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.

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.

Best Practices for Postoperative Brain Health: Recommendations From the Fifth International Perioperative Neurotoxicity Working Group.

As part of the American Society of Anesthesiology Brain Health Initiative goal of improving perioperative brain health for older patients, over 30 experts met at the fifth International Perioperative Neurotoxicity Workshop in San Francisco, CA, in May 2016, to discuss best practices for optimizing perioperative brain health in older adults (ie, >65 years of age). The objective of this workshop was to discuss and develop consensus solutions to improve patient management and outcomes and to discuss what older adults should be told (and by whom) about postoperative brain health risks. Thus, the workshop was provider and patient oriented as well as solution focused rather than etiology focused. For those areas in which we determined that there were limited evidence-based recommendations, we identified knowledge gaps and the types of scientific knowledge and investigations needed to direct future best practice. Because concerns about perioperative neurocognitive injury in pediatric patients are already being addressed by the SmartTots initiative, our workshop discussion (and thus this article) focuses specifically on perioperative cognition in older adults. The 2 main perioperative cognitive disorders that have been studied to date are postoperative delirium and cognitive dysfunction. Postoperative delirium is a syndrome of fluctuating changes in attention and level of consciousness that occurs in 20%-40% of patients >60 years of age after major surgery and inpatient hospitalization. Many older surgical patients also develop postoperative cognitive deficits that typically last for weeks to months, thus referred to as postoperative cognitive dysfunction. Because of the heterogeneity of different tools and thresholds used to assess and define these disorders at varying points in time after anesthesia and surgery, a recent article has proposed a new recommended nomenclature for these perioperative neurocognitive disorders. Our discussion about this topic was organized around 4 key issues: preprocedure consent, preoperative cognitive assessment, intraoperative management, and postoperative follow-up. These 4 issues also form the structure of this document. Multiple viewpoints were presented by participants and discussed at this in-person meeting, and the overall group consensus from these discussions was then drafted by a smaller writing group (the 6 primary authors of this article) into this manuscript. Of course, further studies have appeared since the workshop, which the writing group has incorporated where appropriate. All participants from this in-person meeting then had the opportunity to review, edit, and approve this final manuscript; 1 participant did not approve the final manuscript and asked for his/her name to be removed.

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.

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.

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.

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.

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.

The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease.

Isoflurane is known to increase ß-amyloid aggregation and neuronal damage. We hypothesized that isoflurane will have similar effects on the polyglutamine huntingtin protein and will cause alterations in intracellular calcium homeostasis. We tested this hypothesis in striatal cells from the expanded glutamine huntingtin knock-in mouse (STHdh(Q111/Q111)) and wild type (STHdh(Q7/Q7)) striatal neurons. The primary cultured neurons were exposed for 24h to equipotent concentrations of isoflurane, sevoflurane, and desflurane in the presence or absence of extracellular calcium and with or without xestospongin C, a potent endoplasmic reticulum inositol 1,4,5-trisphosphate (InsP(3)) receptor antagonist. Aggregation of huntingtin protein, cell viability, and calcium concentrations were measured. Isoflurane, sevoflurane, and desflurane all increased the aggregation of huntingtin in STHdh(Q111/Q111) cells, with isoflurane having the largest effect. Isoflurane induced greater calcium release from the ER and relatively more cell damage in the STHdh(Q111/Q111) huntingtin cells than in the wild type STHdh(Q7/Q7) striatal cells. However, sevoflurane and desflurane caused less calcium release from the ER and less cell damage. Xestospongin C inhibited the isoflurane-induced calcium release from the ER, aggregation of huntingtin, and cell damage in the STHdh(Q111/Q111) cells. In summary, the Q111 form of huntingtin increases the vulnerability of striatal neurons to isoflurane neurotoxicity through combined actions on the ER IP(3) receptors. Calcium release from the ER contributes to the anesthetic induced huntingtin aggregation in STHdh(Q111/Q111) striatal cells.

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.

Anesthesia in presymptomatic Alzheimer's disease: a study using the triple-transgenic mouse model.

BACKGROUND: Experimental evidence suggests that anesthetics accelerate symptomatic neurodegenerative disorders such as Alzheimer's disease (AD). Because AD pathology precedes symptoms, we asked ourselves whether anesthetic exposure in the presymptomatic interval accelerated neuropathology and appearance of symptoms. METHODS: Triple-transgenic AD mice were exposed to general aesthetics, either halothane or isoflurane, at 2, 4, and 6 months of age, they then underwent water maze cognitive testing 2 months later, and subsequently their brains were analyzed using enzyme-linked immunosorbent assay, immunoblots, and immunohistochemistry for amyloid and tau pathology and biomarkers. RESULTS: Learning and memory improved after halothane exposure in the 2-month-old group relative to controls, but no changes were noted in the isoflurane group. When gender was examined in all age groups, females exposed to halothane performed better as compared with those exposed to isoflurane or controls. Therefore, improvement in the 2-month exposure group is most likely because of a gender effect. Level of phospho-tau in the hippocampus was significantly increased 2 months after anesthesia, especially in the 6-month exposure group, but changes in amyloid, caspase, microglia, or synaptophysin levels were not detected. CONCLUSIONS: These results indicate that exposure to two different inhalation-type anesthetics during the presymptomatic phase of AD does not accelerate cognitive decline, after 2 months, and may cause a stress response, marked by hippocampal phosphorylated tau, resulting in preconditioning against the ongoing neuropathology, primarily in female mice.

