Effects of Intranasal Dantrolene Nanoparticles on Brain Concentration and Behavior in PS19 Tau Transgenic Mice.

Background: Repurposing dantrolene to treat Alzheimer's disease has been shown to be effective in amyloid transgenic mouse models but has not been examined in a model of tauopathy. Objective: The effects of a nanoparticle intranasal formulation, the Eagle Research Formulation of Ryanodex (ERFR), in young adult and aged wild type and PS19 tau transgenic mice was investigated. Methods: The bioavailability of intranasal ERFR was measured in 2 and 9-11-month-old C57BL/6J mice. Blood and brain samples were collected 20 minutes after a single ERFR dose, and the plasma and brain concentrations were analyzed. Baseline behavior was assessed in untreated PS19 tau transgenic mice at 6 and 9 months of age. PS19 mice were treated with intranasal ERFR, with or without acrolein (to potentiate cognitive dysfunction), for 3 months, beginning at 2 months of age. Animal behavior was examined, including cognition (cued and contextual fear conditioning, y-maze), motor function (rotarod), and olfaction (buried food test). Results: The dantrolene concentration in the blood and brain decreased with age, with the decrease greater in the blood resulting in a higher brain to blood concentration ratio. The behavioral assays showed no significant changes in cognition, olfaction, or motor function in the PS19 mice compared to controls after chronic treatment with intranasal ERFR, even with acrolein. Conclusions: Our studies suggest the intranasal administration of ERFR has higher concentrations in the brain than the blood in aged mice and has no serious systemic side effects with chronic use in PS19 mice.

Effects of intranasal dantrolene nanoparticles on brain concentration and behavior in PS19 tau transgenic mice.

Background: Repurposing dantrolene as a potential disease-modifying treatment for Alzheimer's disease has been shown to be effective in amyloid transgenic mouse models but has not been examined in a model of tauopathy. Objective: The effects of a nanoparticle intranasal formulation, the Eagle Research Formulation of Ryanodex (ERFR), in young adult and aged wild type and PS19 tau transgenic mice was investigated. Methods: The bioavailability of intranasal ERFR was measured in 2 months and 9-12 month old C57BL/6J male mice. Mice received a single intranasal dose of ERFR and, after 20 min, blood and brain samples were collected. Dantrolene concentrations in the plasma and brain were analyzed by High Performance Liquid Chromatography. Animal behavior was examined in PS19 tau transgenic mice, with/without acrolein treatment to exacerbate cognitive deficits. Behavioral tests included cognition (cued and contextual fear conditioning, y-maze), motor function (rotarod), and olfaction (buried food test). Results: Dantrolene concentration in the blood and brain decreased with age, though the decrease was greater in the blood resulting in a higher brain to blood concentration ratio. The behavioral assays showed no significant changes in cognition, olfaction or motor function in the PS19 mice compared to controls after chronic ERFR treatment even with acrolein treatment. Conclusion: Our studies suggest that while we did not find PS19 mice to be a reliable Alzheimer animal model to test the therapeutic efficacy of dantrolene, the results suggest a potential for ERFR to be an effective chronic therapy for Alzheimer's disease and that further studies are indicated.

Anesthetic Effects on the Progression of Parkinson Disease in the Rat DJ-1 Model.

