Postoperative Delirium is a Risk Factor of Poor Evolution Three Years After Cardiac Surgery: An Observational Cohort Study.

BACKGROUND: After cardiac surgery, postoperative delirium (POD) is common and is associated with long-term changes in cognitive function. Impact on health-related quality of life (QOL) and long-term dependence are not well known. This aim of this study is to evaluate the role of POD in poor evolution at three years after surgery including poor QOL and dependence and mortality. PATIENTS AND METHODS: We enrolled and followed 173 patients 60 years of age or older who were planning to undergo cardiac surgery with cardiopulmonary bypass. The primary composite outcome was death of any causes, or patients with either a loss of QOL (evaluated with of EuroQuol verbal 5D EQ5D less than 50), or a loss of two points on the instrumental activities of daily living occurring three years after surgery. POD was diagnosed with the use of Confusion Assessment Method. Multivariate logistic regression was performed. RESULTS: At three years, 74 patients (42.8%) had a poor evolution. Independent risk factors in poor patient evolution were sex (female gender; OR: 3.6; 95%CI: 1.45-8.7; p=0.006), metabolic status (diabetic patients; OR: 4; 95%CI: 1.6-10.2; p=0.002), Euroscore 2 (Euroscore 2 >1.5; OR: 5.2; 95%CI: 1.7-15.4; p=0.003) and POD (OR: 3.3; 95%CI 1.4-7.8; p=0.006). Coronary disease was protective (OR: 0.3; 95%CI: 0.14-0.71; p=0.006). CONCLUSION: After cardiac surgery, POD significantly altered patient evolution and increased risk of dependence and loss of QOL.

Efficacy of multimodal analgesic treatment of severe traumatic acute pain in mice pretreated with chronic high dose of buprenorphine inducing mechanical allodynia.

Managing severe acute nociceptive pain in buprenorphine-maintained individuals for opioid use disorder management is challenging owing to the high affinity and very slow dissociation of buprenorphine from µ-opioid receptors that hinders the use of full agonist opioid analgesics. In a translational approach, the aim of this study was to use an animal setting to investigate the effects of a chronic high dose of buprenorphine treatment on nociceptive thresholds before and after applying a severe acute nociceptive traumatic surgery stimulus and to screen postoperative pharmacological analgesic strategies. A chronic treatment of mice with a high dose of buprenorphine (BUP HD, 2 × 200 µg/kg/day; i.p.) revealed significant mechanical allodynia. One and two days after having discontinued buprenorphine administration and having induced a severe nociceptive acute pain by a closed tibial fracture, acute administration of morphine at a dose which has analgesic effects in absence of pretreatment (4.5 mg/kg; i.p.), was ineffective to reduce pain in the BUP HD group. However, mimicking multimodal analgesia strategy used in human postoperative context, the combination of morphine (administered at the same dose) with a NMDA receptor antagonist (ketamine) or an NSAID (ketoprofen) produced antinociceptive responses in these animals. The mouse model of closed tibial fracture could be useful to identify analgesic strategies of postoperative pain for patients with chronic exposure to opioids and suffering from hyperalgesia.

Tibial post fracture pain is reduced in kinin receptors deficient mice and blunted by kinin receptor antagonists.

BACKGROUND: Tibial fracture is associated with inflammatory reaction leading to severe pain syndrome. Bradykinin receptor activation is involved in inflammatory reactions, but has never been investigated in fracture pain. METHODS: This study aims at defining the role of B1 and B2-kinin receptors (B1R and B2R) in a closed tibial fracture pain model by using knockout mice for B1R (B1KO) or B2R (B2KO) and wild-type (WT) mice treated with antagonists for B1R (SSR 240612 and R954) and B2R (HOE140) or vehicle. A cyclooxygenase (COX) inhibitor (ketoprofen) and an antagonist (SB366791) of Transient Receptor Potential Vaniloid1 (TRPV1) were also investigated since these pathways are associated with BK-induced pain in other models. The impact on mechanical and thermal hyperalgesia and locomotion was assessed by behavior tests. Gene expression of B1R and B2R and spinal cord expression of c-Fos were measured by RT-PCR and immunohistochemistry, respectively. RESULTS: B1KO and B2KO mice demonstrated a reduction in post-fracture pain sensitivity compared to WT mice that was associated with decreased c-Fos expression in the ipsilateral spinal dorsal horn in B2KO. B1R and B2R mRNA and protein levels were markedly enhanced at the fracture site. B1R and B2R antagonists and inhibition of COX and TRPV1 pathways reduced pain in WT. However, the analgesic effect of the COX-1/COX-2 inhibitor disappeared in B1KO and B2KO. In contrast, the analgesic effect of the TRPV1 antagonist persisted after gene deletion of either receptor. CONCLUSIONS: It is suggested that B1R and B2R activation contributes significantly to tibial fracture pain through COX. Hence, B1R and B2R antagonists appear potential therapeutic agents to manage post fracture pain.

