ABSTRACT
The COVID-19 pandemic is a major human health concern. The pathogen responsible for COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), invades its host through the interaction of its spike (S) protein with a host cell receptor, angiotensin-converting enzyme 2 (ACE2). In addition to ACE2, heparan sulfate (HS) on the surface of host cells also plays a significant role as a co-receptor. Our previous studies demonstrated that sulfated glycans, such as heparin and fucoidans, show anti-COVID-19 activities. In the current study, rhamnan sulfate (RS), a polysaccharide with a rhamnose backbone from a green seaweed, Monostroma nitidum, was evaluated for binding to the S-protein from SARS-CoV-2 and inhibition of viral infectivity in vitro. The structural characteristics of RS were investigated by determining its monosaccharide composition and performing two-dimensional nuclear magnetic resonance. RS inhibition of the interaction of heparin, a highly sulfated HS, with the SARS-CoV-2 spike protein (from wild type and different mutant variants) was studied using surface plasmon resonance (SPR). In competitive binding studies, the IC50 of RS against the S-protein receptor binding domain (RBD) binding to immobilized heparin was 1.6 ng/mL, which is much lower than the IC50 for heparin (~750 ng/mL). RS showed stronger inhibition than heparin on the S-protein RBD or pseudoviral particles binding to immobilized heparin. Finally, in an in vitro cell-based assay, RS showed strong antiviral activities against wild type SARS-CoV-2 and the delta variant.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Deoxy Sugars/pharmacology , Mannans/pharmacology , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Seaweed , Antiviral Agents/therapeutic use , Aquatic Organisms , Deoxy Sugars/therapeutic use , Humans , Mannans/therapeutic use , Plant Extracts/therapeutic use , Protein Binding/drug effects , Spike Glycoprotein, Coronavirus/drug effects , Structure-Activity RelationshipABSTRACT
Influenza viruses cause a significant public health burden each year despite the availability of anti-influenza drugs and vaccines. Therefore, new anti-influenza virus agents are needed. Rhamnan sulfate (RS) is a sulfated polysaccharide derived from the green alga Monostroma nitidum. Here, we aimed to demonstrate the antiviral activity of RS, especially against influenza A virus (IFV) infection, in vitro and in vivo. RS showed inhibitory effects on viral proliferation of enveloped viruses in vitro. Evaluation of the anti-IFV activity of RS in vitro showed that it inhibited both virus adsorption and entry steps. The oral administration of RS in IFV-infected immunocompetent and immunocompromised mice suppressed viral proliferation in both mouse types. The oral administration of RS also had stimulatory effects on neutralizing antibody production. Fluorescent analysis showed that RS colocalized with M cells in Peyer's patches, suggesting that RS bound to the M cells and may be incorporated into the Peyer's patches, which are essential to intestinal immunity. In summary, RS inhibits influenza virus infection and promotes antibody production, suggesting that RS is a potential candidate for the treatment of influenza virus infections.
Subject(s)
Antiviral Agents/pharmacology , Chlorophyta , Deoxy Sugars/pharmacology , Immunosuppression Therapy , Influenza A virus/drug effects , Mannans/pharmacology , Administration, Oral , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Deoxy Sugars/administration & dosage , Deoxy Sugars/therapeutic use , Disease Models, Animal , Female , Humans , Influenza, Human/drug therapy , Japan , Mannans/administration & dosage , Mannans/therapeutic use , Mice , Mice, Inbred BALB C , Oceans and Seas , PhytotherapyABSTRACT
Rhamnan sulfate (RS) is a polysaccharide with a rhamnose backbone isolated from Monostroma nitidum. Like heparin, it exerts anticoagulant activity in the presence of antithrombin. Endothelial cells facilitate the crosstalk between blood coagulation and vascular inflammation. In this study, we compared the effect of RS with that of heparin on blood coagulation and vascular endothelial cells in the presence or absence of inflammatory factors, using human umbilical vein endothelial cells. We found that RS significantly enhances inhibition of thrombin and factor Xa in the presence of antithrombin as well as heparin, and that RS inhibits tissue factor expression and von Willebrand factor release from the endothelial cells treated with or without lipopolysaccharide, tumor necrosis factor-α, or thrombin. Heparin did not show any effects on endothelial cell inflammation. Our findings suggest that RS, like heparin, is an antithrombin-dependent anticoagulant and, unlike heparin, is a potent anti-inflammatory agent acting on vascular endothelial cells.
