General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain.

General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells. Oligodendrocytes perform essential roles in the central nervous system, including myelin sheath formation, axonal metabolism, and neuroplasticity regulation. They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation, differentiation, and apoptosis. Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes. These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways, but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function. In this review, we summarize the effects of general anesthetic agents on oligodendrocytes. We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.

Preclinical evidence for anaesthesia-induced neurotoxicity.

Preclinical research concerning anaesthesia-induced neurotoxicity was initiated in 1999. A decade later, the earliest clinical observational data showed mixed results in neurodevelopmental outcomes following anaesthesia exposure at a young age. Hence to date, preclinical studies remain the cornerstone of research in this field, primarily because of the vulnerability of clinical observational studies to confounding bias. This review summarises current preclinical evidence. Most studies used rodent models, although non-human primates have also been employed. Across all gestational and postnatal ages, there is evidence that all commonly used general anaesthetics induce neuronal injury (e.g. apoptosis) and cause neurobehavioural impairment (e.g. learning and memory deficits). These deficits were more pronounced when animals were subjected to either repeated exposure, prolonged durations of exposure or higher doses of anaesthesia. To interpret these results in the clinical context, the strengths and limitations of each model and experiment should be carefully considered, as these preclinical studies were often biased by supraclinical durations and a lack of control with regard to physiological homeostasis.

Application of Nonhuman Primate Models in the Studies of Pediatric Anesthesia Neurotoxicity.

Numerous animal models have been used to study developmental neurotoxicity associated with short-term or prolonged exposure of common general anesthetics at clinically relevant concentrations. Pediatric anesthesia models using the nonhuman primate (NHP) may more accurately reflect the human condition because of their phylogenetic similarity to humans with regard to reproduction, development, neuroanatomy, and cognition. Although they are not as widely used as other animal models, the contribution of NHP models in the study of anesthetic-induced developmental neurotoxicity has been essential. In this review, we discuss how neonatal NHP animals have been used for modeling pediatric anesthetic exposure; how NHPs have addressed key data gaps and application of the NHP model for the studies of general anesthetic-induced developmental neurotoxicity. The appropriate application and evaluation of the NHP model in the study of general anesthetic-induced developmental neurotoxicity have played a key role in enhancing the understanding and awareness of the potential neurotoxicity associated with pediatric general anesthetics.

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits.

BACKGROUND: Increasing evidence suggests that multiple or long-time exposure to general anaesthesia (GA) could be detrimental to cognitive development in young subjects and might also contribute to accelerated neurodegeneration in the elderly. Iron is essential for normal neuronal function, and excess iron in the brain is implicated in several neurodegenerative diseases. However, the role of iron in GA-induced neurotoxicity and cognitive deficits remains elusive. METHODS: We used the primary hippocampal neurons and rodents including young rats and aged mice to examine whether GA impacted iron metabolism and whether the impact contributed to neuronal outcomes. In addition, a pharmacological suppression of iron metabolism was performed to explore the molecular mechanism underlying GA-mediated iron overload in the brain. RESULTS: Our results demonstrated that GA, induced by intravenous ketamine or inhalational sevoflurane, disturbed iron homeostasis and caused iron overload in both in vitro hippocampal neuron culture and in vivo hippocampus. Interestingly, ketamine- or sevoflurane-induced cognitive deficits, very likely, resulted from a novel iron-dependent regulated cell death, ferroptosis. Notably, iron chelator deferiprone attenuated the GA-induced mitochondrial dysfunction, ferroptosis, and further cognitive deficits. Moreover, we found that GA-induced iron overload was activated by NMDAR-RASD1 signalling via DMT1 action in the brain. CONCLUSION: We conclude that disturbed iron metabolism may be involved in the pathogenesis of GA-induced neurotoxicity and cognitive deficits. Our study provides new vision for consideration in GA-associated neurological disorders.

WBQ5187, a Multitarget Directed Agent, Ameliorates Cognitive Impairment in a Transgenic Mouse Model of Alzheimer's Disease and Modulates Cerebral ß-Amyloid, Gliosis, cAMP Levels, and Neurodegeneration.