BACKGROUND: Parkinson disease is a chronic and progressive movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The causes of Parkinson disease are not clear but may involve genetic susceptibilities and environmental factors. As in other neurodegenerative disorders, individuals predisposed to Parkinson disease may have an accelerated onset of symptoms following perioperative stress such as anesthesia, surgery, pain, and inflammation. We hypothesized that anesthesia alone accelerates the onset of Parkinson disease-like pathology and symptoms. METHODS: A presymptomatic Parkinson rat model (the protein, DJ-1, encoded by the Park7 gene [DJ-1], PARK7 knockout) was exposed to a surgical plane of isoflurane or 20% oxygen balanced with nitrogen for 2 hours on 3 occasions between 6 and 7 months of age. Acute and long-term motor and neuropathological effects were examined from 7 to 12 months of age in male DJ-1 rats, using the ladder rung, rotarod, and novel object recognition assays, as well as the immunohistochemical localization of tyrosine hydroxylase in dopaminergic neurons in the substantia nigra and ionized calcium-binding adaptor protein-1 (Iba-1) microglial activation in the substantia nigra and hippocampus. RESULTS: In the acute group, after the third anesthetic exposure at 7 months of age, the isoflurane group had a significant reduction in the density of dopaminergic neurons in the SNpc compared to controls. However, this reduction was not associated with increased microglial activation in the hippocampus or substantia nigra. With the ladder rung motor skills test, there was no effect of anesthetic exposure on the total number of foot faults or the ladder rung pattern in the acute group. The rotarod test also detected no differences before and after the third exposure in controls. For the long-term group, immunohistochemical analyses detected no differences in the density of dopaminergic neurons or microglial cells compared to unexposed DJ-1 rats from 8 to 12 months of age. The ladder rung test in the long-term group showed no differences in the total number of foot faults with time and exposure or between ladder rung patterns. The rotarod test detected no significant effect of exposure with time or between groups at any time point. The novel object recognition task in the long-term group revealed no differences in short- or long-term memory or in the number of rearings as a function of exposure. CONCLUSIONS: Multiple isoflurane exposures in this rat model of Parkinson disease transiently enhanced dopaminergic neurodegeneration in the SNpc that resolved over time and had no effects on progression in this Parkinson disease-like phenotype.

Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice.

BACKGROUND/OBJECTIVE: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice. METHODS: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration. RESULTS: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice. CONCLUSIONS: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality.

Intranasal administration of dantrolene increased brain concentration and duration.

Dantrolene has been demonstrated to be neuroprotective for multiple neurodegenerative diseases. However, dantrolene's limited penetration into the CNS hampers its effectiveness as a neuroprotective agent. Here, we studied whether the intranasal administration of dantrolene provided better penetration into the brain than the commonly used oral approach. C57BL/6 mice, aged 2-4 months, received a single dose of either intranasal or oral dantrolene (5mg/kg). Inhibition of dantrolene clearance from the brain was examined by co-administration with P-gp/BCRP inhibitors, nimodipine or elacridar. The concentration of dantrolene in the brain and plasma was measured at 10, 20, 30, 50, 70, 120, 150 and 180 minutes after administration. Separate cohorts of mice were given intranasal dantrolene (5mg/kg) or vehicle, 3 times/ week, for either 3 weeks or 4 months, to examine potential adverse side effects on olfaction and motor coordination, respectively. We found that Dantrolene concentrations were sustained in the brain after intranasal administration for 180 min, while concentrations fell to zero at 120 min for oral administration. Chronic use of intranasal dantrolene did not impair olfaction or motor function in these mice. Blood brain barrier pump inhibitors did not further increase dantrolene peak concentrations in the brain. Our results suggested that Intranasal administration of dantrolene is an effective route to increase its concentration and duration in the brain compared to the oral approach, without any obvious side effects on olfaction or motor function.

Perioperative Neurocognitive Disorder: State of the Preclinical Science.

The purpose of this article is to provide a succinct summary of the different experimental approaches that have been used in preclinical postoperative cognitive dysfunction research, and an overview of the knowledge that has accrued. This is not intended to be a comprehensive review, but rather is intended to highlight how the many different approaches have contributed to our understanding of postoperative cognitive dysfunction, and to identify knowledge gaps to be filled by further research. The authors have organized this report by the level of experimental and systems complexity, starting with molecular and cellular approaches, then moving to intact invertebrates and vertebrate animal models. In addition, the authors' goal is to improve the quality and consistency of postoperative cognitive dysfunction and perioperative neurocognitive disorder research by promoting optimal study design, enhanced transparency, and "best practices" in experimental design and reporting to increase the likelihood of corroborating results. Thus, the authors conclude with general guidelines for designing, conducting and reporting perioperative neurocognitive disorder rodent research.

