative lidocaine infusion has been reported to reduce postoperative pain in patients after abdominal surgery; however, no study has examined lidocaine's effect on acute postoperative pain after supratentorial tumor surgery. METHODS: A total of 94 patients scheduled for supratentorial craniotomy were enrolled. Patients received either lidocaine through an intravenous bolus (1.5 mg/kg) after induction followed by infusion at a rate of 2 mg/kg/h until the end of surgery or the same volume of normal saline. Mean arterial blood pressure, heart rate, and bispectral index were recorded at different intraoperative time points. Patients were assessed for pain in the postoperative anesthesia care unit (PACU) by the numeric rating scale (NRS). Other complications including hypertension, tachycardia, dysphoria, and postoperative nausea and vomiting (PONV) were reported. RESULTS: There was no significant difference between the normal saline and lidocaine group for mean arterial blood pressure, heart rate, and bispectral index at any time point (P>0.05). There was no significant difference in the incidence of hypertension, tachycardia, dysphoria, and PONV between groups (P>0.05). The incidence of mild pain (NRS between 1 and 3) after surgery in PACU was lower in lidocaine group than that in the normal saline group (P=0.014); the number of patients with an NRS pain score of 0 before leaving the PACU was significantly greater in the lidocaine group. No patient in either group had moderate or severe pain. CONCLUSIONS: Intraoperative infusion of lidocaine significantly decreases the proportion of patients with acute pain after supratentorial tumor surgery in the PACU.

Lidocaine Did Not Reduce Neuropsychological-Cognitive Decline in Patients 6 Months After Supratentorial Tumor Surgery: A Randomized, Controlled Trial.

UNLABELLED: : There is equivocal evidence examining cognitive improvement in response to lidocaine during cardiac surgery; however, no study has examined its effect on postoperative neuropsychological-cognitive decline after supratentorial tumor surgery. METHODS: Ninety-four patients scheduled for supratentorial craniotomy were enrolled. Patients received either a dose of lidocaine (2%) via an intravenous bolus (1.5 mg/kg) after induction followed by an infusion at a rate of 2 mg/kg/h until the end of surgery (Lidocaine group) or the same volume of normal saline. The neuropsychological-cognitive decline was evaluated using the following tests: the Mini-Mental State Examination, the Information-Memory-Concentration test, the Hamilton Rating Scale for Depression, and the Hamilton Rating Scale for Anxiety. The cerebral oxygen extraction ratio and the difference in lactic acid levels between the bulb of the jugular vein and a peripheral artery were measured. RESULTS: Eighty patients completed the neuropsychological tests, with 40 patients in each group. The incidence of postoperative decline at up to 6 months in the Lidocaine group was not significantly different than that in the Normal saline group. When the 2 cognitive tests were examined independent of the other tests, there was no difference between groups at 6 months. The cerebral oxygen extraction ratio was significantly lower in the Lidocaine group after surgery (P<0.05), and the arteriovenous difference of lactic acid was lower in the Lidocaine group (P<0.05). CONCLUSIONS: Intraoperative infusion of lidocaine does not significantly decrease the incidence of postoperative neuropsychological-cognitive decline in patients 6 months after supratentorial tumor surgery.

Sevoflurane preconditioning attenuates the fall in adenosine triphosphate levels, but does not alter the changes in sodium and potassium levels during hypoxia in rat hippocampal slices.