Previously, we designed, synthesized, and evaluated a series of quinolone-benzofuran derivatives as multitargeted anti-Alzheimer's disease (anti-AD) compounds, and we discovered that WBQ5187 possesses superior anti-AD bioactivity. In this work, we investigated the pharmacokinetics of this new molecule, as well as its therapeutic efficacy in restoring cognition and neuropathology, in the APP/PS1 mouse model of AD. Pharmacokinetic analyses demonstrated that WBQ5187 possessed rational oral bioavailability, metabolic stability, and excellent blood-brain barrier (BBB) permeability. Pharmacodynamics studies indicated that a 12-week treatment with the lead compound at doses of 40 mg/kg or higher significantly enhanced the learning and memory performance of the APP/PS1 transgenic mice, and the effect was more potent than that of clioquinol (CQ). Furthermore, WBQ5187 notably reduced cerebral ß-amyloid pathology, gliosis, and neuronal cell loss and increased the levels of cAMP in the hippocampus of these mice. The surrogate measures of emesis indicated that WBQ5187 had no effect at its cognitive effective doses. Overall, our results demonstrated that this compound markedly improves cognitive and spatial memory functions in AD mice and represents a promising pharmaceutical agent with potential for the treatment of AD.

General anesthetic neurotoxicity in the young: Mechanism and prevention.

General anesthesia (GA) is usually considered to safely induce a reversible unconscious state allowing surgery to be performed without pain. A growing number of studies, in particular pre-clinical studies, however, demonstrate that general anesthetics can cause neuronal death and even long-term neurological deficits. Herein, we report our literature review and meta-analysis data of the neurological outcomes after anesthesia in the young. We also review available mechanistic and epigenetic data of GA exposure related to cognitive impairment per se and the potential preventive strategies including natural herbal compounds to attenuate those side effects. In summary, anesthetic-induced neurotoxicity may be treatable and natural herbal compounds and other medications may have great potential for such use but warrants further study before clinical applications can be initiated.

Anesthetics: from modes of action to unconsciousness and neurotoxicity.

Modern anesthetic compounds and advanced monitoring tools have revolutionized the field of medicine, allowing for complex surgical procedures to occur safely and effectively. Faster induction times and quicker recovery periods of current anesthetic agents have also helped reduce health care costs significantly. Moreover, extensive research has allowed for a better understanding of anesthetic modes of action, thus facilitating the development of more effective and safer compounds. Notwithstanding the realization that anesthetics are a prerequisite to all surgical procedures, evidence is emerging to support the notion that exposure of the developing brain to certain anesthetics may impact future brain development and function. Whereas the data in support of this postulate from human studies is equivocal, the vast majority of animal research strongly suggests that anesthetics are indeed cytotoxic at multiple brain structure and function levels. In this review, we first highlight various modes of anesthetic action and then debate the evidence of harm from both basic science and clinical studies perspectives. We present evidence from animal and human studies vis-à-vis the possible detrimental effects of anesthetic agents on both the young developing and the elderly aging brain while discussing potential ways to mitigate these effects. We hope that this review will, on the one hand, invoke debate vis-à-vis the evidence of anesthetic harm in young children and the elderly, and on the other hand, incentivize the search for better and less toxic anesthetic compounds.

Inhibitory actions of general anesthetics on hippocampal CA1 neurons modified by activation of amygdala circuitry are demonstrated on the novel amygdala-hippocampal slice preparation.

In order to examine effects of general anesthetics on hippocampal synaptic transmission in the absence and presence of amygdala circuitry activation, we have developed a unique amygdala-hippocampal slice preparation in which projections between amygdala and hippocampal CA1 are conserved. Stimulating electrodes were placed in radiatum stratum (Rad) to stimulate CA1, and in amygdala-hippocampal area (AH) to simulate amygdala inputs to hippocampus. Two sets of extracellular recording microelectrodes were positioned in cell bodies and dendrites of CA1 to record population spikes (PSs) and excitatory post-synaptic potentials (EPSPs), respectively. Intravenous anesthetics did not elicit consistent effects on PS and EPSP following a test stimulus on Rad. A pre-pulse of AH in addition to a test-pulse on Rad produced significant reduction of PS amplitude without a change in EPSP. Pre-treatment with tetanus-pulse on AH reversed the anesthetic-induced reduction of PS. The results suggest that inhibitory actions of general anesthetics in CA1 can be modified by activation of amygdala, suggesting that preoperative anxiety and fear could modify anesthetic actions. The modification was more prominent in the presence of intravenous anesthetics than with volatile agents.