Stroke 112: A Universal Stroke Awareness Program to Reduce Language and Response Barriers.

BACKGROUND AND PURPOSE: To improve stroke awareness and reduce life-threatening prehospital delays worldwide, a universal stroke educational program is needed. To meet this unmet need, we developed a universal program without language barriers and tested its acceptance in Taiwan, where Chinese is the native language. METHODS: Stroke 112 was developed using the universal emergency phone number, 112. The numbers imply an emergency and correspond to the 3 stroke recognition signs used in FAST (Face, Arm, Speech, and Time): 1 uneven face (crooked mouth); 1 weak arm (arm weakness); 2 incoherent lips (slurred speech). An online survey was used to determine the acceptance of the Stroke 112 program compared with that of FAST in Chinese. The surveys were delivered using SurveyMonkey (http://www.surveymonkey.com) on 2 separate occasions in Taiwan; in August 2017 for an initial estimation of the acceptance of Stroke 112 and in March 2018, 2 weeks after the official release of Stroke 112 in Taiwan, including a special introductory lecture for neurologists hosted by the STARS-Taiwan (Stroke Treatment and Research Society-Taiwan). RESULTS: The initial survey with 465 survey responders, 54.6% thought that Stroke 112 was easier to remember for people in Taiwan compared with FAST (41.2%). After Stroke 112's official release in Taiwan, 610 individuals completed the survey, and the majority (66.4%) thought that Stroke 112 was easier to remember, a significant increase compared with the initial survey (P=0.0001). Among the 130 neurologists who attended the Stroke 112 introductory lecture, 55 completed the online survey. A greater acceptance of Stroke 112 (74.6%) compared with FAST (16.4%) was observed among these 55 neurologists (P=0.0001). CONCLUSIONS: Stroke 112, a universal stroke educational program without language barriers was developed. It could potentially be implemented worldwide, especially where 112 is used as an emergency phone number.

Absence of Neuropathology With Prolonged Isoflurane Sedation in Healthy Adult Rats.

BACKGROUND: The use of isoflurane sedation for prolonged periods in the critical care environment is increasing. However, isoflurane-mediated neurotoxicity has been widely reported. The goal of the present study was to determine whether long-term exposure to low-dose isoflurane in mechanically ventilated rodents is associated with evidence of neurodegeneration or neuroinflammation. METHODS: Adult female Sprague-Dawley rats were used in this study. Experimental animals (n=11) were induced with 1.5% isoflurane, intubated, and given a neuromuscular blockade with α-cobratoxin. EEG electrodes were surgically implanted, subcutaneous precordial EKG Ag wire electrodes, and bladder, femoral artery, and femoral vein cannulas permanently placed. After these procedures, the isoflurane concentration was reduced to 0.5% and, in conjunction with the neuromuscular blockade, continued for 7 days. Arterial blood gases and chemistry were measured at 3 time points and core body temperature servoregulated and maintenance IV fluids were given during the 7 days. Experimental animals and untreated controls (n=9) were euthanized on day 7. RESULTS: Immunohistochemical and cytochemical assays did not detect evidence of microgliosis, astrocytosis, neuronal apoptosis or necrosis, amyloidosis, or phosphorylated-tau accumulation. Blood glucose levels were significantly reduced on days 3/4 and 6/7 and partial pressure of oxygen was significantly reduced, but still within the normal range, on day 6/7. All other blood measurements were unchanged. CONCLUSIONS: No neuropathologic changes consistent with neurotoxicity were detected in the brain after 1 week of continuous exposure to 0.5% isoflurane in healthy rats. These data suggest that even long exposures to low concentrations of isoflurane have no overt consequences on neuropathology.

