The effects of repeated propofol anesthesia on spatial memory and long-term potentiation in infant rats under hypoxic conditions.
ABSTRACT: Propofol is widely used as an intravenous drug for induction and maintenance in general anesthesia. Hypoxemia is a common complication during perianesthesia. We want to know the effect of propofol on spatial memory and LTP (Long-term potentiation) under hypoxic conditions. In this study, 84 seven-day-old Sprague-Dawley rats were randomly assigned into six groups (n = 14)-four control groups: lipid emulsion solvent + 50% oxygen (CO), lipid emulsion solvent + room air (CA), lipid emulsion solvent + 18% oxygen (CH), and propofol + 50% oxygen (propofol-oxygen, PO); and two experiment groups: propofol + room air (propofol-air, PA), and propofol + 18% oxygen (propofol-hypoxia, PH). After receiving propofol (50 mg/kg) or the same volume of intralipid intraperitoneal (5.0 ml/kg), injected once per day for seven consecutive days, the rats were exposed to 18% oxygen, 50% oxygen and air, until recovery of the righting reflex. We found that the apoptotic index and activated caspase-3 increased in the PH group (P < 0.05) compared with the PA group, fEPSP (field excitatory postsynaptic) potential and success induction rate of LTP reduced in all propofol groups (P < 0.05). Compared with the PO group, the fEPSP and success induction rate of LTP reduced significantly in the PA and PH groups (P < 0.05). Moreover, compared with CH group, the average time of escape latency was longer, and the number of platform location crossings was significantly reduced in the PH group (P < 0.05). Thus, we believe that adequate oxygen is very important during propofol anesthesia.
Project description:Cannabinoids exert powerful action on various forms of synaptic plasticity. These retrograde messengers modulate GABA and glutamate release from presynaptic terminals by acting on presynaptic CB1 receptors. In particular, they inhibit long-term potentiation (LTP) elicited by electrical stimulation of excitatory pathways in rat hippocampus. Recently, LTP of the field excitatory postsynaptic potential (fEPSP) induced by exogenous ATP has been thoroughly explored. The present study demonstrates that cannabinoids inhibit ATP-induced LTP in hippocampal slices of rat. Administration of 10 ?M of ATP led to strong inhibition of fEPSPs in CA1/CA3 hippocampal synapses. Within 40 min after ATP removal from bath solution, robust LTP was observed (fEPSP amplitude comprised 130.1 ± 3.8% of control, n = 10). This LTP never appeared when ATP was applied in addition to cannabinoid receptor agonist WIN55,212-2 (100 nM). Selective CB1 receptor antagonist, AM251 (500 nM), completely abolished this effect of WIN55,212-2. Our data indicate that like canonical LTP elicited by electrical stimulation, ATP-induced LTP is under control of CB1 receptors.
Project description:Pulmonary hypertension (PH) is a devastating condition for which no disease-modifying therapies exist. PH is recognized as proliferative disease of the pulmonary artery (PA). In the experimental newborn calf model of hypoxia-induced PH, adventitial fibroblasts in the PA wall exhibit a heightened replication index. Because elevated platelet-derived growth factor ? receptor (PDGF?-R) signalling is associated with PH, we tested the hypothesis that the activation of PDGF?-R contributes to fibroblast proliferation and adventitial remodelling in PH.Newborn calves were exposed to either ambient air (P(B) = 640 mmHg) (Neo-C) or high altitude (P(B) = 445 mm Hg) (Neo-PH) for 2 weeks. PDGF?-R phosphorylation was markedly elevated in PA adventitia of Neo-PH calves as well as in cultured PA fibroblasts isolated from Neo-PH animals. PDGF?-R activation with PDGF-BB stimulated higher replication in Neo-PH cells compared with that of control fibroblasts. PDGF-BB-induced proliferation was dependent on reactive oxygen species generation and extracellular signal-regulated kinase1/2 activation in both cell populations; however, only Neo-PH cell division via PDGF?-R activation displayed a unique dependence on c-Jun N-terminal kinase1 (JNK1) stimulation as the blockade of JNK1 with SP600125, a pharmacological antagonist of the JNK pathway, and JNK1-targeted siRNA selectively blunted Neo-PH cell proliferation.Our data strongly suggest that hypoxia-induced modified cells engage the PDGF?-R-JNK1 axis to confer distinctively heightened proliferation and adventitial remodelling in PH.