Subject(s)
Anticoagulants/therapeutic use , Blood Coagulation/drug effects , Deoxy Sugars/therapeutic use , Endothelial Cells/drug effects , Inflammation/drug therapy , Mannans/therapeutic use , Seaweed/drug effects , Sulfates/therapeutic use , Anticoagulants/pharmacology , Deoxy Sugars/pharmacology , Humans , Mannans/pharmacology , Sulfates/pharmacologyABSTRACT
The active sulfated polysaccharide from seaweed possesses important pharmaceutical and biomedical potential. In the study, Monostroma sulfated polysaccharide (MSP) was obtained from Monostroma angicava, and the low-molecular-weight fragments of MSP (MSP-Fs: MSP-F1â»MSP-F6) were prepared by controlled acid degradation. The molecular weights of MSP and MSP-F1â»MSP-F6 were 335 kDa, 240 kDa, 90 kDa, 40 kDa, 24 kDa, 12 kDa, and 6.8 kDa, respectively. The polysaccharides were sulfated rhamnans that consisted of â3)-α-l-Rhap-(1â and â2)-α-l-Rhap-(1â units with partial sulfation at C-2 of â3)-α-l-Rhap-(1â and C-3 of â2)-α-l-Rhap-(1â. Anticoagulant properties in vitro of MSP and MSP-F1â»MSP-F6 were evaluated by studying the activated partial thromboplastin time, thrombin time, and prothrombin time. Anticoagulant activities in vivo of MSP and MSP-F4 were further evaluated; their fibrin(ogen)olytic activities in vivo and thrombolytic properties in vitro were also assessed by D-dimer, fibrin degradation products, plasminogen activator inhibitior-1, and clot lytic rate assays. The results showed that MSP and MSP-F1â»MSP-F4 with molecular weights of 24â»240 kDa had strong anticoagulant activities. A decrease in the molecular weight of MSP-Fs was accompanied by a decrease in the anticoagulant activity, and higher anticoagulant activity requires a molecular weight of over 12 kDa. MSP and MSP-F4 possessed strong anticoagulant activities in vivo, as well as high fibrin(ogen)olytic and thrombolytic activities. MSP and MSP-F4 have potential as drug or helpful food supplements for human health.
Subject(s)
Anticoagulants/pharmacology , Chlorophyta/chemistry , Deoxy Sugars/pharmacology , Fibrinolytic Agents/pharmacology , Mannans/pharmacology , Seaweed/chemistry , Acids/chemistry , Animals , Anticoagulants/chemistry , Anticoagulants/isolation & purification , Blood Coagulation Tests , Deoxy Sugars/chemistry , Deoxy Sugars/isolation & purification , Dietary Supplements , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/isolation & purification , Humans , Male , Mannans/chemistry , Mannans/isolation & purification , Molecular Weight , Rats , Rats, Sprague-Dawley , Spectrum Analysis/methods , Sulfates/chemistryABSTRACT
Two new fluvirucin aglycones, named fluvirucinins C, and C2 (1-2), have been isolated from the ethyl acetate mycelial cake extract of the fermentation broth of.a marine sponge-associated actinomycete. Fluvirucinins C, (1) and C2 (2) represent a new type of 14-membered macrolactam aglycon, structurally related with the common aglycon of the known fluvirucins. Their structures were elucidated on the basis of ID and 2D NMR analyses, as well as HRESIMS experiments. The antimicrobial and cytotoxic activities of compounds 1 and 2 have been evaluated, but no significant activities found for fluvirucinins C, and C2.