From the Cover: Volatile Anesthetics Transiently Disrupt Neuronal Development in Neonatal Rats.

Volatile anesthetics can cause neuronal and glial toxicity in the developing mammalian brain, as well as long-term defects in learning and memory. The goals of this study were to compare anesthetics using a clinically relevant exposure paradigm, and to assess the anesthetic effects on hippocampal development and behavior. Our hypothesis was that volatile anesthetics disrupt hippocampal development, causing neurobehavioral defects later in life. Bromodeoxyuridine (BrdU) was administered to rats on postnatal day (P)1, and the rats were exposed to volatile anesthetics (isoflurane, sevoflurane, or desflurane) for 2 h on P2. On days P7 and P14, the BrdU-labeled cells were quantified in the hippocampal dentate gyrus using immunohistochemical assays and fluorescent microscopy. Caspase-3 positive cells were quantified on P2 to evaluate apoptosis. The remaining animals underwent behavioral testing at ages 6 weeks and 6 months, using the Morris Water Maze. Significantly fewer BrdU-positive cells were detected in the hippocampal dentate gyrus in both isoflurane and desflurane-treated animals compared with controls at P7, but there were no changes in cell numbers after sevoflurane exposure. Cell counts for all three anesthetics compared with controls were equivalent at P14. Isoflurane or desflurane exposure yielded slight differences in the behavioral tests at 6 weeks, but no differences at 6 months post-exposure. We conclude that a single 2-h exposure at P2 to either isoflurane or desflurane causes a transient disruption of hippocampal neuronal development with no significant detectable long-term effects on learning and memory, whereas the same exposure to sevoflurane has no effects.

Macroscopic and macromolecular specificity of alkylphenol anesthetics for neuronal substrates.

We used a photoactive general anesthetic called meta-azi-propofol (AziPm) to test the selectivity and specificity of alkylphenol anesthetic binding in mammalian brain. Photolabeling of rat brain sections with [(3)H]AziPm revealed widespread but heterogeneous ligand distribution, with [(3)H]AziPm preferentially binding to synapse-dense areas compared to areas composed largely of cell bodies or myelin. With [(3)H]AziPm and propofol, we determined that alkylphenol general anesthetics bind selectively and specifically to multiple synaptic protein targets. In contrast, the alkylphenol anesthetics do not bind to specific sites on abundant phospholipids or cholesterol, although [(3)H]AziPm shows selectivity for photolabeling phosphatidylethanolamines. Together, our experiments suggest that alkylphenol anesthetic substrates are widespread in number and distribution, similar to those of volatile general anesthetics, and that multi-target mechanisms likely underlie their pharmacology.

Long-term dantrolene treatment reduced intraneuronal amyloid in aged Alzheimer triple transgenic mice.

In this study, we investigated the long-term treatment of dantrolene on amyloid and tau neuropathology, brain volume, and cognitive function in aged triple transgenic Alzheimer (3xTg-AD) mice. Fifteen-month old 3xTg-AD mice and wild-type controls were treated with oral dantrolene (5 mg/kg) or vehicle control twice a week for 6 months. Learning and memory were examined using the Morris Water Maze at 21 and 22 months of age. After the behavioral testing, hippocampal and cortical brain volumes were calculated with magnetic resonance imaging and motor function was evaluated using the rotorod. The amyloid burden and tau neurofibrillary tangles in the hippocampus were determined using immunohistochemistry. We found that dantrolene significantly decreased the intraneuronal amyloid accumulation by as much as 76% compared with its corresponding vehicle control, together with a trend to reduce phosphorylated tau in the hippocampus. No significant differences could be detected in hippocampal or cortical brain volume, motor function or cognition among all experimental groups, indicating that the mice were still presymptomatic for Alzheimer disease. Thus, presymptomatic and long-term dantrolene treatment significantly decreased the intraneuronal amyloid burden in aged 3xTg-AD mice before significant changes in brain volume, or cognition.