Activation of nociceptin/orphanin FQ receptors inhibits contextual fear memory reconsolidation.

Several neuropeptidergic systems act as modulators of cognitive performances. Among them, nociceptin, an opioid-like peptide also known as orphanin FQ (N/OFQ), has recently gained attention. Stimulation of its receptor, the N/OFQ opioid receptor (NOP), which is expressed in brain regions involved in emotion, memory and stress response, has inhibitory effects on the acquisition and/or consolidation of spatial and emotional memory in rodents. Recently, N/OFQ was also proposed to be linked to the pathogenesis of Post-Traumatic Stress Disorder in humans. However, until now the effect of the activation of the N/OFQ-NOP system on already consolidated memory, such as during retrieval and reconsolidation phases, has never been explored. In the present study, we investigated the consequences of systemic injection of NOP agonists or i.c.v. injection of the N/OFQ peptide on the retrieval and the reconsolidation of contextual fear memory in mice. We demonstrate that the activation of the N/OFQ system impairs the reconsolidation of context-dependent but not cue-dependent aversive memories. We also show that this amnestic effect is associated with decreased c-Fos expression in the hippocampus and amygdala. Our data thus provide the first evidence that the NOP receptor could be targeted during the reconsolidation process to weaken maladaptive memories. The N/OFQ-NOP system might constitute in the future an interesting pharmacological target for interfering with so-called "pathological memories", in particular those involving maladaptive contextual memories.

Cognitive deficit in hippocampal-dependent tasks in Werner syndrome mouse model.

Mammalian aging is often characterized by metabolic disturbances, cognitive declines and DNA repairs deficiency, but the underlying molecular mechanisms are still not well understood. Alterations in DNA repair can significantly exacerbate aging. Mammalian neuronal cells which accumulate unrepaired DNA damage over time could potentially lead to brain functions disorders. Focusing on the ATP-dependent RecQ-type DNA helicase, an enzyme involved in repair of double strand DNA, a mouse model of Werner syndrome (WS) had been proposed as a model of accelerated aging. Until now, no study has investigated the impact of this premature aging syndrome on learning and memory. Spatial memory and cognitive flexibility are particularly affected by the aging process in both men and rodents. Studies have shown that aged mice exhibited similar performance than young adult mice on non-hippocampus dependent memory whereas their performances were decreased in hippocampus-dependent tasks. In this study, we have submitted 3, 5 and 8 month-old WS mice to several behavioral paradigms to evaluate hippocampus-dependent (spatial object location, Morris water maze and fear conditioning) and non hippocampus-dependent (object recognition) memories. No effect on the locomotion activity and anxiety level has been observed in adult WS mice. Interestingly, the 8 month-old WS mice exhibit long-term memory impairment similar to aged mice, suggesting that adult WS mice do develop some aspects of cognitive aging.

Beneficial effects of levobupivacaine regional anaesthesia on postoperative opioid induced hyperalgesia in diabetic mice.