Project description:Bronchopulmonary dysplasia (BPD), a common complication of preterm birth, is associated with pulmonary hypertension (PH) in 25% of infants with moderate to severe BPD. Neonatal mice exposed to hyperoxia for 14d develop lung disease similar to BPD, with evidence of associated PH. The cyclic guanosine monophosphate (cGMP) signaling pathway has not been well studied in BPD-associated PH. In addition, there is little data about the natural history of hyperoxia-induced PH in mice or the utility of phosphodiesterase-5 (PDE5) inhibition in established disease. C57BL/6 mice were placed in room air or 75% O2 within 24h of birth for 14d, followed by recovery in room air for an additional 7 days (21d). Additional pups were treated with either vehicle or sildenafil for 7d during room air recovery. Mean alveolar area, pulmonary artery (PA) medial wall thickness (MWT), RVH, and vessel density were evaluated at 21d. PA protein from 21d animals was analyzed for soluble guanylate cyclase (sGC) activity, PDE5 activity, and cGMP levels. Neonatal hyperoxia exposure results in persistent alveolar simplification, RVH, decreased vessel density, increased MWT, and disrupted cGMP signaling despite a period of room air recovery. Delayed treatment with sildenafil during room air recovery is associated with improved RVH and decreased PA PDE5 activity, but does not have significant effects on alveolar simplification, PA remodeling, or vessel density. These data are consistent with clinical studies suggesting inconsistent effects of sildenafil treatment in infants with BPD-associated PH.
Project description:Effects of pH (6-8), protein concentration (6-11%, w/v), heating temperature (70-95 °C) and time (5-30 min) on functional and antioxidative properties of heat-induced polymerized whey protein were systematically investigated. All samples were determined for solubility at pH 4.6, emulsion capacity and stability, and antioxidative properties involving 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis(2-ethylbenzothiazoline-6-sulfonate) (ABTS) scavenging abilities. Heating resulted in significant loss in solubility, emulsion capacity and stability for whey protein, <i>p</i>?<?0.05. Heating decreased DPPH but enhanced ABTS scavenging ability for whey protein significantly, <i>p</i>?<?0.05. Changes caused by pH variation were much stronger than those observed for other factors. Both protein concentration and heating time had negative effects while heating temperature had positive effect on emulsion capacity of whey protein. Data indicates that functional and antioxidative properties of whey protein could be altered by factors including pH, protein concentration, heating temperature and time.
Project description:BACKGROUND:There are scenarios where pre-mixing and infusing analgesic and anaesthetic agents as a single intravenous (IV) solution is highly desirable; however, it is important to ensure the agents are compatible when mixed. As such, the long-term stability of a remifentanil-propofol mixture, and means of improving this, were assessed across a range of remifentanil concentrations, diluents, and time points. METHODS:Remifentanil was reconstituted with ultrapure water, 0.9% saline, 20% saline, or 8.4% sodium bicarbonate solution (the latter two chosen for their pH characteristics, rather than their use in pharmaceutical reconstitution) and then mixed with propofol (1%) or further diluted with water to derive concentrations of 10-50??g?mL-?1. Remifentanil and propofol concentrations were determined initially and then periodically for up to 24?h using high performance liquid chromatography (HPLC). Mass spectrometry (MS) was used to detect degradation products in solutions containing 30??g?mL-?1 of remifentanil. Statistical analysis was performed using ANOVA and Student's t-test, with a significance value of 0.05. RESULTS:Isolated remifentanil (pH <?4) and propofol (pH?7.35) did not degrade significantly when reconstituted with water or saline solution over 24?h, while remifentanil reconstituted with sodium bicarbonate degraded significantly (P <?0.001, pH?8.65). Mixing with propofol substantially increased the pH of the mixture and resulted in significant remifentanil degradation for all reconstitution solutions used, while propofol remained stable (pH?6.50). The amount of degradation product detected in samples containing isolated remifentanil and a mixture of the drugs was proportional to the remifentanil degradation observed. CONCLUSIONS:Remifentanil stability is affected by both the reconstitution solution used and when mixed with propofol, with pH appearing to be a contributing factor to degradation. If the pH of the solution and concentration of remifentanil are correctly controlled, e.g. through the use of a more acidic diluent, an admixture of remifentanil and propofol may be useful clinically.