Anesthetic preconditioning inhibits isoflurane-mediated apoptosis in the developing rat brain.

BACKGROUND: We hypothesized that preconditioning (PC) with a short exposure to isoflurane (ISO) would reduce neurodegeneration induced by prolonged exposure to ISO in neonatal rats, as previously shown in neuronal cell culture. METHODS: We randomly divided 7-day-old Sprague-Dawley rats into 3 groups: control, 1.5% ISO, and PC + 1.5% ISO. The control group was exposed to carrier gas (30% oxygen balanced in nitrogen) for 30 minutes and then to carrier gas again for 6 hours the following day. The 1.5% ISO group was exposed to carrier gas for 30 minutes and then to 1.5% ISO for 6 hours the following day. The PC + 1.5% ISO group was preconditioned with a 30-minute 1.5% ISO exposure and then exposed to 1.5% ISO for 6 hours the following day. Blood and brain samples were collected 2 hours after the exposures for determination of neurodegenerative biomarkers, including caspase-3, S100ß, caspase-12, and an autophagy biomarker Beclin-1. RESULTS: Prolonged exposure to ISO significantly increased cleaved caspase-3 expression in the cerebral cortex of 7-day-old rats compared with the group preconditioned with ISO and the controls using Western blot assays. However, significant differences were not detected for other markers of neuronal injury. CONCLUSIONS: The ISO-mediated increase in cleaved caspase-3 in the postnatal day 7 rat brain is ameliorated by PC with a brief anesthetic exposure, and differences were not detected in other markers of neuronal injury.

Differential general anesthetic effects on microglial cytokine expression.

Post-operative cognitive dysfunction has been widely observed, especially in older patients. An association of post-operative cognitive dysfunction with the neurodegenerative diseases, such as Alzheimer's disease, has been suggested. Neuroinflammation contributes to Alzheimer pathology, through elevated pro-inflammatory cytokines and microglial activation in the CNS leading to neuronal damage, synaptic disruption and ultimately cognitive dysfunction. We compare the effects of three different, clinically-used, anesthetics on microglial activation with, and without, the prototypical inflammatory trigger, lipopolysaccharide (LPS). Microglial BV-2 cell cultures were first exposed to isoflurane, sevoflurane (each at 2 concentrations) or propofol for 6 h, and cytokine levels measured in lysates and media. The same experiments were repeated after 1 h LPS pre-treatment. We found; 1) anesthetics alone have either no or only a small effect on cytokine expression; 2) LPS provoked a large increase in microglia cytokine expression; 3) the inhaled anesthetics either had no effect on LPS-evoked responses or enhanced it; 4) propofol nearly eliminated the LPS pro-inflammatory cytokine response and improved cell survival as reflected by lactate dehydrogenase release. These data suggest that propofol may be a preferred anesthetic when it is desirable to minimize neuroinflammation.

Modulation of murine Alzheimer pathogenesis and behavior by surgery.

OBJECTIVE: Previous research suggests that a link between anesthetic exposure and Alzheimer disease exists. Because anesthetics are rarely given alone, we ask whether addition of surgery further modulates Alzheimer disease. BACKGROUND: Cognitive dysfunction occurs after surgery in humans. Anesthesia alone produces cognitive decline in both older wild-type (WT) mice and rats, and the addition of surgery produces transient decline in young, adult WT mice. Because neuroinflammation has been implicated and occurs early in Alzheimer disease, we hypothesized that the neuroinflammatory stress associated with surgery would accelerate the progression of Alzheimer disease. METHODS: Cecal ligation and excision were performed on presymptomatic 5- to 11-month-old triple-transgenic Alzheimer disease (3×TgAD) and C57BL/6 WT mice under desflurane anesthesia. Surgery animals were compared with aged-matched 3×TgAD and WT mice exposed to air or desflurane alone. Cognitive function was assessed via Morris water maze at 2 and 13 weeks postoperatively. Amyloid and tau pathology and inflammation and synaptic markers were quantified with immunohistochemistry, Luminex assay, enzyme-linked immunosorbent assay, or Western blot assays. RESULTS: A significant cognitive impairment in 3×TgAD mice that underwent surgery compared with air or desflurane controls persisted to at least 14 weeks after surgery. Microglial activation, amyloidopathy, and tauopathy were enhanced by surgery as compared with desflurane alone. No differences between surgery, anesthetic, or air controls were detected in WT mice CONCLUSIONS: Surgery causes a durable increment in Alzheimer pathogenesis, primarily through a transient activation of neuroinflammation.

