Transforming growth factor-beta1 regulation of resting zone chondrocytes is mediated by two separate but interacting pathways

Previous studies have shown that transforming growth factor-beta1 (TGF-beta1) stimulates protein kinase C (PKC) via a mechanism that is independent of phospholipase C or tyrosine kinase, but involves a pertussis toxin-sensitive G-protein. Maximal activation occurs at 12 h and requires new gene expression. To understand the signaling pathways involved, resting zone chondrocytes were incubated with TGF-beta1 and PKC activity was inhibited with chelerythrine, staurosporine or H-7. [(35)S]Sulfate incorporation was inhibited, indicating that PKC mediates the effects of TGF-beta1 on matrix production. However, there was little, if any, effect on TGF-beta1-dependent increases in [(3)H]thymidine incorporation, and TGF-beta1-stimulated alkaline phosphatase was unaffected, indicating that these responses to the growth factor are not regulated via PKC. TGF-beta1 caused a dose-dependent increase in prostaglandin E(2) (PGE(2)) production which was further increased by PKC inhibition. The increase was regulated by TGF-beta1-dependent effects on phospholipase A(2) (PLA(2)). Activation of PLA(2) inhibited TGF-beta1 effects on PKC, and inhibition of PLA(2) activated TGF-beta1-dependent PKC. Exogenous arachidonic acid also inhibited TGF-beta1-dependent increases in PKC. The effects of TGF-beta1 on PKC involve genomic mechanisms, but not regulation of existing membrane-associated enzyme, since no direct effect of the growth factor on plasma membrane or matrix vesicle PKC was observed. These results support the hypothesis that TGF-beta1 modulates its effects on matrix production through PKC, but its effects on alkaline phosphatase are mediated by production of PGE(2) and protein kinase A (PKA). Inhibition of PKA also decreases TGF-beta1-dependent proliferation. We have previously shown that PGE(2) stimulates alkaline phosphatase through its EP2 receptor, whereas EP1 signaling causes a decrease in PKC. Thus, there is cross-talk between the two pathways.     

CSF-1 receptor signalling from endosomes mediates the sustained activation of Erk1/2 and Akt in macrophages

Colony stimulating factor-1 (CSF-1) mediates its pleiotropic effects on macrophages through the CSF-1 receptor (CSF-1R), a receptor tyrosine kinase. Current models of CSF-1 signalling imply that the CSF-1R activates signalling pathways exclusively at the plasma membrane and the subsequent internalisation of the CSF-1R simply facilitates its lysosomal degradation in order to prevent on-going signalling. Here, we sought to establish if the CSF-1R may in fact continue to signal following its internalisation. Erk1/2, Akt and Stat3 activation were abrogated when the internalisation of the CSF-1R was impaired, with the effects on Stat3 distinct from those for Erk1/2 and Akt. Pharmacologic inhibition of the CSF-1R following its internalisation resulted in less sustained Erk1/2 and Akt activity, whereas Stat3 activity was unaffected. Significantly, the suppressive effects of the CSF-1R inhibitor on the up-regulation of gene expression by CSF-1 (e.g. cyclin D1 and Bcl-xL gene expression) were comparable irrespective of whether the inhibitor was added prior to CSF-1 stimulation or following the internalisation of the CSF-1R. Similarly, pharmacologic inhibition of Erk1/2 (or Akt) activity either prior to CSF-1 stimulation or subsequent to CSF-1R internalisation had comparable effects on the regulation of gene expression by CSF-1. Together, our data argue that key signalling responses to CSF-1 depend on the ability of the CSF-1R to signal from endosomes following its internalisation, thus adding an important spatiotemporal aspect to CSF-1R signalling.     

The Hydroxyl at Position C1 of Genipin Is the Active Inhibitory Group that Affects Mitochondrial Uncoupling Protein 2 in Panc-1 Cells