BACKGROUND: Diabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. The aim of this study was to assess the effect of regional anaesthesia on post surgery opioid induced hyperalgesia in diabetic and non-diabetic mice. METHODS: Diabetic and non-diabetic mice underwent plantar surgery. Levobupivacaine and sufentanil were used before surgery, for sciatic nerve block (regional anaesthesia) and analgesia, respectively. Diabetic and non-diabetic groups were each randomly assigned to three subgroups: control, no sufentanil and no levobupivacaine; sufentanil and no levobupivacaine; sufentanil and levobupivacaine. Three tests were used to assess pain behaviour: mechanical nociception; thermal nociception and guarding behaviours using a pain scale. RESULTS: Sufentanil, alone or in combination with levobupivacaine, produced antinociceptive effects shortly after administration. Subsequently, sufentanil induced hyperalgesia in diabetic and non-diabetic mice. Opioid-induced hyperalgesia was enhanced in diabetic mice. Levobupivacaine associated to sufentanil completely prevented hyperalgesia in both groups of mice. CONCLUSION: The results suggest that regional anaesthesia can decrease opioid-induced hyperalgesia in diabetic as well as in non-diabetic mice. These observations may be clinically relevant for the management of diabetic patients.

Anisomycin injection in area CA3 of the hippocampus impairs both short-term and long-term memories of contextual fear.

Protein synthesis is involved in the consolidation of short-term memory into long-term memory. Previous electrophysiological data concerning LTP in CA3 suggest that protein synthesis in that region might also be necessary for short-term memory. We tested this hypothesis by locally injecting the protein synthesis inhibitor anisomycin in hippocampal area CA1 or CA3 immediately after contextual fear conditioning. As previously shown, injections in CA1 impaired long-term memory but spared short-term memory. Conversely, injections in CA3 impaired both long-term and short-term memories. We conclude that early steps of experience-induced plasticity occurring in CA3 and underlying short-term memory require protein synthesis.

1H NMR metabolomic signatures in five brain regions of the AßPPswe Tg2576 mouse model of Alzheimer's disease at four ages.

In the quest for biomarkers of onset and progression of Alzheimer's disease, a 1H NMR-based metabolomic study was performed on the simple single-transgenic Tg2576 mouse model. These mice develop a slow cognitive decline starting by 6 months and express amyloid plaques from 10 months of age. The metabolic profiles of extracts from five brain regions (frontal cortex, rhinal cortex, hippocampus, midbrain, and cerebellum) of Tg2576 male mice were compared to those of controls, at 1, 3, 6 and 11 months of age. The most obvious differences were due to brain regions. Age was also a discriminating parameter. Metabolic perturbations were already detected in the hippocampus and the rhinal cortex of transgenic mice as early as 1 month of age with decreased concentrations of glutamate (Glu) and N-acetylaspartate (NAA) compared to those in wild-type animals. Metabolic changes were more numerous in the hippocampus and the rhinal cortex of 3 month-old transgenic mice and involved Glu, NAA, myo-inositol, creatine, phosphocholine, and γ-aminobutyric acid (only in the hippocampus) whose concentrations decreased. A metabolic disruption characterized by an increase in the hippocampal concentrations of Glu, creatine, and taurine was detected in 6 month-old transgenic mice. At this time point, the chemical profile of the cerebellum was slightly affected. At 11 months, all the brain regions analyzed (except the frontal cortex) were metabolically altered, with mainly a marked increase in the formation of the neuroprotective metabolites creatine and taurine. Our findings demonstrate that metabolic modifications occur long before the onset of behavioral impairment.

Roles of the ubiquitin proteasome system in the effects of drugs of abuse.

Because of its ability to regulate the abundance of selected proteins the ubiquitin proteasome system (UPS) plays an important role in neuronal and synaptic plasticity. As a result various stages of learning and memory depend on UPS activity. Drug addiction, another phenomenon that relies on neuroplasticity, shares molecular substrates with memory processes. However, the necessity of proteasome-dependent protein degradation for the development of addiction has been poorly studied. Here we first review evidences from the literature that drugs of abuse regulate the expression and activity of the UPS system in the brain. We then provide a list of proteins which have been shown to be targeted to the proteasome following drug treatment and could thus be involved in neuronal adaptations underlying behaviors associated with drug use and abuse. Finally we describe the few studies that addressed the need for UPS-dependent protein degradation in animal models of addiction-related behaviors.