BACKGROUND: Sevoflurane preconditioning improves recovery after hypoxia. Sevoflurane administered before and during hypoxia improved recovery and attenuated the changes in intracellular sodium, potassium, and adenosine triphosphate (ATP) levels during hypoxia. In this study, the authors examine the effects of sevoflurane applied only before hypoxia on sodium, potassium, and ATP. METHODS: Hippocampal slices from adult male Sprague-Dawley rats were pretreated with 4% sevoflurane, washed, and then subjected to hypoxia (n≥8 animals/group). The cornus ammonis 1 regions of the hippocampal slices were micro-dissected and sodium, potassium, and ATP concentrations measured. RESULTS: Pretreatment with sevoflurane for 15 or 60 min did not attenuate the increase in intracellular sodium or the decrease in intracellular potassium during hypoxia. After 60 min of preconditioning and 5 min of hypoxia, sodium increased 57% (vs. nonpreconditioned hypoxia 54% increase) and potassium decreased 31% (vs. 26%). These changes were not statistically significant versus untreated hypoxia. The 60-min sevoflurane preconditioning group had statistically significant higher ATP levels at 5 min of hypoxia (3.8 nmol/mg dry wt.) when compared to untreated hypoxic tissue (2.1 nmol/mg). There was no significant difference in ATP levels between the sevoflurane preconditioned and the untreated tissue before hypoxia (8.9 vs. 8.5 nmoles/mg, respectively). CONCLUSION: Preconditioning with sevoflurane for 60 min before hypoxia does not alter changes in intracellular sodium and potassium during hypoxia but does attenuate the fall in intracellular ATP levels during hypoxia. Thus, there are differences between anesthetic preconditioning and when anesthetics are present before and during hypoxia.

Metabotropic actions of the volatile anaesthetic sevoflurane increase protein kinase M synthesis and induce immediate preconditioning protection of rat hippocampal slices.

Anaesthetic preconditioning occurs when a volatile anaesthetic, such as sevoflurane, is administered before a hypoxic or ischaemic insult; this has been shown to improve neuronal recovery after the insult. We found that sevoflurane-induced preconditioning in the rat hippocampal slice enhances the hypoxic hyperpolarization of CA1 pyramidal neurons, delays and attenuates their hypoxic depolarization, and increases the number of neurons that recover their resting and action potentials after hypoxia. These altered electrophysiological effects and the improved recovery corresponded with an increase in the amount of a constitutively active, atypical protein kinase C isoform found in brain, protein kinase M zeta (PKMζ). A selective inhibitor of this kinase, zeta inhibitory peptide (ZIP), blocked the increase in the total amount of PKMζ protein and the amount of the activated form of this kinase, phospho-PKMζ (p-PKMζ); it also blocked the altered electrophysiological effects and the improved recovery. We found that both cycloheximide, a general protein synthesis inhibitor, and rapamycin, a selective inhibitor of the mTOR pathway for regulating protein synthesis, blocked the increase in p-PKMζ, the electrophysiological changes, and the improved recovery due to sevoflurane-induced preconditioning. Glibenclamide, a KATP channel blocker, when present only during the hypoxia, prevented the enhanced hyperpolarization, the delayed and attenuated hypoxic depolarization, and the improved recovery following sevoflurane-induced preconditioning. To examine the function of persistent PKMζ and KATP channel activity after the preconditioning was established, we administered 4% sevoflurane for 30 min and then discontinued it for 30 min before 10 min of hypoxia. When either tolbutamide, a KATP channel blocker, or ZIP were administered at least 15 min after the washout of sevoflurane, there was little recovery compared with sevoflurane alone. Thus, continuous KATP channel and PKMζ activity are required to maintain preconditioning protection. We conclude that sevoflurane induces activation of the mTOR pathway, increasing the new protein synthesis of PKMζ, which is constitutively phosphorylated to its active form, leading to an increased KATP channel-induced hyperpolarizaton. This hyperpolarization delays and attenuates the hypoxic depolarization, improving the recovery of neurons following hypoxia. Thus, sevoflurane acts via a metabotropic pathway to improve recovery following hypoxia.

Posthypoxic moderate hypothermia improves electrophysiological recovery in the rat hippocampal slice.

BACKGROUND: Animal studies have shown that prehypoxic or intrahypoxic hypothermia is protective against hypoxic neuronal injury, whereas posthypoxic hypothermia produced divergent findings. This study examined the protective effects of posthypoxic hypothermia on the electrophysiological recovery in the rat hippocampal slice. METHODS: Eighty-three male Sprague-Dawley rats were used after approval of the Institutional Animal Care and Use Committee. Hippocampal slices were obtained and electrophysiological recordings from the CA1 pyramidal cell layer were used as an indicator of cell function. Moderate hypothermia (30°C) was used for only 30 minutes after hypoxia in the study group, whereas normothermia was maintained throughout the experiment in the control group. Three different periods of hypoxia were used (3, 3.5, and 4 min). Recovery was measured as the ratio of the amplitude of the population spike at the end of 2 hours of recovery to that of the baseline that was obtained immediately before hypoxia. RESULTS: Posthypoxic hypothermia improved electrophysiological recovery in slices exposed to 3 minutes of hypoxia but not in those exposed to 3.5 or 4 minutes of hypoxia. CONCLUSIONS: Moderate hypothermia (30°C) applied after hypoxia is protective against short periods (3 min) of hypoxia but not after slightly longer periods (3.5 or 4 min) of hypoxia.