Genipin (GNP) effectively inhibits uncoupling protein 2 (UCP2), which regulates the leakage of protons across the inner mitochondrial membrane. UCP2 inhibition may induce pancreatic adenocarcinoma cell death by increasing reactive oxygen species (ROS) levels. In this study, the hydroxyls at positions C10 (10-OH) and C1 (1-OH) of GNP were hypothesized to be the active groups that cause these inhibitory effects. Four GNP derivatives in which the hydroxyl at position C10 or C1 was replaced with other chemical groups were synthesized and isolated. Differences in the inhibitory effects of GNP and its four derivatives on pancreatic carcinoma cell (Panc-1) proliferation were assessed. The effects of GNP and its derivatives on apoptosis, UCP2 inhibition and ROS production were also studied to explore the relationship between GNP’s activity and its structure. The derivatives with 1-OH substitutions, geniposide (1-GNP1) and 1-ethyl-genipin (1-GNP2) lacked cytotoxic effects, while the other derivatives that retained 1-OH, 10-piv-genipin (10-GNP1) and 10-acetic acid-genipin (10-GNP2) exerted biological effects similar to those of GNP, even in the absence of 10-OH. Thus, 1-OH is the key functional group in the structure of GNP that is responsible for GNP’s apoptotic effects. These cytotoxic effects involve the induction of Panc-1 cell apoptosis through UCP2 inhibition and subsequent ROS production.     

Lack of tolerance and morphine-induced cross-tolerance to the analgesia of chimeric peptide of Met-enkephalin and FMRFa

Chimeric peptide of Met-enkephalin and FMRFa (YGGFMKKKFMRFa-YFa), a κ-opioid receptor specific peptide, did not induce tolerance and cross-tolerance effects to its analgesic action on day 5 after pretreatment with either YFa or morphine for 4 days. However, pretreatment with YFa for 4 days led to the development of cross-tolerance to the analgesic effects of morphine and also 4 days of pretreatment of morphine resulted in the expression of tolerance to its own analgesic effects. Similar expression of tolerance and cross-tolerance were also observed when YFa was compared with the κ receptor agonist peptide dynorphin A(1–13) [DynA(1–13)]. Cross-tolerance effects between YFa and DynA(1–13) analgesia were also not observed on day 5. Interestingly, when YFa and DynA(1–13) were tested for their analgesic effects for 5 days, reduction in analgesia on day 3 was observed in case of DynA(1–13) whereas YFa maintained its analgesia for 5 days. Thus, chimeric peptide YFa may serve as a useful probe to understand pain modulation and expression of tolerance and cross-tolerance behavior with other opioids.     

Pressure effects on tryptophan and its derivatives

The high pressure effects on fluorescence of free tryptophan (Trp) and its derivatives, N-acetyl-tryptophan (AT), N-acetyl-tryptophanamide (NATA), tryptophanamide (TA), and tryptophan, containing 6-polypeptides in aqueous solution, were investigated in a pressure range from 0.1 to 650 MPa. It was found by analyzing the center of spectral mass in the wavelength range from 300 to 450 nm that high pressure shifted the fluorescence spectra of all these species to red direction: 421 cm(-1) for Trp, 305 cm(-1) for AT, 310 cm(-1) for NATA, 265 cm(-1) for TA, and 220 cm(-1) for single tryptophan containing 6-polypeptides. All the fluorescence efficiencies (i.e., quantum yield) of the compounds were reduced with pressure except free tryptophan where its fluorescence efficiency was enhanced with pressure. Glycerol, ethanol, and pH obviously influenced the pressure effects on their fluorescence characteristics. Since the tryptophan fluorescence is usually used as a probe for protein structural investigation, these findings suggested that the intrinsic pressure effect on tryptophan (or its derivatives) must be taken in consideration to explain the phenomenon observed in high pressure study on biomolecules when using the usual fluorospectroscopic approaches. In the present investigation, the mechanisms involved for pressure effects on tryptophan and its derivatives were explored and discussed.     

表没食子儿茶素没食子酸酯对活性氧的抑制作用

生物体内的活性氧(Reactive oxygen species,ROS)过量引起氧化应激将导致脂质、DNA和蛋白质氧化损伤,从而引发一系列生理和病理反应。绿茶中茶多酚的主要成分表没食子儿茶素没食子酸酯((-)-Epigallocatechin-3-gallate,EGCG)具有强抗氧化性,能有效抑制ROS。本文简要介绍了生物体内ROS的来源和EGCG的特性及其对ROS的抑制作用。通过检测玫瑰红水溶液在光敏化时所产生~1O_2的1 270 nm近红外发光,分析比较了EGCG和迭代钠(NaN_3)对~1O_2发光的淬灭过程,发现EGCG对~1O_2的淬灭效果比NaN_3更好,为EGCG淬灭~1O_2的定量研究提供理论依据。     

Expression of the regulation of energy balance on the ingestive behavior of grazing beef cattle supplemented by grain