Subject(s)
Actinobacteria/metabolism , Anti-Bacterial Agents/chemistry , Deoxy Sugars/chemistry , Lactams/chemistry , Anti-Bacterial Agents/isolation & purification , Aquatic Organisms/metabolism , Deoxy Sugars/isolation & purification , Lactams/isolation & purification , Molecular StructureABSTRACT
A low molecular weight fraction, designated LMWP, was prepared by mild acid hydrolysis of sulfated rhamnan from Monostroma latissimum and purified by anion-exchange and gel-permeation chromatography. Chemical and spectroscopic analyses showed that LMWP was mainly composed of rhamnose, and its molecular weight was about 33.6 kDa. The backbone of LMWP consists of 1,3-linked α-L-rhamnose units with partially sulfate groups at the C-2 position. Approximately 25% of 1,3-linked α-L-rhamnose units is substituted at C-2 by sulfated or non-sulfated 1,3-linked α-L-rhamnose and 1,2-linked α-L-rhamnose units. LMWP effectively prolonged clotting time as evaluated by the activated partial thromboplastin time assay and was a potent thrombin inhibitor mediated by heparin cofactor II. The investigation demonstrated that LMWP is a novel sulfated polysaccharide with anticoagulant activity.
Subject(s)
Blood Coagulation/drug effects , Chlorophyta/chemistry , Deoxy Sugars/chemical synthesis , Deoxy Sugars/pharmacology , Mannans/chemical synthesis , Mannans/pharmacology , Plant Extracts/chemistry , Plant Extracts/pharmacology , Acids/chemistry , Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Humans , Hydrolysis , Sulfates/chemistryABSTRACT
A convenient method has been developed for the diastereoselective synthesis of methyl 5-deoxy-5-(dialkylphosphono)-5-(dialkylphosphorylamido)-2,3-O-isopropylidene-beta-d-ribofuranosides under mild conditions, namely the reaction of a dialkyl phosphoramidate with a dialkyl phosphite and methyl 2,3-O-isopropylidene-beta-D-ribo-pentodialdo-1,4-furanoside in acetyl chloride in a one-pot procedure.
Subject(s)
Acetals/chemical synthesis , Deoxy Sugars/chemistry , Furans/chemistry , Ribose/analogs & derivatives , Ribose/chemistry , Carbohydrates/chemistry , Immunotherapy/methods , Models, Chemical , Molecular Conformation , Molecular Structure , Phosphorus/chemistry , Ribose/chemical synthesis , StereoisomerismABSTRACT
The synthesis and biological evaluation of three series of 6-phosphogluconate (6PG) analogues is described. (2R)-2-Methyl-4,5-dideoxy, (2R)-2-methyl-4-deoxy and 2,4-dideoxy analogues of 6PG were tested as inhibitors of 6-phosphogluconate dehydrogenase (6PGDH) from sheep liver and also Trypanosoma brucei where the enzyme is a validated drug target. Among the three series of analogues, seven compounds were found to competitively inhibit 6PGDH from T. brucei and sheep liver enzymes at micromolar concentrations. Six inhibitors belong to the (2R)-2-methyl-4-deoxy series (6, 8, 10, 12, 21, 24) and one is a (2R)-2-methyl-4,5-dideoxy analogue (29b). The 2,4-dideoxy analogues of 6PG did not inhibit both enzymes. The trypanocidal effect of the compounds was also evaluated in vitro against T. brucei rhodesiense as well as other related trypanosomatid parasites (i.e., Trypanosoma cruzi and Leishmania donovani).