Modifications of hippocampal circuits and early disruption of adult neurogenesis in the tg2576 mouse model of Alzheimer's disease.

At advanced stages of Alzheimer's disease, cognitive dysfunction is accompanied by severe alterations of hippocampal circuits that may largely underlie memory impairments. However, it is likely that anatomical remodeling in the hippocampus may start long before any cognitive alteration is detected. Using the well-described Tg2576 mouse model of Alzheimer's disease that develops progressive age-dependent amyloidosis and cognitive deficits, we examined whether specific stages of the disease were associated with the expression of anatomical markers of hippocampal dysfunction. We found that these mice develop a complex pattern of changes in their dentate gyrus with aging. Those include aberrant expression of neuropeptide Y and reduced levels of calbindin, reflecting a profound remodeling of inhibitory and excitatory circuits in the dentate gyrus. Preceding these changes, we identified severe alterations of adult hippocampal neurogenesis in Tg2576 mice. We gathered converging data in Tg2576 mice at young age, indicating impaired maturation of new neurons that may compromise their functional integration into hippocampal circuits. Thus, disruption of adult hippocampal neurogenesis occurred before network remodeling in this mouse model and therefore may account as an early event in the etiology of Alzheimer's pathology. Ultimately, both events may constitute key components of hippocampal dysfunction and associated cognitive deficits occurring in Alzheimer's disease.

Role of kinin B2 receptors in opioid-induced hyperalgesia in inflammatory pain in mice.

Postoperative pain management is a clinical challenge that can be complicated by opioid-induced hyperalgesia (OIH). Kinin receptors could mediate both the acute and chronic phases of inflammation and pain. A few recent studies suggest that dynorphin A could maintain neuropathic pain by activating the bradykinin (BK) receptor. Thus, the effect of a single administration of sufentanil (a µ-opioid receptor agonist) was investigated in a model of carrageenan-induced inflammatory pain using three strains of mice, i.e., knockout mice for one kinin receptor, B1R or B2R (B1KO, B2KO), and wild-type C57/BL6J mice (WT) treated with either a B1R (R954) or a B2R antagonist (HOE140) or a KKS inhibitor (aprotinin). Pain was assessed and compared between the different groups using two behavioral tests exploring mechanical (von Frey filaments) and thermal (Hargreaves test) sensitivity. Pretreatment with sufentanil induced a sustained increase in pain sensitivity with a delayed return to baseline values characterizing an OIH in carrageenan-injected mice only. Sufentanil-induced OIH was not observed in B2KO but persisted in B1KO and was blunted by aprotinin and the B2R antagonist only. Collectively, our data indicate that the B2R receptor and BK synthesis or availability are essential peripheral steps in the mechanism leading to OIH in a pain context.

Involvement of protein degradation by the ubiquitin proteasome system in opiate addictive behaviors.

Plastic changes in the nucleus accumbens (NAcc), a structure occupying a key position in the neural circuitry related to motivation, are among the critical cellular processes responsible for drug addiction. During the last decade, it has been shown that memory formation and related neuronal plasticity may rely not only on protein synthesis but also on protein degradation by the ubiquitin proteasome system (UPS). In this study, we assess the role of protein degradation in the NAcc in opiate-related behaviors. For this purpose, we coupled behavioral experiments to intra-accumbens injections of lactacystin, an inhibitor of the UPS. We show that protein degradation in the NAcc is mandatory for a full range of animal models of opiate addiction including morphine locomotor sensitization, morphine conditioned place preference, intra-ventral tegmental area morphine self-administration and intra-venous heroin self-administration but not for discrimination learning rewarded by highly palatable food. This study provides the first evidence of a specific role of protein degradation by the UPS in addiction.

Copper chelator induced efficient episodic memory recovery in a non-transgenic Alzheimer's mouse model.