A change-over design was used to measure the effect of 0.0, 2.5 and 5.0 kg day⁻¹ of ground corn (Zea mays L.) kernels on the ingestive behavior of 12 tethered 2-year-old Angus (Bos taurus) heifers receiving a basal grain ration of 2.5 kg day⁻¹ and grazing summer regrowth pastures of ‘Boone’ orchardgrass (Dactylis glomerata L.). The experimental design allowed the estimation of the immediate effects (direct effects) of grain on ingestive behavior, its carry-over effects expressed the next day (first residual effects), and the combined effects of direct and first residual effects (permanent effects). Grain had no direct effect on ingestive behavior. Heifers ingested herbage dry matter (DM) at 1.64 kg h⁻¹, forming bites of 745 mg DM at 37 bites min⁻¹. The first residual effect was significant for residual dry matter, utilization, intake and rate of biting. Five kg of grain depressed the rate of herbage DM intake from 1.67 to 1.50 kg DM h⁻¹ on the day following its ingestion. This residual effect was not expressed in herbage intake per bite, but rate of biting was reduced from 39 to 35 bites min⁻¹. The 2.5-kg treatment had a small positive residual effect on rate of herbage intake. Data indicate the operation of energy balance regulation mechanisms on the ingestive behavior of grazing beef cattle.     

Irbesartan attenuates ischemic brain damage by inhibition of MCP-1/CCR2 signaling pathway beyond AT₁ receptor blockade

Angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are known to prevent the onset of stroke and to attenuate neural damage. Additional beneficial effects of ARBs, independent of AT(1) receptor blockade, have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C-C chemokine receptor 2 (CCR2), due to its molecular structure. We examined the possible synergistic effects of co-administration of irbesartan with propagermanium, a CCR2 antagonist, on ischemic brain damage. Administration of propagermanium decreased ischemic brain area after middle cerebral artery occlusion (MCAO). To study the possible synergistic effects of propagermanium with ARBs, we employed non-effective lower doses of irbesartan and losartan. Administration of irbesartan with propagermanium decreased the ischemic brain area more markedly compared with propagermanium alone, but co-administration of losartan did not. MCP-1 mRNA level was significantly increased on the ipsilateral side after MCAO, and administration of irbesartan with propagermanium decreased the MCP-1 level, whereas co-administration of losartan did not. Similar results were obtained for MCP-1 protein level. CCR2 mRNA expression was significantly elevated on the ipsilateral side; however, no significant difference was observed between each group. mRNA levels of other inflammatory cytokines such as TNF-α and IL-1β also significantly increased on the ipsilateral side, but the expression levels were not changed by each drug treatment. Taking these findings together, irbesartan exerts more beneficial effects on ischemic brain damage with an MCP-1 receptor blocker, at least due to its inhibitory effects on MCP-1/CCR2 signaling beyond AT(1) receptor blockade.     

Glucagon-like peptide-1 relaxes gastric antrum through nitric oxide in mice

Glucagon-like-peptide-1 (GLP-1) is a proglucagon-derived peptide expressed in the intestinal enteroendocrine-L cells and released after meal ingestion. GLP-1 reduces postprandial glycemia not only by its hormonal effects, but also by its inhibitory effects on gastrointestinal motility. Recently, we showed that GLP-1 acts in the enteric nervous system of mouse intestine. Therefore our working hypothesis was that GLP-1 may have also a direct influence on the gastric mechanical activity since the major part of experimental studies about its involvement in the regulation of gastric motility have been conducted in in vivo conditions. The purposes of this study were (i) to examine exogenous GLP-1 effects on mouse gastric mechanical activity using isolated whole stomach; (ii) to clarify the regional activity of GLP-1 using circular muscular strips from gastric fundus or antrum; (iii) to analyze the mechanism of action underlying the observed effects; (iv) to verify regional differences of GLP-1 receptors (GLP-1R) expression by RT-PCR. In the whole stomach GLP-1 caused concentration-dependent relaxation significantly anatagonized by exendin (9-39), an antagonist of GLP-1R and abolished by tetrodotoxin (TTX) or N_ω-nitro-l-arginine methyl ester (l-NAME), inhibitor of nitric oxide (NO) synthase. GLP-1 was without any effect in fundic strips, but it induced concentration-dependent relaxation in carbachol-precontracted antral strips. The effect was abolished by TTX or l-NAME. RT-PCR analysis revealed a higher expression of GLP-1R mRNA in antrum than in fundus. These results suggest that exogenous GLP-1 is able to reduce mouse gastric motility by acting peripherally in the antral region, through neural NO release.     