Anesthetic effects in Alzheimer transgenic mouse models.

Research has improved the diagnosis of Alzheimer's disease, and at earlier stages, but effective therapy continues to be elusive. Current effort is focused on delay. Environmental factors are thought to interact with genetics to modulate the progression of the disease, and one such environmental factor is exposure to general anesthetics. The possibility that some anesthetic effects have long-term consequences is of general interest and concern. The difficulty of studying a chronic, age-related disease in humans combined with the fact that anesthetics are rarely given without surgery, has led to a focus on animal models. Transgenic mouse models have been developed to mimic the hallmarks of Alzheimer's disease, including amyloid beta accumulation (plaque), neurofibrillary tangles, and cognitive dysfunction. While none of the models recapitulate the human disease with high fidelity, they allow a first look at anesthetic-Alzheimer interactions in a reasonable time frame. In studies found to date, none have concluded that anesthetics alone cause a significant change in cognitive decline, but rather an acceleration in Alzheimer neuropathology. Further studies are required to define the best anesthetic paradigm for our elderly population to mitigate changes in neuropathology and potentially cognition.

Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice.

Disruption of intracellular calcium homeostasis via abnormal and excessive activation of ryanodine receptors plays an important role in the neuropathology of Alzheimer's disease. We investigated the therapeutic effect of dantrolene, a ryanodine receptor antagonist, on cognitive dysfunction and neuropathology in the triple transgenic Alzheimer mouse model (3xTg-AD). 3xTg-AD mice were treated with dantrolene from 2 to 13 months of age. Learning and memory were measured with the Morris Water Maze at 6, 10, and 13 months of age. Amyloid and tau neuropathology and biomarkers for synaptic dysfunction and neurodegeneration were examined in the brain using immunoblotting or immunohistochemistry. Dantrolene treatment for 11 months significantly reduced both memory deficits and amyloid plaque load in the hippocampus in 13-month-old 3xTg-AD mice. Dantrolene treatment, however, had no effect on phosphorylated tau, phosphorylated or total GSK-3ß, synaptic markers, or mitochondrial or cytosolic cytochrome C. Our results suggest that dantrolene significantly improves cognition in a murine model of Alzheimer's disease and is associated with a reduction in amyloid plaque burden, forming the basis for a novel therapeutic approach for Alzheimer's disease.

Is hydrogen sulfide-induced suspended animation general anesthesia?

Hydrogen sulfide (H(2)S) depresses mitochondrial function and thereby metabolic rates in mice, purportedly resulting in a state of "suspended animation." Volatile anesthetics also depress mitochondrial function, an effect that may contribute to their anesthetic properties. In this study, we ask whether H(2)S has general anesthetic properties, and by extension, whether mitochondrial effects underlie the state of anesthesia. We compared loss of righting reflex, electroencephalography, and electromyography in mice exposed to metabolically equipotent concentrations of halothane, isoflurane, sevoflurane, and H(2)S. We also studied combinations of H(2)S and anesthetics to assess additivity. Finally, the long-term effects of H(2)S were assessed by using the Morris water maze behavioral testing 2 to 3 weeks after exposures. Exposure to H(2)S decreases O(2) consumption, CO(2) production, and body temperature similarly to that of the general anesthetics, but fails to produce a loss of righting reflex or muscle atonia at metabolically equivalent concentrations. When combined, H(2)S antagonizes the metabolic effects of isoflurane, but potentiates the isoflurane-induced loss of righting reflex. We found no effect of prior H(2)S exposure on memory or learning. H(2)S (250 ppm), not itself lethal, produced delayed lethality when combined with subanesthetic concentrations of isoflurane. H(2)S cannot be considered a general anesthetic, despite similar metabolic suppression. Metabolic suppression, presumably via mitochondrial actions, is not sufficient to account for the hypnotic or immobilizing components of the anesthetic state. Combinations of H(2)S and isoflurane can be lethal, suggesting extreme care in the combination of these gases in clinical situations.

