Melatonin pretreatment prevents propofol-induced sleep disturbance by modulating circadian rhythm in rats.

Postoperative sleep disorder frequently occurs in patients after surgery. Sleep disturbance aggravates pain, anxiety, and delirium, which is an important risk factor for poor recovery. Circadian rhythm disorder induced by general anesthesia plays important role in postoperative sleep disorders. A large number of clinical studies have shown that various forms and duration of general anesthesia can lead to postoperative sleep disorders. In this study, the effect of prolonged propofol anesthesia on biological rhythm was comprehensively evaluated by wireless physiological telemetry system, and the therapeutic effect of exogenous melatonin pretreatment was further investigated. The results showed that prolonged propofol anesthesia had significant impacts on the circadian rhythm of sleep, body temperature, locomotor activity and endogenous melatonin secretion within 24 h following anesthesia, resulting in diminished oscillation amplitude. In hypothalamus, the expression of circadian factor PER and CRY were inhibited by propofol, possibly through activation of CAMK-CREB signaling pathway. Post-translational factors GSK-3ß, SIRT1, AMPK were also involved in the regulation of circadian factors after propofol anesthesia. Melatonin pretreatment could restore circadian rhythm process by regulating circadian factor expression through post-translational modulation and prohibit the over-synthesis of melatonin in pineal gland. This study verified the effects of anesthetics on circadian rhythm and further evaluated the potential therapeutic effect of melatonin on postoperative circadian rhythm and sleep disorders.

Rapid anti-PTSD-like activity of the TSPO agonist YL-IPA08: Emphasis on brain GABA, neurosteroids and HPA axis function.

There is a serious need for fast-acting drugs to treat post-traumatic stress disorder (PTSD). Our previous studies revealed that YL-IPA08, a novel small-molecule TSPO agonist, exerted significant anti-PTSD effects in various animal models. However, the onset time of YL-IPA08 and its underlying mechanisms remain unclear. In the present study, we first investigated the time course of YL-IPA08 compared to selective serotonin reuptake inhibitors (SSRIs) in the well-known time-dependent sensitization model of PTSD. YL-IPA08 required only 2-4 days of treatment to take effect in behavioural models of PTSD, whereas sertraline required 7-8 days. Furthermore, the mechanism study revealed that YL-IPA08 elicited anti-PTSD-like effects associated with increased GABA levels and allopregnanolone efflux in the hippocampus and prefrontal cortex and increased corticosterone levels in the serum after only 5 days of treatment, whereas sertraline required 9 days. Our results demonstrate that YL-IPA08 can exert fast-onset anti-PTSD-like effects, and its mechanisms may be related to the increased GABA levels, allopregnanolone efflux and the hypothalamic-pituitary-adrenal (HPA) axis function.

Overexpression of the 18 kDa translocator protein (TSPO) in the hippocampal dentate gyrus produced anxiolytic and antidepressant-like behavioural effects.

The 18 kDa translocator protein (TSPO) is a five transmembrane domain protein that plays a crucial role in neurosteroid (e.g., allopregnanolone) synthesis by promoting the transport of cholesterol to the inner mitochondrial membrane. This protein is predominantly expressed in steroid-synthesizing tissues, including the central and peripheral nervous system, affecting stress-related disorders such as anxiety and depression. Recent studies have focused on the hippocampal dentate gyrus, which is very important for involvement of anxiety and depression. However, the exact role that TSPO plays in the pathophysiology of anxiety and depression and the involvement of the hippocampal dentate gyrus in regulating these behavioural effects remain elusive. This study used the lentiviral vectors mediating TPSO overexpression to assess the effects of TPSO overexpression in the hippocampal dentate gyrus on anxiolytic and antidepressant-like behavioural effects in mice. The expression of TSPO and the concentration of allopregnanolone in hippocampus tissues (3 mm in diameter around the injection site on both sides) were measured by Western blot and ELISA, respectively. The results indicated that microinjection of the LV-TSPO resulted in a significant increase in TSPO expression and allopregnanolone concentration in the hippocampus. Moreover, TSPO overexpression of the mouse hippocampal dentate gyrus generated significant anxiolytic and antidepressant-like behavioural effects in a series of behavioural models. These effects were completely blocked by the TSPO antagonist PK11195 (3 mg/kg, intraperitoneally) and the 5α-reductase inhibitor finasteride (5 mg/kg,intraperitoneally). Meanwhile, the increased allopregnanolone was also reversed by PK11195 and finasteride. In addition, neither PK11195 nor finasteride had an effect on the expression of TSPO. Overall, our results are the first to suggest that the overexpression of TSPO in the hippocampal dentate gyrus produced anxiolytic and antidepressant-like behavioural effects that are partially mediated by downstream allopregnanolone biosynthesis. Our results suggest that TSPO would be a potential anxiolytic and antidepressant therapeutic target.