Anesthetic modulation of neuroinflammation in Alzheimer's disease.

PURPOSE OF REVIEW: To summarize key studies and recent thought on the role of neuroinflammation in chronic neurodegeneration, and whether it can be modulated by anesthesia and surgery. RECENT FINDINGS: A large and growing body of evidence shows that neuroinflammation participates in the development of neurodegeneration associated with Alzheimer's disease. Modulation may be possible early in the pathogenesis, and less so when cognitive symptoms appear. A dysfunctional hypoinflammatory response may permit accelerated damage due to other mechanisms in late disease. The peripheral inflammatory response elicited by surgery itself appears to provoke a muted neuroinflammatory response, which enhances ongoing neurodegeneration in some models. Anesthetics have both anti-inflammatory and proinflammatory effects depending on the drug and concentration, but in general, appear to play a small role in neuroinflammation. Human studies at the intersection of chronic neurodegeneration, neuroinflammation, and surgery/anesthesia are rare. SUMMARY: The perioperative period has the potential to modulate the progression of chronic neurodegenerative diseases. The growing number of elderly having surgery, combined with the expanding life expectancy, indicates the potential for this interaction to have considerable public health implications, and call for further research, especially in humans.

Anesthetic-induced neurodegeneration mediated via inositol 1,4,5-trisphosphate receptors.

The commonly used general anesthetic isoflurane induces widespread neurodegeneration in the developing mammalian brain through poorly understood mechanisms. We have investigated whether excessive Ca2+ release from the endoplasmic reticulum via overactivation of inositol 1,4,5-trisphosphate receptors (InsP3Rs) is a contributing factor in such neurodegeneration in rodent primary cultured neurons and developing rat brain. We also investigated the correlation between isoflurane exposure and cognitive decline in rats at 1 month of age. Our results show that isoflurane increases cytosolic calcium in the primary cortical neurons through release from the endoplasmic reticulum and influx from the extracellular space. Pharmacological inhibition of InsP3R activity and knockdown of its expression nearly abolishes the isoflurane-mediated elevation of the cytosolic calcium concentration and cell death in rodent primary cortical and hippocampal neurons. Inhibition of InsP3R activity by its antagonist xestospongin C significantly inhibits neurodegeneration induced by isoflurane at clinically used concentration in the developing brain of postnatal day 7 rats. Moreover, our results show that isoflurane activates beta-site amyloid beta precursor protein-cleaving enzyme via activation of the InsP3R. We also noted that mice exposed to isoflurane during early postnatal development showed transient memory and learning impairments, which did not correlate well with the noted neuropathological defects. Taken together, our results suggest that Ca2+ dysregulation through overactivation of the InsP3R may be a contributing factor in the mechanism of isoflurane-induced neurodegeneration in rodent neuronal cell culture and during brain development.

Acute anemia elicits cognitive dysfunction and evidence of cerebral cellular hypoxia in older rats with systemic hypertension.

BACKGROUND: Postoperative cognitive dysfunction occurs frequently after cardiac, major vascular, and major orthopedic surgery. Aging and hypertensive cerebrovascular disease are leading risk factors for this disorder. Acute anemia, common to major surgery, has been identified as a possible contributor to postoperative cognitive dysfunction. The effect of hypoxia upon cognition and the cellular and molecular processes involved in learning and memory has been well described. Cerebrovascular changes related to chronic hypertension may expose cells to increased hypoxia with anemia. METHODS: Young to aged spontaneously hypertensive rats underwent testing for visuospatial memory and learning in the Morris water maze, measurement of cerebral tissue oxygenation via tissue oxygen probe, and measurement of hypoxia-sensitive genes and proteins, under conditions of sham and experimental isovolemic anemia. RESULTS: Acute isovolemic anemia elicited evidence of aging-dependent visuospatial working memory and learning impairment. Isovolemic anemia did not result in cerebral tissue hypoxia, when measured via tissue oxygen probe. Evidence of cellular hypoxia was, however, identified in response to the anemic challenge, as hypoxia-sensitive genes and proteins were up-regulated. Importantly, cellular hypoxic gene responses were increased with anemia in an age-dependent manner in this model of aging with chronic hypertension. CONCLUSIONS: In a translational model of chronic hypertension, clinically relevant levels of acute anemia were associated with an age-dependent visuospatial working memory and learning impairment that was matched by an age-dependent cellular sensitivity to anemic hypoxia. These data offer support for a possible link between anemic hypoxia and postoperative cognitive dysfunction in humans.

Anesthesia and the old brain.

The perioperative period may have long-term consequences on cognitive function in the elderly patient. In this special article, we summarize the rationale and evidence that the anesthetic per se is a contributor. The evidence at this point is considered suggestive and further research is needed, especially in humans.

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.

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.