Neurotoxicidad de la anestesia general, niños menores de 3 años y la FDA: ¿cuál es el alcance de la alarma? / Neurotoxicity of general anaesthesia in children younger than 3 years and FDA: how far is the warning?

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Disruption of Hippocampal Multisynaptic Networks by General Anesthetics.

BACKGROUND: Previous studies showed that synaptic transmission is affected by general anesthetics, but an anesthetic dose response in freely moving animals has not been done. The hippocampus provides a neural network for the evaluation of isoflurane and pentobarbital on multisynaptic transmission that is relevant to memory function. METHODS: Male Long-Evans rats were implanted with multichannel and single electrodes in the hippocampus. Spontaneous local field potentials and evoked field potentials were recorded in freely behaving rats before (baseline) and after various doses of isoflurane (0.25 to 1.5%) and sodium pentobarbital (10 mg/kg intraperitoneal). RESULTS: Monosynaptic population excitatory postsynaptic potentials at the basal and apical dendrites of CA1 were significantly decreased at greater than or equal to 0.25% (n = 4) and greater than or equal to 1.0% (n = 6) isoflurane, respectively. The perforant path evoked multisynaptic response at CA1 was decreased by ~50% at greater than or equal to 0.25% isoflurane (n = 5). A decreased population excitatory postsynaptic potential was accompanied by increased paired-pulse facilitation. Population spike amplitude in relation to apical dendritic population excitatory postsynaptic potential was not significantly altered by isoflurane. Spontaneous hippocampal local field potential at 0.8 to 300 Hz was dose-dependently suppressed by isoflurane (n = 6), with local field potential power in the 50- to 150-Hz band showing the highest decrease with isoflurane dose, commensurate with the decrease in trisynaptic CA1 response. Low-dose pentobarbital (n = 7) administration decreased the perforant path evoked trisynaptic CA1 response and hippocampal local field potentials at 78 to 125 Hz. CONCLUSIONS: Hippocampal networks are sensitive to low doses of isoflurane and pentobarbital, possibly through both glutamatergic and γ-aminobutyric acid-mediated transmission. Network disruption could help explain the impairment of hippocampal-dependent cognitive functions with low-dose anesthetic.

Current thinking regarding potential neurotoxicity of general anesthesia in infants.

PURPOSE OF REVIEW: Numerous preclinical studies have shown that general anesthetics adversely influence the development of young brains. These adverse effects are dose-dependent occurring in specific stages of brain development. Histologic examinations show increased apoptosis, pathological neurogenesis and dendritic formation after exposure in infant animals to virtually all general anesthetics at a clinically effective dose which are associated with memory and behavioral changes at adulthood. RECENT FINDINGS: Clinical research into the long-term effects of anesthesia during early childhood on brain development is mainly limited to retrospective cohort studies, with conflicting results. Only recently, the interim analysis of a prospective randomized clinical trial examining the effects of general anesthesia has been published. In this GAS-study the influence up to 1 h of general anesthesia versus regional anesthesia in young infants has been assessed on the neurocognitive functioning at the age of 2 years. No differences were found between the two groups. However, the primary outcome analysis which is the 5-year outcomes will not be complete until 2018. SUMMARY: Pending clear evidence, anesthesiologists should discuss the indication of anesthesia for surgery and diagnostic procedures with caregivers and parents taking into consideration the risks and benefits of the planned procedure.

The choice of general anesthetics may not affect neuroinflammation and impairment of learning and memory after surgery in elderly rats.

Postoperative cognitive dysfunction (POCD) often occurs in elderly patients and may involve neuroinflammation. This study was to determine whether anesthetic choice (intravenous vs. volatile anesthetics) affects cognitive impairment and neuroinflammation in elderly rat. Total 54 twenty-month old male Fischer 344 rats were assigned randomly to control, right carotid exposure under propofol-buprenorphine or isoflurane-buprenorphine anesthesia groups. They were tested by Barnes maze and fear conditioning from 6 days after the surgery. Their brains were harvested 24 h after the surgery for quantifying interleukin (IL) 1ß, tumor necrosis factor (TNF)α and ionized calcium binding adaptor molecule 1 (Iba-1). We showed that the heart rates and mean arterial blood pressure were similar during surgery under propofol-buprenorphine or isoflurane-buprenorphine anesthesia. There was no difference in the surgery-induced increase of the plasma IL-1ß and TNFα levels under these two types of anesthesia. Rats subjected to surgery took longer than control rats to identify the target hole 8 days after the completion of training sessions in Barnes maze [32 ± 23 s for control, 118 ± 64 s for propofol group (P < 0.05 vs. control), 107 ± 64 s for isoflurane group (P < 0.05 vs. control)] and had less freezing behavior in the fear conditioning test. Surgery and anesthesia increased IL-1ß and Iba-1 but did not affect tau phosphorylated at S199/202 and S396 in the cerebral cortex and hippocampus. Our results suggest that surgery under general anesthesia induces neuroinflammation and cognitive impairment. Anesthetic choice may not be a significant modifiable factor for these effects.

Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure.

BACKGROUND: Neonatal exposure to general anesthetics may pose significant neurocognitive risk. Human epidemiological studies demonstrate higher rates of learning disability among children with multiple, but not single, exposures to anesthesia. The authors employ a rat model to provide a histological correlate for these population-based observations. The authors examined long-term differences in hippocampal synaptic density, mitochondrial density, and dendritic spine morphology. METHODS: Twenty male rat pups (n = 5/condition) were exposed to 2.5% sevoflurane under one of four conditions: single 2-h exposure on postnatal day 7 (P7); single 6-h exposure on P7; repeated 2-h exposures on P7, P10, and P13 for a cumulative 6 h of general anesthetics; or control exposure to 30% oxygen on P7, P10, and P13. RESULTS: Repeated exposure to general anesthetics resulted in greater synaptic loss relative to a single 2-h exposure (P < 0.001). The magnitude of synaptic loss induced by three 2-h exposures (1.977 ± 0.040 µm [mean ± SEM]) was more profound than that of a single 6-h exposure (2.280 ± 0.045 µm, P = 0.022). Repeated exposures did not alter the distribution of postsynaptic density length, indicating a uniform pattern of loss across spine types. In contrast, mitochondrial toxicity was best predicted by the cumulative duration of exposure. Relative to control (0.595 ± 0.017), both repeated 2-h exposures (0.479 ± 0.015) and a single 6-h exposure (0.488 ± 0.013) were associated with equivalent reductions in the fraction of presynaptic terminals containing mitochondria (P < 0.001). CONCLUSION: This suggests a "threshold effect" for general anesthetic-induced neurotoxicity, whereby even brief exposures induce long-lasting alterations in neuronal circuitry and sensitize surviving synapses to subsequent loss.

[Potential neurotoxicity of general anaesthetics to the developing brain]. / Generelle anæstetikas potentielle neurotoksicitet for den immature hjerne.

Animal studies (including non-human primates) have shown that most general anaesthetics cause enhanced neuroapoptosis with subsequent long-term neurocognitive deficits later in life. Some human cohort studies have indicated an association between anaesthesia/surgery and adverse neurocognitive outcome whereas other studies have not. Overall, the data do not justify any change in paediatric anaesthetic clinical practice. Naturally, the risks and benefits of a procedure should always be carefully considered before exposing a child to general anaesthesia.

Reacciones adversas a medicamentos en una unidad quirúrgica de urgencia / Adverse reactions to drugs in a surgical emergency unit

Introducción: las reacciones adversas a medicamentos en unidades quirúrgicas constituyen un problema de salud poco conocido, por lo que son escasas las investigaciones referentes a este tema.Objetivo: caracterizar las reacciones adversas a medicamentos en pacientes operados en la Unidad Quirúrgica de Urgencias del Hospital Militar Central Dr. Luis Díaz Soto. Métodos: estudio descriptivo, prospectivo y observacional que utilizó métodos de farmacovigilancia activa y pasiva. La muestra fue de los 2 128 pacientes operados durante el 2010, quienes fueron monitoreados diariamente a través de un listado de síndromes orientadores de reacciones adversas y la notificación de los profesionales de la salud. Resultados: de los pacientes operados, 65 (3,05 por ciento) presentaron al menos una reacción adversa a medicamentos, con un índice de aparición del 1,12 por ciento. La mayoría de las notificaciones fueron en pacientes de 45-59 años (40,0 por ciento) y del sexo femenino (69,2 por ciento). Los anestésicos generales y los antimicrobianos aportaron el mayor porcentaje de notificaciones (36,9 por ciento y 18,5 por ciento respectivamente); la cefazolina y la ketamina resultaron los fármacos más notificados con un 13,8 por ciento. La piel fue el sistema de órganos más afectado y el rash cutáneo la manifestación clínica más frecuente (17,8 por ciento). Las reacciones adversas moderadas se presentaron con mayor frecuencia. Conclusiones: se pone de manifiesto la importancia de la vigilancia farmacológica de los medicamentos, en especial en áreas sensibles como las unidades quirúrgicas, donde las reacciones adversas a medicamentos son muy frecuentes(AU)