Effect of perioperative dexmedetomidine on the endocrine modulators of stress response: a meta-analysis.

This study examined the effects of perioperative dexmedetomidine treatment on physiological modulators of surgical stress response. The quality of the included studies was assessed prior to performing meta-analyses of the weighted mean differences in the changes from baseline of stress hormones and interpreted in the light of statistical heterogeneity between the studies. Nineteen studies (844 surgical subjects) data were used for this meta-analysis. Dexmedetomidine administration significantly decreased blood cortisol levels (µg/dL) postoperatively (mean difference with 95% confidence interval (CI) from controls: -18.78 (-28.45, -9.10); P < 0.05). In the subgroup analysis, the mean difference between dexmedetomidine-treated and saline-treated subjects in the changes from baseline of the cortisol levels was -20.10 (-30.96, -9.25; P < 0.05) but, between dexmedetomidine- and comparator-treated subjects, it was not statistically significantly different (-15.13 (-49.78, 19.52); P < 0.05). Compared with controls, dexmedetomidine treatment also decreased adrenaline and noradrenaline levels significantly (mean difference in the percent changes from baseline: -90.41 (-145.79, -35.03)%; P < 0.05 and -62.82 (-85.47, -0.40.17)%; P < 0.05, respectively). Dexmedetomidine also decreased prolactin levels with a mean difference of -19.42 (-39.37, 0.52) µg/L (P = 0.06). In conclusion, perioperative use of dexmedetomidine reduces serum catecholamine and cortisol levels but the decrease in cortisol levels was not statistically different from the comparator anaesthetics. More data will be required to assess the effects of dexmedetomidine on corticotropin, prolactin, and growth hormone.

Anxiolytic effects of ketamine in animal models of posttraumatic stress disorder.

This study investigated the effectiveness of ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, in alleviating the enhanced anxiety and fear response in both a mouse model of PTSD induced by inescapable electric foot shocks and a rat model of PTSD induced by a time-dependent sensitization (TDS) procedure. First, we evaluated the effect of ketamine on behavioral deficits in a mouse model of PTSD that consisted of foot shocks followed by three situational reminders. Our results showed that the aversive procedure induced several behavioral deficiencies, such as increased freezing behavior and anxiety, as well as reduced time spent in an aversive-like context, which were reversed by repeated treatment with ketamine. The effect of ketamine on behavioral changes after exposure to TDS was also investigated, and the levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were measured. The results revealed that after TDS, the rats showed a significant increase in contextual freezing and a decrease in the percentage of time spent in and numbers of entries into open arms in the elevated plus maze test. As a positive control drug, sertraline (Ser, 15 mg/kg, i.g.), a selective serotonin reuptake inhibitor (SSRI) ameliorated these behavioral deficits. These behavioral effects were mimicked by chronic ketamine treatment. Furthermore, ketamine normalized the decreased BDNF level in the hippocampus in post-TDS rats. Taken together, these results suggest that ketamine exerts a therapeutic effect on PTSD that might be at least partially mediated by an influence on BDNF signaling in the hippocampus.

Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of the total flavonoids extracted from Xiaobuxin-Tang.

Our previous studies have demonstrated that the total flavonoids (XBXT-2) isolated from the extract of Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, exerted antidepressant-like effects. Recently, accumulating studies have suggested that l-arginine-NO is implicated in the regulation of depression. Therefore, the aim of current study attempts to explore the involvement of l-arginine-NO pathway in the antidepressant-like effect of XBXT-2 in the mouse forced swim test (FST). Our results showed that the antidepressant-like action of XBXT-2 (100mg/kg, i.g.) was reversed by pretreatment with l-arginine (a nitric oxide precursor, 750mg/kg, i.p.). While co-administration of aminoguanidine (a specific inducible NOS inhibitor, 40, 80mg/kg, i.p.) and sub-effective dose of XBXT-2 (50mg/kg, i.g.) did not significantly alter the immobility in FST. In contrast, combined administration of 7-nitroindazole (a specific neuronal NOS inhibitor, 50mg/kg, i.p.) potentiated the antidepressant-like effect of non-effective doses of XBXT-2 (50mg/kg, i.g.). Meanwhile, NO modulators were devoid of any locomotor effects on the animals. In conclusion, the antidepressant-like action of XBXT-2 may be involvement of NO signaling pathway.

[Protective effects of propofol combined with reserpine on cultured PC12 cells impaired by ischemia and reperfusion].