Subject(s)
Gluconates/chemical synthesis , Phosphogluconate Dehydrogenase/antagonists & inhibitors , Trypanocidal Agents/chemical synthesis , Trypanosomiasis, African/veterinary , Animals , Deoxy Sugars/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Gluconates/chemistry , Gluconates/pharmacology , Leishmania donovani/drug effects , Liver/enzymology , Phosphogluconate Dehydrogenase/metabolism , Sheep , Structure-Activity Relationship , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/enzymology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/enzymology , Trypanosomiasis, African/drug therapyABSTRACT
Rhamnan sulfate (RS), a natural sulfated polysaccharide isolated from Monostroma latissimum, showed potent inhibitory effects on the virus replication of herpes simplex virus type 1 (HSV-1), human cytomegalovirus (HCMV), and human immunodeficiency virus type 1 (HIV-1) in vitro. The antiviral action of RS was not only due to the inhibition of virus adsorption, but also might involve the later steps of viral replication in host cells on the basis of the results of time-of-addition experiments. Furthermore, RS and 3'-azido-3'-deoxythymidine (AZT) were synergistic in their anti-HIV-1 activities. These data indicate that RS is a potent antiviral substance against HSV-1, HCMV, and HIV-1.
Subject(s)
Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Deoxy Sugars/pharmacology , HIV-1/drug effects , Herpesvirus 1, Human/drug effects , Mannans/pharmacology , Seaweed , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/isolation & purification , Anti-HIV Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Cell Line , Cell Wall/chemistry , Chlorocebus aethiops , Cytomegalovirus/physiology , Deoxy Sugars/chemistry , Deoxy Sugars/isolation & purification , Drug Synergism , HIV-1/physiology , Herpesvirus 1, Human/physiology , Humans , Mannans/chemistry , Mannans/isolation & purification , Vero Cells , Virus Replication/drug effects , Zidovudine/pharmacologyABSTRACT
Evidence for the anomeric configurations and attachment sites of 3-deoxy-D-lyxo-2-heptulosaric acid (DHA) and apiosyl residues has been obtained through the characterization of two oligoglycosyl fragments isolated from rhamnogalacturonan II (RG-II). One of the oligoglycosyl fragments, a pentaglycosyl aldonic acid generated by Smith degradation of RG-II, was composed of four D-galactopyranosyluronic acid residues, a DHA residue, and a threonic acid residue (derived from a D-galactopyranosyluronic acid residue). The structural analysis of the pentaglycosyl aldonic acid established the beta-D-configuration for the DHA residue. Furthermore, it established that a previously identified diglycosyl side chain, 5-O-(beta-L-arabinofuranosyl)-DHA was directly attached to O-3 of a D-galactopyranosyluronic acid residue in the backbone of RG-II. The second oligoglycosyl fragment, a peralkylated diglycosyl hex-1-enitol, was generated by hex-5-enose degradation of permethylated and carboxyl-reduced RG-II. The structure of the peralkylated diglycosyl hex-1-enitol, beta-L-Rhap-(1----3')-beta-D-Apif-(1----5)-hex-1-enitol++ +, was determined by a combination of glycosyl-linkage composition analysis and n.m.r. spectroscopy. The n.m.r. data indicated the beta-configuration for the D-apiosyl residue. The isolation and characterization of the diglycosyl hex-1-enitol also established that a previously identified heptaglycosyl side chain was directly attached to O-2 of a D-galactopyranosyluronic acid in the backbone of RG-II.