Analysis of the role of leukocyte function-associated antigen-1 in activation of human influenza virus-specific T cell clones

The role of leukocyte function-associated Ag-1 (LFA-1) in intercellular adhesion is well documented. Previously, we demonstrated that the LFA-1 molecule (CD11a/CD18) can also regulate the induction of proliferation of peripheral blood T cells. In these studies, we observed opposite effects of antibodies against CD11a (LFA-1-alpha-chain) or CD18 (LFA-1-beta-chain). Here, we determined the effects of anti-CD11a and anti-CD18 mAb on proliferation of cloned influenza virus-specific T cells. Anti-CD18 mAb had similar inhibiting effects on the proliferative response of T cell clones induced by immobilized anti-CD3 mAb as it had on the response of peripheral blood T cells. In contrast to its costimulatory effect on resting peripheral blood T cells, anti-CD11a mAb did not increase the proliferation of cloned T cells. Similar differences in effects of anti-CD11a and anti-CD18 mAb were observed when proliferation of the T cell clones was induced by immobilized anti-TCR mAb. When proliferation was induced by influenza virus presented by monocytes as APC, both anti-CD11a and anti-CD18 mAb inhibited T cell proliferation. However, when EBV-transformed B cells were used as APC, neither anti-CD11a nor anti-CD18 mAb inhibited proliferation. These results demonstrate that the effects of antibodies against CD11a (LFA-1-alpha) or CD18 (LFA-1-beta) on T cell proliferation depend on 1) the stage of activation of the T cells, 2) the activation stimulus and its requirement for intercellular adhesion involving LFA-1, and 3) the type of cell used to present Ag.     

Oleuropein inhibits migration ability through suppression of epithelial-mesenchymal transition and synergistically enhances doxorubicin-mediated apoptosis in MCF-7 cells

Distinct metastasis is one of the main causes of breast cancer (BC)-related mortality and epithelial-mesenchymal transition (EMT) is a primary step in metastasis dissemination. On the other hand, doxorubicin (DOX) is an effective chemotherapeutic agent against BC; unfortunately, its clinical use is limited by dose-dependent side effects. Therefore, extensive efforts have been dedicated to suppressing metastasis of BC and also to overcome DOX side effects together with keeping its antitumor efficacy. Studies supported the role of oleuropein (OLEU) in reducing DOX-induced side effects besides its antitumor actions. In this study, the antimigratory effect of OLEU was assessed and real-time PCR (RT-PCR) was used to detect OLEU effect on the expression level of EMT markers, in MCF-7 cells. The cytotoxic effect of OLEU and DOX was assessed by MTT assay, whereas the ratio of apoptosis was investigated by flow cytometry. The results showed that migration ability of MCF-7 cells remarkably decreased in OLEU treated group and RT-PCR results showed that OLEU may exert its antimigratory action by suppressing EMT through downregulation of sirtuin1 (SIRT1). Also, the results indicated that both OLEU and DOX were cytotoxic to MCF-7 cells, whereas DOX-OLEU cotreatment led to additive cytotoxicity and apoptosis rate. This study provides evidence regarding the suppressive role of OLEU on MCF-7 cells migration ability through suppression of EMT, and for the first time, it was proposed that SIRT1 downregulation can be involved in the OLEU antimigratory effect. Also, the findings demonstrated that OLEU can reduce DOX-induced side effects by reducing its effective dose.     

Tyr-MIF-1 and hemorphin can act as opiate agonists as well as antagonists in the guinea pig ileum.

The brain peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) was tested for its effects on electrically stimulated contractions in the guinea pig ileum assay. Tyr-MIF-1 acted as an opiate agonist in reducing these contractions. Its IC50 was about 9 microM, and its effects were reversed by naloxone and CTOP. The ability of Tyr-MIF-1 also to antagonize the inhibitory effects of opiates on electrically stimulated contractions was more evident in the ileum removed from a guinea pig tolerant to morphine or after partial inactivation of opiate receptors with beta-CNA. Similar results were observed with hemorphin. The endogenous peptide Tyr-MIF-1 and the blood-derived peptide hemorphin, therefore, can act as agonists as well as antagonists in the guinea pig ileum. The effects as antagonists are best observed in preparations of ileum with reduced receptor reserve (tolerant or beta-CNA treated) and are consistent with the idea that properties of endogenous peptides as opiate antagonists are enhanced in the tolerant state.     