Effects of midazolam on brain injury after transient focal cerebral ischemia in rats*.

The benzodiazepine, midazolam, is commonly used for sedation and anesthesia in the operating room and the intensive care unit where there is a risk of cerebral ischemia. We therefore examined its ability to reduce damage subsequent to cerebral ischemia. Male Wistar rats were randomly assigned to a high-dose midazolam group or a matched vehicle group and a lower dose of midazolam group or a matched vehicle group. The rats underwent 90 minutes of middle cerebral artery occlusion. In the midazolam groups, the first dose of midazolam (10 or 25 mg/kg) was given by a 10-minute intravenous infusion before ischemia; a second dose of (1/2) the initial dose (5 or 12.5 mg/kg) was given 1 hour after the onset of ischemia. In the vehicle groups, a similar volume of vehicle was given at the same time intervals. Infarct size, NeuN immunopositive cells in the ischemic penumbral and core regions, and neurologic outcome were determined 7 days after ischemia. Compared with vehicle-treated rats, the higher-dose midazolam (25 mg/kg)-treated rats had a smaller infarct size (93.9+/-63.5 mm vs. 152.0+/-53.7 mm, P<0.05), more NeuN immunopositive cells in the ischemic core region (206.7+/-211.3/mm vs. 40.0+/-66.3/mm, P<0.01), and better neurologic outcome (P<0.05). Midazolam at a lower dose (10 mg/kg) had no significant effects. Although midazolam generated dose-dependent hemolysis, this hemolysis was transient. Midazolam (25 mg/kg) caused a loss of the righting reflex in rats that lasted until 19.9+/-1.3 min after the injection, the anesthetic dose of midazolam in rats is approximately 100x greater than the anesthetic dose for humans. An anesthetic dose of midazolam in rats reduced neuronal damage and improved neurologic outcome 7 days after focal cerebral ischemia, however, it also caused transient hemolysis.

Pre- or postinsult administration of lidocaine or thiopental attenuates cell death in rat hippocampal slice cultures caused by oxygen-glucose deprivation.

UNLABELLED: Lidocaine and thiopental improve recovery when administrated during hypoxia and ischemia; however, the effect of pre- or postinsult treatment alone is unknown. We applied either lidocaine or thiopental to hippocampal slice cultures from 20-day-old rats either before or after 10 min of oxygen-glucose deprivation (OGD). Propidium iodide (PI) fluorescence was used as an indicator of neuronal death for 7 days after OGD. OGD-induced neuronal death, in both the Cornus Ammonis 1 (CA1) and the dentate gyrus regions, peaked the first day after ischemia. Preinsult administration of either lidocaine (10, 100 microM) or thiopental (250, 600 microM) significantly reduced the damage measured on the first and second days after OGD; these drugs also significantly decreased the summed daily post-OGD PI fluorescence in both regions. Postinsult administration of lidocaine (10, 100 microM) or thiopental (250, 600 microM) significantly decreased the PI fluorescence on the first day after OGD; postinsult administration of these drugs also attenuated the summed daily post-OGD PI. These data indicate that the administration of lidocaine or thiopental either before or directly after OGD reduced neuronal damage in this in vitro model of cerebral ischemia. Postischemic administration is frequently the first opportunity for treatment. IMPLICATIONS: Lidocaine or thiopental applied either 10 min before or 10 min directly after oxygen-glucose deprivation reduced neuronal cell death in rat hippocampal slice cultures. Postinsult administration is often the first opportunity for treatment after stroke; lidocaine and thiopental reduced damage caused by oxygen-glucose deprivation, an in vitro model of stroke.