OBJECTIVE: To evaluate the protective action of propofol and reserpine, as well as a combination of the two drugs on cultured pheochromocytoma cells (PC12 cells) impaired by mimic ischemia reperfusion (IR), and its possible mechanisms. METHODS: PC12 cells were subjected to IR to reproduce the experimental model. They were divided into IR group, propofol (P) group, reserpine (R) group, and fospropofol/reserpine combined treatment (PR) group. The scale of cell impairment in each group was assessed by the content of lactate dehydrogenase (LDH) and by the absorption (A) at 570 nm with the methyl thiazolyl tetrazolium (MTT) assay. The change in [Ca2+]i was detected by Fura-2/AM fluorescence assay after the treatment of propofol, reserpine, or both. RESULTS: Compared with IR group, the release of LDH was decreased and the A values increased in P, R and PR groups (P < 0.05 or P < 0.01). When combined with reserpine (40 micromol/L), different concentrations of propofol (12.4, 37.3 and 112.0 micromol/L) rendered the cells to release less LDH, with an increase in A value (all P < 0.05). Both propofol (12.4 micromol/L and 37.3 micromol/L) and reserpine (40 micromol/L) could lessen the overload of intra-cellular calcium after IR [(279.66+/-18.00) nmol/L vs. (219.41+/-12.53) nmol/L, (279.66+/-18.00) nmol/L vs. (210.50+/-11.03) nmol/L, (279.66+/-18.00) nmol/L vs. (254.82+/-10.45) nmol/L,P < 0.05 or P < 0.01]. [Ca2+]i could be further lowered when the cells were treated with propofol and reserpine in combination [(191.19+/-10.36) nmol/L and (183.82+/-9.83) nmol/L, both P < 0.05]. CONCLUSION: Both propofol and reserpine can protect cells from IR injury, and attenuate [Ca2+]i overload induced by IR. The attenuation of [Ca2+]i overload in impaired cells may be one of the mechanisms for their protective actions.

Inhibition of N-methyl-D-aspartate receptor function appears to be one of the common actions for antidepressants.

In order to explore the possible common action mechanisms of three kinds of classical antidepressants, inhibition of drugs on the N-methyl-D-aspartate (NMDA)-Ca(2)-nitric oxide synthase (NOS) signal pathway was observed. With 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and lactic dehydrogenase (LDH) assay, classical antidepressants, desipramine (1, 10 microM), fluoxetine (0.625-10 microM) or moclobemide (2.5, 10 microM) antagonized NMDA 300 M induced-lesion in PC12 cells. Using fura-2/AM (acetoxymethyl ester) labelling assay, desipramine or fluoxetine at doses 1, 5 microM attenuated the intracellular Ca(2) overload induced by NMDA 200 microM for 24 h in PC12 cells. Meanwhile, using confocal microscope, it was also found that desipramine 5 microM, fluoxetine 2.5 microM or moclobemide 10 microM decreased the NMDA 20 microM induced intracellular Ca(2) overload in primarily cultured rat hippocampal neurons. Furthermore, desipramine (1, 5 microM), fluoxetine (1, 5 microM) or moclobemide (2.5, 10 microM) significantly inhibited NOS activity in NMDA (300 microM) treated PC12 cells for 4h. In summary, we suggest that inhibition on the function of NMDA-Ca(2) -NOS signal pathway appears to be one of the common actions for antidepressants despite their remarkably different structures, which is expected to have great implication for the evaluation and screening in vitro of new antidepressants.

Moclobemide up-regulates proliferation of hippocampal progenitor cells in chronically stressed mice.

AIM: To explore the action mechanism of antidepressants. METHODS: The PC12 cell proliferation was detected by flow cytometry. The proliferation of hippocampal progenitor cells and level of brain-derived neurotrophic factor (BDNF) were measured by immunohistochemistry. RESULTS: Treatment with N-methylaspartate (NMDA) 600 micromol/L for 3 d significantly decreased the percentage of S-phase in PC12 cells, while in the presence of classical antidepressant, moclobemide (MOC) 2 and 10 micromol/L, the percentage in S-phase increased. Furthermore, the proliferation of progenitor cells in hippocampal dentate gyrus (subgranular zone), as well as the level of BDNF in hippocampus significantly decreased in chronically stressed mice, while chronic administration with MOC 40 mg/kg (ip) up-regulated the progenitor cell proliferation and BDNF level in the same time course. CONCLUSION: Up-regulation of the proliferation of hippocampal progenitor cells is one of the action mechanisms for MOC, which may be closely related to the elevation of BDNF level at the same time. These results also extend evidence for our hypothesis that up-regulation of the hippocampal neurogenesis is one of the common mechanisms for antidepressants.

The cytoprotective effect of inulin-type hexasaccharide extracted from Morinda officinalis on PC12 cells against the lesion induced by corticosterone.