Introduction: adverse drug reactions in surgical units constitute a health problem little known, so there is little research concerning this topic. Objective: to characterize adverse drug reactions in patients operated on at the Surgical Emergency Unit of Dr. Luis D¦az Soto Central Military Hospital. Methods: a prospective, observational study was conducted using active and passive methods of Drug Safety. The sample consisted of 2128 patients operated in 2010.These patients were monitored daily through a counseling list of syndromes for adverse reactions and by health professional reports. Results: out of the patients operated on, 65 (3.05 percent) had at least one adverse drug reaction with a rate of occurrence of 1.12 percent. Most reports were in patients aged 45-59 years (40.0 percent) and female (69.2 percent). the highest rate of reporting was contributed by general anesthetics and antimicrobial (36.9 percent and 18.5 percent respectively); cefazolin and ketamine were the most reported drugs with 13.8 percent. Skin was the most affected organ system and skin rash was the most common clinical manifestation (17.8 percent). Moderate adverse reactions occurred more frequently. Conclusions: the importance of pharmacovigilance is highlighted, especially in sensitive areas such as surgical units, where adverse drug reactions are common(AU)

Reacciones adversas a medicamentos en una unidad quirúrgica de urgencia / Adverse reactions to drugs in a surgical emergency unit

INTRODUCCIÓN: las reacciones adversas a medicamentos en unidades quirúrgicas constituyen un problema de salud poco conocido, por lo que son escasas las investigaciones referentes a este tema.OBJETIVO: caracterizar las reacciones adversas a medicamentos en pacientes operados en la Unidad Quirúrgica de Urgencias del Hospital Militar Central "Dr. Luis Díaz Soto". MÉTODOS: estudio descriptivo, prospectivo y observacional que utilizó métodos de farmacovigilancia activa y pasiva. La muestra fue de los 2 128 pacientes operados durante el 2010, quienes fueron monitoreados diariamente a través de un listado de síndromes orientadores de reacciones adversas y la notificación de los profesionales de la salud. RESULTADOS: de los pacientes operados, 65 (3,05 %) presentaron al menos una reacción adversa a medicamentos, con un índice de aparición del 1,12 %. La mayoría de las notificaciones fueron en pacientes de 45-59 años (40,0 %) y del sexo femenino (69,2 %). Los anestésicos generales y los antimicrobianos aportaron el mayor porcentaje de notificaciones (36,9 % y 18,5 % respectivamente); la cefazolina y la ketamina resultaron los fármacos más notificados con un 13,8 %. La piel fue el sistema de órganos más afectado y el rash cutáneo la manifestación clínica más frecuente (17,8 %). Las reacciones adversas moderadas se presentaron con mayor frecuencia. CONCLUSIONES: se pone de manifiesto la importancia de la vigilancia farmacológica de los medicamentos, en especial en áreas sensibles como las unidades quirúrgicas, donde las reacciones adversas a medicamentos son muy frecuentes.

INTRODUCTION: adverse drug reactions in surgical units constitute a health problem little known, so there is little research concerning this topic. OBJECTIVE: to characterize adverse drug reactions in patients operated on at the Surgical Emergency Unit of "Dr. Luis Díaz Soto" Central Military Hospital. METHODS: a prospective, observational study was conducted using active and passive methods of Drug Safety. The sample consisted of 2128 patients operated in 2010.These patients were monitored daily through a counseling list of syndromes for adverse reactions and by health professional reports. RESULTS: out of the patients operated on, 65 (3.05 %) had at least one adverse drug reaction with a rate of occurrence of 1.12 %. Most reports were in patients aged 45-59 years (40.0 %) and female (69.2 %). the highest rate of reporting was contributed by general anesthetics and antimicrobial (36.9 % and 18.5 % respectively); cefazolin and ketamine were the most reported drugs with 13.8 %. Skin was the most affected organ system and skin rash was the most common clinical manifestation (17.8 %). Moderate adverse reactions occurred more frequently. CONCLUSIONS: the importance of pharmacovigilance is highlighted, especially in sensitive areas such as surgical units, where adverse drug reactions are common.