Neurodevelopmental consequences of sub-clinical carbon monoxide exposure in newborn mice.

Carbon monoxide (CO) exposure at high concentrations results in overt neurotoxicity. Exposure to low CO concentrations occurs commonly yet is usually sub-clinical. Infants are uniquely vulnerable to a variety of toxins, however, the effects of postnatal sub-clinical CO exposure on the developing brain are unknown. Apoptosis occurs normally within the brain during development and is critical for synaptogenesis. Here we demonstrate that brief, postnatal sub-clinical CO exposure inhibits developmental neuroapoptosis resulting in impaired learning, memory, and social behavior. Three hour exposure to 5 ppm or 100 ppm CO impaired cytochrome c release, caspase-3 activation, and apoptosis in neocortex and hippocampus of 10 day old CD-1 mice. CO increased NeuN protein, neuronal numbers, and resulted in megalencephaly. CO-exposed mice demonstrated impaired memory and learning and reduced socialization following exposure. Thus, CO-mediated inhibition of neuroapoptosis might represent an important etiology of acquired neurocognitive impairment and behavioral disorders in children.

Human Alzheimer and inflammation biomarkers after anesthesia and surgery.

BACKGROUND: The prevalence of postoperative cognitive disturbance, coupled with growing in vitro, cell, and animal evidence suggesting anesthetic effects on neurodegeneration, calls for additional study of the interaction between surgical care and Alzheimer neuropathology. The authors studied human cerebrospinal fluid (CSF) biomarkers during surgery. METHODS: Eleven patients undergoing idiopathic nasal CSF leak correction were admitted to this Institutional Review Board-approved study. Lumbar subarachnoid catheters were placed before the procedure. Anesthesia was total intravenous propofol or remifentanil or inhalational sevoflurane, depending on provider choice. CSF samples were taken after catheter placement (base), at procedure end (0 h), and then at 6, 24, and 48 h. CSF was analyzed using xMAP Luminex immunoassay (Luminex, Austin, TX). RESULTS: Of the 11 patients (age range, 53 ± 6 yr), 8 were women; 4 received intravenous anesthesia, 6 sevoflurane, and 1 mixed. Procedures lasted 6.4 ± 2 h. Mean CSF amyloid-ß(1-42) remained unchanged, but total-tau and phosphorylated-tau181P increased progressively until at least 48 h. Total-tau, phosphorylated-tau, or amyloid-ß(1-42) concentrations were not different between anesthetic groups. CSF interleukin-10, S100Beta, and tumor necrosis factor α were increased similarly in both anesthetic groups at 24 h, but interleukin-6 was increased more in the inhalational group. CONCLUSION: These data indicate a robust neuroinflammatory response, including not only the usual markers (interleukin-6, tumor necrosis factor α, interleukin-10), but also S100Beta and tau, markers of injury. The total-tau/amyloid-ß(1-42) ratio increased in a pattern consistent with Alzheimer disease, largely because of an increase in total-tau rather than a decline in amyloid-ß(1-42). The differences in CSF interleukin-6 concentrations suggest that anesthetic management may make a difference in neuroinflammatory response.