High concentration of corticosterone (Cort) 0.2 mM was incubated with PC12 cells to simulate the lesion state of brain neurons in depressive illness, it was found that the inulin-type oligosaccharides extracted from Morinda officinalis, inulin-type hexasaccharide (IHS) at the doses of 0.625, 1.25 microM or desipramine (DIM) 0.25, 1 microM protected the PC12 cells from the lesion induced by Cort. With Fura-2/AM labeling assay, DIM 0.25, 1 microM or IHS 2.5, 10 microM attenuated the intracellular Ca2+ overloading induced by Cort 0.1 mM for 48 h in PC12 cells. Using RT-PCR, treatment with Cort 0.1 mM for 48 h decreased the nerve growth factor (NGF) mRNA level in PC12 cells, IHS 5, 10 microM reversed this change. In summary, IHS attenuate the intracellular Ca2+ overloading and thereby up-regulate the NGF mRNA expression in Cort-treated PC12 cells, which may be consisted at least part of the cytopretective effect of IHS. These results also extend evidence for our hypothesis that neuroprotective action is one of the common mechanisms for antidepressants.

Antidepressant-like effect of agmatine and its possible mechanism.

In mammalian brain, agmatine is an endogenous neurotransmitter and/or neuromodulator, which is considered as an endogenous ligand for imidazoline receptors. In this study, the antidepressant-like action of agmatine administered p.o. or s.c. was evaluated in three behavioral models in mice or rats. Agmatine at doses 40 and 80 mg/kg (p.o.) reduced immobility time in the tail suspension test and forced swim test in mice or at dose 20 mg/kg (s.c.) in the forced swim test. Agmatine also reduced immobility time at 10 mg/kg (p.o.) or at 1.25, 2.5 and 5 mg/kg (s.c.) in the forced swim test in rats. These results firstly indicated that agmatine possessed an antidepressant-like action. With 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and lactic dehydrogenase (LDH) assay, 1, 10 and 100 microM agmatine or a classical antidepressant, 2.5 and 10 microM desipramine, protected PC12 cells from the lesion induced by 300 microM N-methyl-D-aspartate (NMDA) treatment for 24 h. Using high-performance liquid chromatography with electrochemical detection (HPLC-ECD), it was found that the levels of monoamines including norepinephrine, epinephrine, dopamine or 5-hydroxytryptamine (5-HT) in PC12 cells decreased after the treatment with 200 microM NMDA for 24 h, while in the presence of 1 and 10 microM agmatine or 1 and 5 microM desipramine, the levels of norepinephrine, epinephrine or dopamine were elevated significantly while 5-HT did not change. Moreover, norepinephrine, 5-HT or dopamine had the same cytoprotective effect as agmatine at doses 0.1, 1 and 10 microM. In the fura-2/AM (acetoxymethyl ester) labeling assay, 1 and 10 microM agmatine, 1 and 5 microM desipramine or monoamines norepinephrine, 5-HT at doses 0.1 and 1 microM attenuated the intracellular Ca(2+) overloading induced by 200 microM NMDA treatment for 24 h in PC12 cells. In summary, we firstly demonstrated that agmatine has an antidepressant-like effect in mice and rats. A classical antidepressant, desipramine, as well as agmatine or monoamines protect the PC12 cells from the lesion induced by NMDA treatment. Agmatine reverses the NMDA-induced intracellular Ca(2+) overloading and the decrease of monoamines (including norepinephrine, epinephrine or dopamine) contents in PC12 cells, indicating that agmatine's antidepressant-like action may be related to its modulation of NMDA receptor activity and/or reversal of the decrease of monoamine contents and Ca(2+) overloading induced by NMDA.

Molecular epidemiological study of dengue virus type 1 in Taiwan.

Taiwan has experienced several major outbreaks of dengue (DEN) virus since 1981. The predominant virus type involved has been dengue virus type one (DEN-1), which first appeared in 1987. To understand the molecular epidemiology of this virus, 15 strains of DEN-1 isolated during 1987-1991 and 1994-1995, including 11 epidemic strains, two sporadic strains, and two imported strains have been studied. Fragments of 490 nucleotides (nt) from the E/NS1 junction were amplified by reverse transcription-polymerase chain reaction and the nt sequences were determined. Of the 490 nt of the E/NS1 junction, 240 nt (nt 2282-2521) were aligned and compared. Nucleotide substitutions were found at 54 positions among 15 isolates. Most nt changes were synonymous substitutions, and only three amino acid changes were found. A total of 61 strains isolated worldwide were analyzed by the Neighbor-joining method, and separated phylogenetically into three distinct genotypes, I-III. Genotype I comprised isolates from Japan and Hawaii collected in the 1940s. Genotype II included most strains isolated from Asia in 1977-1995. Genotype III consisted of isolates from three continents in 1964-1995: Asia, the Americas, and Africa. Genotype III was divided further into two subgenotypes, IIIA and IIIB. Most recent isolates from Taiwan, except for the sporadic strain isolated in 1995, were similar genetically and have been classified as Genotype II.