Project description:Background:Propofol is the most widely used intravenous sedative-hypnotic anesthetic in clinical practice. However, many serious side effects have been related to its lipid emulsion formulation. The pro-drug design approach was used to develop the water-soluble propofol, which could effectively resolve the limitations associated with the lipid emulsion formulation. Thus, the new water-soluble pro-drug of propofol, HX0969W, was designed and synthesized. The objective of this study was to conduct preclinical pharmacological studies on this novel water-soluble pro-drug of propofol. Methods:The assessment of the loss of the righting reflex (LoRR) was used for the pharmacodynamic study, and liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography- fluorescence were used for the pharmacokinetic study. Results:The potency of HX0969W (ED50 [95% CI], 46.49 [43.89-49.29] mg/kg) was similar to that of fospropofol disodium (43.66 [43.57-43.75] mg/kg), but was lower than that of propofol (4.82 [4.8-14.82] mg/kg). Administered with a dose of 2-fold ED50, propofol required a shorter time to cause LoRR than that of HX0969W and fospropofol. However, the LoRR duration was significantly longer in response to the administration of HX0969W and fospropofol disodium than that caused by propofol. In the pharmacokinetic study, the Cmax of fospropofol was higher than that of HX0969W. HX0969W had a shorter mean residual time and a rapid clearance rate than that of fospropofol disodium. There was no significant difference between the Tmax of the propofol whether it was released by HX0969W or fospropofol disodium; the Cmax of propofol released by HX0969W was similar to that of propofol, which was higher than the propofol released by fospropofol disodium.
Project description:Prenatal ethanol exposure (PAE) induces behavioral maladptations in offspring, including a deficit in memory formation which is part of the umbrella sign of fetal alcohol spectrum disorder. Clinical and preclinical studies have shown that iron depletion exacerbates cognitive problems in offspring exposed to ethanol <i>in utero</i> and that PAE promotes dysregulation in brain iron homeostasis. However, the mechanisms underlying brain iron dysregulation and neuronal activity defects in adolescent offspring of PAE are unclear and poorly understand. Here, we used a PAE rat model to analyze messenger RNA (mRNA) and protein expression of iron homeostasis genes such as transferrin receptor (TfR), divalent metal transporter (DMT1), ferroportin (FPN1), and ferritin (FT) in brain areas associated with memory formation such as the prefrontal cortex (PFC), ventral tegmental area, and hippocampus. Interestingly, we found that 21 day old PAE rats have higher mRNA expression of DMT1 in the PFC, and TfR in the hippocampus, compared to control animals. In contrast FPN has lower mRNA expression in the PFC, and FT and FPN1 have lower expression in the hippocampus. In agreement with these results, we found a 1.5-2 fold increase of TfR and DMT1 protein levels both in the hippocampus and the PFC. Additionally, using an electrophysiological approach, we found that in hippocampal slices from PAE rats, iron treatment decreased long-term potentiation (LTP), but not AMPAR basal transmission (AMPAR fEPSP). In contrast, in control slices Fe-NTA did not affect LTP but decreased significantly the AMPAR fEPSP. Meanwhile, iron chelation with deferiprone decreased AMPAR transmission in PAE and control slices and decreased LTP only in controls slices. These results suggest that PAE affects iron homeostasis of specific brain areas-PFC and hippocampus-which could be involved in maladaptive cognition observed in this animal model.