General anaesthetics and the developing brain: an overview.

Various experimental studies in animals have shown that general anaesthetics are potentially toxic to the developing brain. By inducing apoptosis or interfering with neurogenesis, anaesthetic exposure during a critical period of neuronal development can have significant impact on neurocognitive function later in life. It remains controversial whether these experimental results can be transferred to human beings and this is under intensive scientific evaluation. To gain more insight into possible neurotoxic effects on the human brain of infants and small children, a number of retrospective studies have been performed. At present, there is no clear evidence that exposure to anaesthesia up to the age of 3-4 years is associated with neurocognitive or behavioural deficits. Currently, the PANDA, MASK and GAS studies are underway to explore this relationship. Anaesthesia is not an end in itself, but necessary to facilitate surgical procedures. There is evidence that maintaining physiological conditions is important for the overall outcome following anaesthesia and surgery. Until proven otherwise, it can be recommended to keep anaesthesia and surgery as short as possible, to use short-acting drugs and/or a combination of general anaesthesia and multimodal pain therapy including systemic analgesics, and local or regional anaesthesia, to reduce the overall drug dosage.

Modeling anesthetic developmental neurotoxicity using human stem cells.

Mounting preclinical evidence in rodents and nonhuman primates has demonstrated that prolonged exposure of developing animals to general anesthetics can induce widespread neuronal cell death followed by long-term memory and learning disabilities. In vitro experimental evidence from cultured neonatal animal neurons confirmed the in vivo findings. However, there is no direct clinical evidence of the detrimental effects of anesthetics in human fetuses, infants, or children. Development of an in vitro neurogenesis system using human stem cells has opened up avenues of research for advancing our understanding of human brain development and the issues relevant to anesthetic-induced developmental toxicity in human neuronal lineages. Recent studies from our group, as well as other groups, showed that isoflurane influences human neural stem cell proliferation and neurogenesis, whereas ketamine induces neuroapoptosis. Application of this high throughput in vitro stem cell neurogenesis approach is a major stride toward ensuring the safety of anesthetic agents in young children. This in vitro human model allows us to (1) screen the toxic effects of various anesthetics under controlled conditions during intense neuronal growth, (2) find the trigger for the anesthetic-induced catastrophic chain of toxic events, and (3) develop prevention strategies to avoid this toxic effect. In this article, we reviewed the current findings in anesthetic-induced neurotoxicity studies, specifically focusing on the in vitro human stem cell model.

Mitochondrial protectant pramipexole prevents sex-specific long-term cognitive impairment from early anaesthesia exposure in rats.

BACKGROUND: Exposure to general anaesthesia during critical stages of brain development results in long-lasting cognitive impairment. Co-administration of protective agents could minimize the detrimental effects of anaesthesia. Co-administration of R(+)pramipexole (PPX), a synthetic aminobenzothiazol derivative that restores mitochondrial integrity, prevents anaesthesia-induced mitochondrial and neuronal damage and prevents early development of cognitive impairment. Here, we determine the protective effects of PPX into late adulthood in male and female rats. METHODS: Postnatal day 7 rats of both sexes were exposed to mock anaesthesia or combined midazolam, nitrous oxide, and isoflurane anaesthesia for 6 h with or without PPX. Cognitive abilities were assessed between 5 and 7 months of age using Morris water maze spatial navigation tasks. RESULTS: Examination of spatial reference memory revealed that female, but not male, neonatal rats exposed to anaesthesia showed slowing of acquisition rates, which was significantly improved with PPX treatment. Examination of memory retention revealed that both male and female anaesthesia-treated rats have impaired memory retention performance compared with sham controls. Co-treatment with PPX resulted in improvement in memory retention in both sexes. CONCLUSION: PPX provides long-lasting protection against cognitive impairment known to occur when very young animals are exposed to anaesthesia during the peak of brain development. Anaesthesia-induced cognitive impairment appears to be sex-specific with females being more vulnerable than males, suggesting that they could benefit more from early prevention.