Magnesium blocks the loss of protein kinase C, leads to a transient translocation of PKC(alpha) and PKC(epsilon), and improves recovery after anoxia in rat hippocampal slices.

Magnesium is a potent neuroprotective agent against damage to synaptic transmission during cerebral anoxia and reoxygenation. We investigated the mechanisms of anoxic transmission damage and magnesium neuroprotection by examining the response of PKC isoforms to an anoxic insult in the rat hippocampal slice model. A 2-min anoxic period, which resulted in almost complete recovery of synaptic function, did not result in PKC downregulation. In contrast, inducing long-term damage with 10-min anoxia resulted in the downregulation of the conventional PKCs betaI, betaII and gamma immediately after the insult and after 1-h reoxygenation. There was additional loss of PKC(alpha) and PKC(epsilon) after 1-h reoxygenation. Magnesium treatment improved the recovery of synaptic transmission, blocked the loss of PKC and resulted in a transient translocation of PKC(alpha) and PKC(epsilon) to the membrane fraction. Selective downregulation of cPKCs and PKC(epsilon) correlated with permanent damage to synaptic transmission while translocation of PKC(alpha) and PKC(epsilon) correlated with preservation of synaptic function. The mechanisms of magnesium neuroprotection may include altering the PKC response to an anoxic insult.

Activation of protein kinase C contributes to the isoflurane-induced improvement of functional and metabolic recovery in isolated ischemic rat hearts.

Isoflurane enhances myocardial functional recovery and improves energy levels after ischemia. We sought to determine whether isoflurane-induced cardioprotection is mediated by protein kinase C (PKC). The Langendorff model was used, and isolated perfused rat hearts were separated into untreated, isoflurane, chelerythrine (PKC inhibitor) plus isoflurane, and chelerythrine groups. All hearts were subjected to treatment before ischemia, followed by 30 min of ischemia and 60 min of reperfusion. We recorded hemodynamic variables, measured metabolites by high-performance liquid chromatography, and analyzed subcellular localization of PKC isoforms by Western blot analysis. Isoflurane significantly improved the recovery of left ventricular developed pressure, attenuated the depletion of myocardial adenosine triphosphate (ATP) and creatine phosphate at 15 min of ischemia, enhanced the recovery of myocardial ATP and creatine phosphate concentrations after ischemia, and was associated with the translocation of PKC-delta and -epsilon to the membrane. Chelerythrine suppressed the translocation of PKC-delta and -epsilon and blocked the improvement of cardiac function and ATP. We conclude that isoflurane delays the decrease in ATP during ischemia and improves the recovery of mechanical function and the energy state 60 min after ischemia. These effects of isoflurane are dependent on the activation of PKC.

Small physiologic changes in calcium and magnesium alter excitability and burst firing of CA1 pyramidal cells in rat hippocampal slices.

The effects of small physiologic changes in Ca and Mg concentrations on neuronal burst firing were examined. Intracellular electrophysiologic recordings were made from CA1 pyramidal neurons in rat hippocampal slices. There was no difference in the resting potential or the input resistance of neurons bathed in the lower Ca-Mg artificial Cerebrospinal fluid (aCSF) (1.4 mM Ca; 1.3 mM Mg) compared with the higher Ca-Mg aCSF (2 mM Ca; 2 mM Mg). However, neurons in the lower Ca-Mg aCSF, but not the higher Ca-Mg aCSF, demonstrated depolarizing waves and bursts of action potentials; no single component of the aCSF accounted for this difference. Reducing the Ca from 2 to 1 mM in the higher Ca-Mg aCSF increased the mean frequency of action potentials from 28 to 171 Hz; the addition of 6-cyano-7-nitroquinoxaline-2,3-dione did not reduce the frequency. The threshold of potassium for inducing bursts was 5.25 with 1 mM Ca, 7.25 with 2 mM Ca, and 11.25 with 3 mM Ca. When Mg was reduced from 2 to 1 mM, the number of potassium-induced bursts increased to 190%; increasing Mg from 2 to 3 mM reduced the bursts to 58% (frequency with 2 mM Mg set to 100%). Small decreases in extracellular Ca and/or Mg led to increased excitability and burst firing, which may alter physiologic and pathophysiologic processes such as enhancing long-term potentiation, pain transmission, epileptogenesis, and neuronal damage and decreasing anesthetic potency. Increases in extracellular Ca and/or Mg would have the opposite effect on these processes. These effects of extracellular divalent ions on burst firing may explain some of the pathophysiologic effects of hypocalcemia and hypomagnesemia.

