Murine thioglycolate-induced peritoneal macrophages (MPMs) and the murine RAW264.7 macrophage-like cell line (RAW cells) constitutively produce vascular endothelial growth factor (VEGF). VEGF production is increased under hypoxic conditions or after cell activation with interferon-gamma (IFNgamma) and endotoxin (lipopolysaccharide, LPS). In contrast, tumor necrosis factor-alpha is produced only by IFNgamma/LPS-activated cells. Lactate (25 mmol/L) does not increase VEGF production by these cells. However, hypoxia, lactate, and IFNgamma/LPS-activated MPMs express angiogenic activity, whereas normoxic, nonactivated MPMs do not. Lack of angiogenic activity is not due to an antiangiogenic factor(s) in the medium of these cells. Angiogenic activity produced by hypoxia and lactate-treated MPMs is neutralized by anti-VEGF antibody, which also neutralizes most of the angiogenic activity produced by IFNgamma/LPS-activated MPMs. The inducible nitric oxide synthase inhibitors Ng-nitro-L-arginine-methyl ester (1.5 mmol/L) and aminoguanidine (1 mmol/L) block production of angiogenic activity by MPMs and RAW cells. In RAW cells, Ng-nitro-L-arginine-methyl ester and AG block IFNgamma/LPS-activated, but not constitutive, VEGF production, whereas in MPMs, neither constitutive nor IFNgamma/LPS-activated VEGF synthesis is affected. Synthesis of tumor necrosis factor-alpha is also unaffected. In contrast to normoxic, nonactivated MPMs, inducible nitric oxide synthase-inhibited, IFNgamma/LPS-activated MPMs produce an antiangiogenic factor(s). We conclude that VEGF is a major contributor to macrophage-derived angiogenic activity, and that activation by hypoxia, lactate, or IFNgamma/LPS switches macrophage-derived VEGF from a nonangiogenic to an angiogenic state. This switch may involve a posttranslational modification of VEGF, possibly by the process of ADP-ribosylation. ADP-ribosylation by MPM cytosolic extracts or by cholera toxin switches rVEGF165 from an angiogenic to a nonangiogenic state. In IFNgamma/LPS-activated MPMs, the inducible nitric oxide synthase-dependent pathway also regulates the expression of an antiangiogenic factor(s) that antagonizes the bioactivity of VEGF and provides an additional regulatory pathway controlling the angiogenic phenotype of macrophages.

DEX attenuates neuronal injury induced by maternal propofol anesthesia in the fetal brains, providing neurocognitive protection in the offspring rats.

Alcohol addiction is a major social and health concern. Here, we determined the expression profile of microRNAs (miRNAs) in the nucleus accumbens (NAc) of rats treated with alcohol. The results suggest that multiple miRNAs were aberrantly expressed in rat NAc after alcohol injection. Among them, miR-382 was down-regulated in alcohol-treated rats. In both cultured neuronal cells in vitro and in the NAc in vivo, we identified that the dopamine receptor D1 (Drd1) is a direct target gene of miR-382. Via this target gene, miR-382 strongly modulated the expression of DeltaFosB. Moreover, overexpression of miR-382 significantly attenuated alcohol-induced up-regulation of DRD1 and DeltaFosB, decreased voluntary intake of and preference for alcohol and inhibited the DRD1-induced action potential responses. The results indicated that miRNAs are involved in and may represent novel therapeutic targets for alcoholism.

Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia. dentate gyrus | spine | glutamatergic transmission | AMPA receptors | schizophrenia S chizophrenia is a disabling psychiatric disorder that affects 1% of the general population. It is thought to be a neurodevelopment disorder, as many symptoms appear or worsen during adolescence, a time of great transition and refinements in brain structure and function (1, 2). Consequently, patients display characteristic positive symptoms including delusions and hallucinations, negative symptoms including abnormal emotional reactivity and anhedonia and cognitive deficits. Underlying pathophysiological mechanisms have been explored extensively. The medial temporal lobe, including hippocampal dentate gyrus (DG), is thought to be involved in mediating aspects of psychosis and memory deficits in schizophrenia (3, 4). Impaired glutamatergic transmission in DG causes deficits in spatial coding, learning, and memory and emotion processing (5-7). However, detailed molecular mechanisms of DG dysfunction in schizophrenia remain unclear.Identification of risk genes in recent genetic studies has contributed to a better understanding of pathophysiological mechanisms of schizophrenia. Transmembrane protein 108 (TMEM108) has recently been linked with schizophrenia and alcoholism in genome-wide association studies (8, 9). In human, TMEM108 is located on chromosome 3q21-q22, a risk locus for bipolar disorder, schizophrenia and other psychosis (10, 11). In particular, an intronic single nucleotide polymorphism (SNP) (rs7624858) is associated with schizophrenia (8). These findings raise an important question regarding the physiological function of TMEM108 a...