Alzheimer's disease (AD) is a neurodegenerative syndrom involving many different biological parameters, including the accumulation of copper metal ions in Aß amyloid peptides due to a perturbation of copper circulation and homeostasis within the brain. Copper-containing amyloids activated by endogenous reductants are able to generate an oxidative stress that is involved in the toxicity of abnormal amyloids and contribute to the progressive loss of neurons in AD. Since only few drugs are currently available for the treatment of AD, we decided to design small molecules able to interact with copper and we evaluated these drug-candidates with non-transgenic mice, since AD is mainly an aging disease, not related to genetic disorders. We created a memory deficit mouse model by a single icv injection of Aß(1-42) peptide, in order to mimic the early stage of the disease and the key role of amyloid oligomers in AD. No memory deficit was observed in the control mice with the antisense Aß(42-1) peptide. Here we report the capacity of a new copper-specific chelating agent, a bis-8-aminoquinoline PA1637, to fully reverse the deficit of episodic memory after three weeks of treatment by oral route on non-transgenic amyloid-impaired mice. Clioquinol and memantine have been used as comparators to validate this fast and efficient mouse model.

Central apelin controls glucose homeostasis via a nitric oxide-dependent pathway in mice.

AIMS: Apelin and its receptor have emerged as promising targets for the treatment of insulin resistance. Indeed, peripheral administration of apelin stimulates glucose utilization and insulin sensitivity via a nitric oxide (NO) pathway. In addition to being expressed on peripheral metabolically active adipose tissues, apelin is also found in the brain. However, no data are available on the role of central effects of apelin on metabolic control. We studied glucose metabolism in response to acute and chronic intracerebroventricular (i.c.v.) injection of apelin performed in normal and obese/diabetic mice. RESULTS: We demonstrate that i.c.v. injection of apelin into fed mice improves glucose control via NO-dependent mechanisms. These results have been strengthened by transgenic (eNOS-KO mice), pharmacological (L-NMMA i.c.v. treated mice), and real-time measurement of NO release with amperometric probes detection. High-fat diet-fed mice displayed a severely blunted response to i.c.v. apelin associated with a lack of NO response by the hypothalamus. Moreover, central administration of high dose apelin in fasted normal mice provoked hyperinsulinemia, hyperglycemia, glucose intolerance, and insulin resistance. CONCLUSION: These data provide compelling evidence that central apelin participates in the regulation of glucose homeostasis and suggest a novel pathophysiological mechanism involved in the transition from normal to diabetic state.

An alarm pheromone modulates appetitive olfactory learning in the honeybee (apis mellifera).

In honeybees, associative learning is embedded in a social context as bees possess a highly complex social organization in which communication among individuals is mediated by dance behavior informing about food sources, and by a high variety of pheromones that maintain the social links between individuals of a hive. Proboscis extension response conditioning is a case of appetitive learning, in which harnessed bees learn to associate odor stimuli with sucrose reward in the laboratory. Despite its recurrent use as a tool for uncovering the behavioral, cellular, and molecular bases underlying associative learning, the question of whether social signals (pheromones) affect appetitive learning has not been addressed in this experimental framework. This situation contrasts with reports underlining that foraging activity of bees is modulated by alarm pheromones released in the presence of a potential danger. Here, we show that appetitive learning is impaired by the sting alarm pheromone (SAP) which, when released by guards, recruits foragers to defend the hive. This effect is mimicked by the main component of SAP, isopentyl acetate, is dose-dependent and lasts up to 24 h. Learning impairment is specific to alarm signal exposure and is independent of the odorant used for conditioning. Our results suggest that learning impairment may be a response to the biological significance of SAP as an alarm signal, which would detract bees from responding to any appetitive stimuli in a situation in which such responses would be of secondary importance.

Modulation of basal and morphine-induced neuronal activity by a NPFF(2) selective agonist measured by c-Fos mapping of the mouse brain.