Project description:NMDA receptor-dependent long-term potentiation (LTP) in the hippocampus is widely accepted as a cellular substrate for memory formation. Age-related declines in the expression of both NMDAR-dependent LTP and NMDAR subunit proteins in the CA1 region of the hippocampus have been well characterized and likely underlie age-related memory impairment. In the current study, we examined NMDAR-dependent LTP in young Fischer 344 rats (4 months old) and aged rats (24 months old) given either a control diet or a diet supplemented with blueberry extract for 6-8 weeks. NMDAR-dependent LTP was evoked by high-frequency stimulation (HFS) in the presence of nifedipine, to eliminate voltage-gated calcium channel LTP. Field excitatory postsynaptic potentials (fEPSPs) were increased by 57% 1 h after HFS in young animals, but this potentiation was reduced to 31% in aged animals. Supplementation of the diet with blueberry extract elevated LTP (63%) in aged animals to levels seen in young. The normalization of LTP may be due to the blueberry diet preventing a decline in synaptic strength, as measured by the slope of the fEPSP for a given fiber potential. The blueberry diet did not prevent age-related declines in NMDAR protein expression. However, phosphorylation of a key tyrosine residue on the NR2B subunit, important for increasing NMDAR function, was enhanced by the diet, suggesting that an increase in NMDAR function might overcome the loss in protein. This report provides evidence that dietary alterations later in life may prevent or postpone the cognitive declines associated with aging.
Project description:Regression of pulmonary hypertension (PH) is often incomplete after successful left-sided valve replacement (LSVR). Proximal pulmonary arterial (PPA) wall disease can be involved in patients with persistent-PH after LSVR, affecting the right ventricular to pulmonary arterial (RV-PA) coupling. Fifteen patients underwent successful LSVR at least one year ago presenting PH by echo (>?50?mmHg). Prosthesis-patient mismatch and left ventricular dysfunction were discarded. All patients underwent hemodynamic and intravascular ultrasound (IVUS) study. We estimated PPA stiffness (elastic modulus [EM]) and the relative area wall thickness (AWT). Acute vasoreactivity was assessed by inhaled nitric oxide (iNO) testing. RV-PA coupling was estimated by the tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure ratio. Patients were classified as isolated post-capillary PH (Ipc-PH; pulmonary vascular resistance [PVR]???3 WU and/or diastolic pulmonary gradient [DPG]?<?7?mmHg) and combined post- and pre-capillary PH (Cpc-PH; PVR?>?3 WU and DPG???7?mmHg). Both Ipc-PH and Cpc-PH showed a significant increase of EM and AWT. Despite normal PVR and DPG, Ipc-PH had a significant decrease in pulmonary arterial capacitance and RV-PA coupling impairment. Cpc-PH had worse PA stiffness and RV-PA coupling to Ipc-PH ( P?<?0.05). iNO decreased RV afterload, improving the cardiac index and stroke volume only in Cpc-PH ( P?<?0.05). Patients with persistent PH after successful LSVR have PPA wall disease and RV-PA coupling impairment beyond the hemodynamic phenotype. Cpc-PH is responsive to iNO, having the worse PA stiffness and RV-PA coupling. The PPA remodeling could be an early event in the natural history of PH associated with left heart disease.
Project description:Administration of propofol, the most frequently used intravenous anesthetic worldwide, has been associated with several iatrogenic infections despite its relative safety. Little is known regarding the global epidemiology of propofol-related outbreaks and the effectiveness of existing preventive strategies. In this overview of the evidence of propofol as a source of infection and appraisal of preventive strategies, we identified 58 studies through a literature search in PubMed, Embase, and Lilacs for propofol-related infections during 1989-2014. Twenty propofol-related outbreaks have been reported, affecting 144 patients and resulting in 10 deaths. Related factors included reuse of syringes for multiple patients and prolonged exposure to the environment when vials were left open. The addition of antimicrobial drugs to the emulsion has been instituted in some countries, but outbreaks have still occurred. There remains a lack of comprehensive information on the effectiveness of measures to prevent future outbreaks.