Effects of delayed administration of low-dose lidocaine on transient focal cerebral ischemia in rats.

BACKGROUND: The authors' previous study demonstrated that a clinical antiarrhythmic dose of lidocaine, when given before ischemia, is neuroprotective in a rat model of transient focal cerebral ischemia. In this study, the authors investigated whether the administration of this dose of lidocaine, when delayed until 45 min after the onset of ischemia, also reduces ischemic brain injury. METHODS: Lidocaine was administered as an intravenous bolus (1.5 mg/kg) followed by an intravenous infusion (2 mg. kg(-1).h(-1)) for 165 min, beginning 45 min after the onset of a 90-min period of transient focal cerebral ischemia. Control animals were given the same volume of saline. Focal cerebral ischemia was induced by occluding the right middle cerebral artery using an intraluminal suture. Neurologic outcome and body weight loss were quantified 7 days later. The brain was fixed 7 days after ischemia and brain sections were stained with hematoxylin and eosin for assessment of infarct size and the number of intact neurons. In separate experiments, local cerebral blood flow and the electroencephalogram were measured during ischemia and 180 min into the reperfusion period. Infarct size was assessed after 24 h. RESULTS: Infarct size, at either 24 h or 7 days after ischemia, was not significantly reduced in the lidocaine group. However, the number of intact neurons was significantly increased in both the ischemic penumbra and core of the lidocaine group 7 days after ischemia, compared with the vehicle group. Rats treated with lidocaine demonstrated better neurologic outcome and less weight loss (P < 0.05). Lidocaine treatment had no significant influence on local cerebral blood flow and electroencephalogram during ischemia and reperfusion. CONCLUSIONS: Administration of a clinical antiarrhythmic dose of lidocaine, beginning 45 min after the onset of ischemia, reduces ischemic brain injury after transient focal cerebral ischemia in the rat. This indicates that delayed administration of neuroprotective agents may reduce brain damage resulting from ischemia.

Sevoflurane improves electrophysiological recovery of rat hippocampal slice CA1 pyramidal neurons after hypoxia.

Sevoflurane is a volatile anesthetic agent that reduces cerebral metabolism and thereby may reduce neuronal damage during energy deprivation. We have examined the effect of sevoflurane on hypoxic neuronal damage in rat hippocampal slices. Slices were subjected to 0%, 2%, or 4% sevoflurane 10 minutes before, during, and 10 minutes after hypoxia. The Schaffer collateral pathway was stimulated every 10 seconds and the evoked population spike recorded in the CA1 pyramidal cell region throughout the experiment. During hypoxia, the postsynaptic evoked response was blocked. The time until the blockade of this response in the 0% sevoflurane group was 158 seconds. Sevoflurane (4%) significantly delayed the loss of the evoked response during hypoxia (242 seconds). The percent recovery of the postsynaptic population spike was calculated by dividing the size of the response 120 minutes after hypoxia by its prehypoxic, presevoflurane amplitude. There was no recovery of the population spike in the 0% sevoflurane group 120 minutes after the end of 5 minutes of hypoxia (6 +/- 6%); there was significantly better recovery after 5 minutes of hypoxia in the sevoflurane (4%) treated group (40 +/- 9%). A lower concentration of sevoflurane (2%) delayed the loss of evoked response during hypoxia (191 seconds), but it did not significantly affect recovery of the population spike after hypoxia (7 +/- 7%). Hypoxia irreversibly damages electrophysiologic activity. A high, but clinically usable, concentration of sevoflurane increases the time during hypoxia until the postsynaptic evoked response is blocked and improves recovery of this response after 5 minutes of hypoxia.