ADP-ribosylation and functional effects of Pseudomonas exoenzyme S on cellular RalA

Exoenzyme S (ExoS) is a bifunctional virulence factor directly translocated into eukaryotic cells by the type III secretory process of Pseudomonas aeruginosa. Bacterial translocation of ExoS into epithelial cells is associated with diverse effects on cell function, including inhibition of growth, alterations in cell morphology, and effects on adherence processes. Preferred substrates of the ADP-ribosyltransferase (ADPRT) portion of ExoS include low molecular weight G-proteins (LMWG-proteins) in the Ras family. In examining the ADP-ribosylation and functional effects of ExoS on RalA, ExoS was found to ADP-ribosylate endogenous RalA and recombinant RalADeltaCAAX at multiple sites, with Arg52 identified as the preferred site of ADP-ribosylation. The binding of RalA to the Ral binding domain (RBD) of its downstream effector, RalBP1, was inhibited by bacterially translocated ExoS, indicating an effect of ExoS on cellular RalA function. In vitro analyses confirmed that ADP-ribosylation of RalA directly interfered with its ability to bind to the RBD of RalBP1. The studies support the fact that RalA is a cellular substrate of bacterially translocated ExoS and that ADP-ribosylation by ExoS affects RalA interaction with its downstream effector, RalBP1.     

Dissociation of TPA-induced down-regulation of T cell antigens from protein kinase C activation

The tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA) has diverse effects on lymphoid cell function. Two of the early effects were the induction of early activation antigen EA1 and the down-regulation of certain T cell differentiation antigens (CD3, CD4, CD7). The mechanisms of these TPA effects were investigated. It was confirmed that EA1 expression was dependent on protein kinase C (PKC) activation. Synthetic diacylglycerols were capable of inducing EA1 expression. In addition, inhibition of PKC by the kinase inhibitor, H7, led to the inhibition of EA1 expression induced by TPA and synthetic diacylglycerols. In contrast, down-regulation of T cell differentiation antigens by TPA was not dependent on PKC activation. Synthetic diacylglycerols did not induce down-regulation of T cell antigens and H7 had no effect on the down-regulation of T cell antigens induced by TPA. These data would suggest that TPA exerted its effects on T cell function by mechanisms in addition to the activation of PKC alone. One possible mechanism would be the activation of the calmodulin-dependent pathway(s) since its inhibition resulted in the reversal of TPA-induced down-regulation of the T cell differentiation antigens.     

邻羟基苯甲酸胁迫对不同杉木无性系叶片膜质过氧化及渗透调节物质的化感效应

研究了杉木自毒物质邻羟基苯甲酸胁迫对2个杉木优良无性系组培苗（分别记为01号、02号）叶片的膜质过氧化及渗透物质的化感效应。结果表明：（1）与对照相比,邻羟基苯甲酸对杉木叶片MDA的化感效应表现为低浓度抑制、高浓度促进,对01号的促进效应低于02号;（2）邻羟基苯甲酸胁迫使杉木叶片电导率及伤害率增加,对照与各胁迫处理间均达显著差异（P〈0．05）,对02号伤害率及电导率的促进效应均大于01号;（3）40mg／L、80mg／L胁迫浓度对2个杉木无性系可溶性糖含量的化感效应随时间变化由抑制转为促进,对01号的促进效应更大、更早,120mg／L胁迫浓度均表现为抑制效应,对01号的抑制效应更小;（4）邻羟基苯甲酸胁迫对杉木叶片游离氨基酸含量均表现为促进效应,且随胁迫浓度升高而增大,对01号的促进效应远远大于02号。研究认为,01号杉木优良无性系具有较强的耐自毒物质胁迫的能力。     

Bronchoconstrictor and antibronchoconstrictor properties of inhaled prostacyclin in asthma