Neuropeptide FF (NPFF) is a neurotransmitter known to modulate opioid-induced analgesia, sensitization, and reward. The expression of the immediate early gene c-Fos was analyzed to map the distribution of neurons whose activity is regulated by central administration of the NPFF(2)-selective agonist dNPA in naive mice and in animals who had received a systemic injection of morphine. The number of c-Fos positive nuclei was quantified in 28 brain regions. Intracerebro-ventricular injection of 1 nmol dNPA alone produced an overall inhibition of basal c-Fos expression in the brain with a statistically significant decrease in the lateral ventral part of the bed nucleus of the stria terminalis, the medial preoptic area, and the medial parvicellular part of the paraventricular nucleus of the hypothalamus. In contrast, intraperitoneal injection of morphine 5 mg.kg(-1) induced a statistically significant increase in c-Fos expression in the prelimbic cortex, the nucleus accumbens core and shell, the ventral pallidum, the lateral hypothalamus, and the nucleus of the tractus solitarius. dNPA counteracted morphine effect only in the nucleus accumbens shell and the ventral pallidum. The inhibitory effects of a low dose of dNPA in the hypothalamus and its afferents suggest that NPFF(2) receptors negatively regulate the hypothalamic-pituitary-adrenal axis in mouse. Moreover, our study identified the nucleus accumbens shell and ventral pallidum as putative sites of interaction between NPFF and opioid systems in relation with the modulation of acute morphine rewarding and locomotor effects.

Central locomotor and cognitive effects of a NPFF receptor agonist in mouse.

NPFF receptors are expressed in several brain regions directly or indirectly involved in cognition and behavior. However, the cognitive effects of the NPFF system have been poorly studied. Therefore, the aim of our study was to analyze the effects of i.c.v. injections of 1 DMe, a stable agonist of NPFF receptors, on behavioral and cognitive performances in C57BL/6J mice. We measured locomotor activity, and an open field with objects was used to estimate the ability of mice to react to spatial changes and to measure short-term retention of information. The Morris navigation task was used to evaluate the acquisition, as well as long-term retention of a hippocampo-dependent spatial memory with a distributed training procedure. Finally, 1 DMe was tested in a contextual fear conditioning paradigm to study its effect on long-term memory of contextual information acquired in a single training session. Altogether, our results demonstrate a small but complex influence of the NPFF system on mouse behavior. 1 DMe injected i.c.v. induces a delayed hyperlocomotion and mildly impairs both short-term and long-term spatial memory processing without affecting contextual fear memory.

Activation of metabotropic glutamate receptor type 2/3 supports the involvement of the hippocampal mossy fiber pathway on contextual fear memory consolidation.

Elucidating the functional properties of the dentate gyrus (DG), CA3, and CA1 areas is critical for understanding the role of the dorsal hippocampus in contextual fear memory processing. In order to specifically disrupt various hippocampal inputs, we used region-specific infusions of DCG-IV, the metabotropic glutamate receptor agonist, which selectively disrupts entorhinal outputs as well as mossy fiber transmission in the hippocampus. The consequences of these injections were studied using a contextual fear conditioning (CFC) paradigm. Selective contextual memory impairment was observed in DG- and CA3-, but not in CA1-treated mice. Our results emphasize the major role played by the DG and CA3 areas in the early phases of contextual memory processing, particularly during the acquisition and early consolidation phases of CFC.

Involvement of hippocampal CA3 K(ATP) channels in contextual memory.

This paper evaluates the involvement of hippocampal ATP-sensitive potassium channels (K(ATP)) in learning and memory. After confirming expression of the Kir6.2 subunit in the CA3 region of C57BL/6J mice, we performed intra-hippocampal pharmacological injections of specific openers and blockers of K(ATP) channels. The opener diazoxide, the blocker tolbutamide, or a mixture of both, were bilaterally injected in the CA3 region before we subjected the animals to a fear conditioning paradigm. Diazoxide strongly impaired contextual memory of mice at both doses tested. This impairment was specifically reversed by co-injecting the blocker tolbutamide. Moreover, we studied the mnemonic abilities of mice deleted for the Kir6.2 subunit. These mice were backcrossed to C57BL/6J mice and tested in two learning paradigms. We found a significant impairment of contextual and tone memories in the Kir6.2 knock-out mice when compared with heterozygous or wild-type animals. Furthermore, these animals were also slightly impaired in a spatial version of the Morris water maze task. Our data suggest a specific involvement of hippocampal K(ATP) Kir6.2/SUR1 channels in memory processes.