Background-It is well documented that several general anesthetics, including propofol, potentiate glycine receptor function. Furthermore, glycine receptors exist throughout the central nervous system, including areas of the brain thought to be involved in sleep. However, the role of glycine receptors in anesthetic-induced hypnosis has not been determined.

Propofol is a general anesthetic widely used in surgical procedures, including those in pregnant women. Preclinical studies suggest that propofol may cause neuronal injury to the offspring of primates if it is administered during pregnancy. However, it is unknown whether those neuronal changes would lead to long-term behavioral deficits in the offspring. In this study, propofol (0.4 mg/kg/min, IV, 2 h), saline, or intralipid solution was administered to pregnant rats on gestational day 18. We detected increased levels of cleaved caspase-3 in fetal brain at 6 h after propofol exposure. The neuronal density of the hippocampus of offspring was reduced significantly on postnatal day 10 (P10) and P28. Synaptophysin levels were also significantly reduced on P28. Furthermore, exploratory and learning behaviors of offspring rats (started at P28) were assessed in open-field trial and eight-arm radial maze. The offspring from propofol-treated dams showed significantly less exploratory activity in the open-field test and less spatial learning in the eight-arm radial maze. Thus, this study suggested that propofol exposure during pregnancy in rat increased cleaved caspsase-3 levels in fetal brain, deletion of neurons, reduced synaptophysin levels in the hippocampal region, and persistent learning deficits in the offspring.

Anesthesiologists among physicians are on the top of the drug abuse list, and the mechanism is unclear. Recent studies suggest occupation-related second-hand exposure to i.v. drugs, including propofol, may play a role. Growing evidence indicates that propofol is one of the choices of drugs being abused. In this study, we show that propofol at minute concentrations increases glutamatergic excitatory synaptic transmission and discharges of dopamine neurons in the ventral tegmental area (VTA). We found that acute application of propofol (0.1-10 nM) to the VTA in midbrain slices of rats increased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (EPSCs) mediated by ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. We observed that propofol increased the amplitude but decreased the paired-pulse ratio of EPSCs evoked by stimulation in the absence and the presence of gabazine (SR 95531), a GABA A receptor antagonist. Moreover, the propofol-induced facilitation of EPSCs was mimicked by 6-phenyl-4-azabicyclo[5.4.0]undeca-7,9,11-triene-9,10-diol (SKF38393), an agonist of dopamine D 1 receptor, and by 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12935), a dopamine reuptake inhibitor, but blocked by (Ϯ)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SKF83566), a D 1 antagonist, or by depleting dopamine stores with reserpine. Finally, 1 nM propofol increased the spontaneous discharge rate of dopamine neurons. These findings suggest that propofol at minute concentrations enhances presynaptic D 1 receptormediated facilitation of glutamatergic synaptic transmission and the excitability of VTA dopamine neurons, probably by increasing extracellular dopamine levels. These changes in synaptic plasticity in the VTA, an addiction-related brain area might contribute to the development of propofol abuse and the increased susceptibility to addiction of other drugs.

Kratom is an herb indigenous to Southeast Asia with psychoactive opioid compounds, often used as a treatment for chronic pain or opiate withdrawal symptoms. It is legally and readily available via Internet sales and has been identified as an emerging drug of abuse in the United States. Kratom use has been associated with psychosis, seizures, and even death. At lower doses, kratom acts as a stimulant, while at higher doses, it produces analgesia and euphoria. Here, we describe the successful management of kratom overdose and withdrawal in a young man with negative toxicology screens.