Prostacyclin (PGI2) is generated in appreciable amounts during allergic reactions in human lung tissue. To define its activity on human airways we have studied the effects of doubling concentrations of inhaled PGI2 and its hydrolysis product 6-oxoprostaglandin F1 alpha (6-oxo-PGF1 alpha) on specific airway conductance (sGaw), maximum expiratory flow at 30% vital capacity (Vmax30), forced expiratory volume in 1 s (FEV1), and static lung volumes in subjects with mild allergic asthma. In a second study the effect of inhaled PGI2 on bronchoconstriction provoked by increasing concentrations of inhaled prostaglandin (PG) D2 and methacholine was observed. Inhalation of PGI2 up to a concentration of 500 micrograms/ml had no significant effect on sGaw but produced a concentration-related decrease in FEV1 and Vmax30 in all subjects. In two of four subjects inhalation of PGI2 also increased residual volume and decreased vital capacity but had no effect on total lung capacity. PGI2, but not 6-oxo-PGF1 alpha, protected against bronchoconstriction provoked by either PGD2 or methacholine whether airway caliber was measured as sGaw, FEV1, or Vmax30. The apparent disparity between the bronchoconstrictor and antibronchoconstrictor effects of PGI2 might be explained by its potent vasodilator effect in causing airway narrowing through mucosal engorgement and reducing the spasmogenic effects of other inhaled mediators by increasing their clearance from the airways.     

A comparative study of the effect of aflatoxin B1 and actinomycin D on HeLa cells

1. The cytotoxic effects of aflatoxin B(1) on HeLa cells were examined and effects of short exposures of the cells to the toxin were found to be reversible. 2. Aflatoxin B(1) inhibited the synthesis of both ribosomal and heterodisperse RNA. It is proposed that the toxin's mechanism of action on ribosomal RNA synthesis is related to its inhibitory effect on the maturation of the 45s-ribosomal-RNA precursor. 3. Protein synthesis is inhibited to a greater extent by aflatoxin B(1) than by actinomycin D. In contrast with actinomycin D, aflatoxin B(1) was shown to disaggregate polyribosomes directly.     

Effect of alpha-tocopherol and its derivatives on ATPase activity and oxidative phosphorylation in rat liver mitochondria

The effects of alpha-tocopherol and its derivatives on the energy metabolism in mitochondria were studied. It was shown that alpha-tocopherol derivatives with short hydrocarbon chain produce uncoupling effects, while alpha-tocopherol itself as well as its long-chain derivatives (tocopheryl acetate and tocopheryl stearate) exert no effect. All the derivatives studied produced an inhibitory effect on DNP-stimulated mitochondrial ATPase. As far as these compounds did not influence the activity of mitochondrial F1 factor, it was concluded that the effects of the compounds were due to membrane modification.     

马缨丹总岩茨烯对小菜蛾和斜纹夜蛾幼虫的拒食作用

从马缨丹叶片中提取总岩茨烯,测定总岩茨烯对小菜蛾2龄幼虫和斜纹夜蛾1、2龄幼虫的拒食作用.结果表明,在非选择性试验中,1.6 mg·ml^-1的总岩茨烯对小菜蛾2龄幼虫和斜纹夜蛾1龄幼虫有拒食作用,8 h的拒食率分别为62.%和31.1%;在选择性试验中,0.4 mg·ml^-1的总岩茨烯即对小菜蛾2龄幼虫有拒食作用,0.4、0.8和1.6 mg·ml^-1浓度处理下的拒食率分别为52.7%、55.5%和78.9%;总岩茨烯只有在高浓度(1.6 mg·ml^-1)时,才对斜纹夜蛾1龄幼虫有拒食作用,拒食率仅为33.0%.在选择性和非选择性试验中,总岩茨烯对斜纹夜蛾2龄幼虫均无拒食作用.     

Effects of fluoxetine and its complexes with glycyrrizhinic acid on behavior and brain monoamine levels in rats

Effects of serotonin uptake inhibitor fluoxetine (F) and it's complexes with glycyrrizhinic acid (GA) in molar proportions 1GA : 1F (FGA-1) and 4GA : 1F (FGA-4) on rat behavior in elevated plus-maze and brain monoamine concentrations were studied. Drugs (25 mg/kg) were administered per os 1 h before investigations. F-treated rats showed increased anxiety and reduced locomotor activity, whereas FGA-1 and FGA-4 had no effects on the behaviors. None of the compounds modified brain tissue serotonin content, but all of them decreased the level of its metabolite 5-hydroxyindole-3-acetic acid level in the hypothalamus, and FGA-4 also decreased it in the cortex. Noradrenaline levels were increased in the hypothalamus of rats treated with F in both combinations with GA. In the striatum, F increased dopamine and its metabolite DOPAC levels, but their ratio (an indicator of the neurotransmitter turnover) was not altered by this drug. Unlike F, FGA-1 significantly activated dopamine turnover in the striatum. The data obtained suggested that application of F in complexes with GA significantly modified the drug behavioral effects and these alterations may be related to specific effects of the pure compound and its complexes on the functions of the brain monoaminergic systems that regulate investigated behavior.