Subject(s)
Cell Wall/chemistry , Deoxy Sugars/metabolism , Mannans/metabolism , Oligosaccharides/chemistry , Pectins/metabolism , Trees/chemistry , Butyrates/chemistry , Carbohydrate Sequence , Cells, Cultured , Deoxy Sugars/chemistry , Glucosides/chemistry , Mannans/chemistry , Molecular Sequence Data , Pectins/chemistry , Pentoses/chemistry , Sugar Acids/chemistry , Sugar Alcohols/chemistryABSTRACT
A six-compartment, nine-parameter kinetic model of 2-deoxyglucose (2DG) metabolism, which includes bidirectional tissue transport, phosphorylation, two-step dephosphorylation, phosphoisomerization, and conjugation to UDP and macromolecules, has been derived. Data for analysis were obtained from 540- and 1,000-microns-thick hippocampal and hypothalamic brain slices, which were incubated in buffer containing [14C]2DG, frozen, extracted with perchlorate, and separated on anion-exchange columns. Solutions of the equations of the model were fit to the data by means of nonlinear least-squares analysis. These studies suggest that dephosphorylation is adequately described by a single reaction so that the model reduces to eight parameters. The in vitro rate constants for transport, phosphorylation, and dephosphorylation are very similar to prior in vivo results. The phosphoisomerization rate constant is similar to dephosphorylation, so glycosylated macromolecules slowly accumulate and gradually assume larger relative importance as other compounds disappear more rapidly. Rate constants for 540-microns slices from hypothalamus and hippocampus are similar, while 1,000-microns slices have smaller tissue transport constants and larger phosphorylation constants. The rate equation for glucose utilization of this model is relatively insensitive to uncertainties regarding the rate constants. Including later metabolic components in kinetic models improves the calculations of glucose utilization with long isotope exposures.
Subject(s)
Brain/metabolism , Deoxy Sugars/pharmacokinetics , Deoxyglucose/pharmacokinetics , Algorithms , Culture Techniques , Glucose/pharmacokinetics , Hippocampus/metabolism , Hypothalamus/metabolismABSTRACT
During the first 2-3 weeks of postnatal life, the hypothalamic-pituitary-adrenocortical axis in rats exists in a relatively dormant state, termed the stress-hyporesponsive period. The development of the hypothalamic-pituitary-adrenal axis in young rats was examined by testing the ability of the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) to stimulate CRF in vitro and ACTH in vivo. Intraperitoneal injection of 2-DG into rats 11-12 days of age or into adult rats resulted in significant hyperglycemia by 60 min that was greater in magnitude in the adults. This response was accompanied by a significant increase in plasma ACTH to levels more than 500% of the noninjected or saline-injected control values in adults. A much smaller (approximately 200%) but still significant ACTH response was observed 60 min after 2-DG injection in the neonates. The drug had no effect on the ACTH response to exogenous CRF in the neonates. The pattern of corticosterone secretion paralleled that of ACTH, with a very moderate rise (from less than 1 to 2 micrograms/dl) seen in the neonate. To test the hypothesis that CRF was driving the ACTH response to glucoprivation induced by 2-DG in the neonate and to determine the ontogeny of hypothalamic responsiveness to this stressor, complete hypothalami were existed from rats 10-35 days of age and incubated in a defined buffer containing 5.5 mM glucose with or without 22 mM 2-DG. There was no effect of the analog on CRF secretion until day 35, at which time the magnitude of the response resembled that previously reported to occur in adult tissue. To determine if the failure to observe a CRF response was due to heightened sensitivity to the negative feedback effects of glucocorticoids, 8- to 10-day-old pups were adrenalectomized and returned to their mothers for 3 days, at which time the hypothalami were removed and tested for CRF secretion. No difference was observed between basal CRF secretory rates in the control or adrenalectomized groups, and there was still no significant response to 2-DG. Moreover, adrenalectomy did not potentiate the ACTH response to injection of 2-DG in vivo. The results suggest that during neonatal life in the rat, the hypothalamic glucostat/CRF cell mechanism is incapable of promoting a normal secretory response to glucoprivation. This deficit is probably not related to the increased sensitivity to negative feedback that has been proposed to account in part for the attenuated ACTH responses to stress in the neonatal animal.(ABSTRACT TRUNCATED AT 400 WORDS)
Subject(s)
Adrenal Cortex/growth & development , Deoxy Sugars/pharmacology , Deoxyglucose/pharmacology , Hypothalamus/growth & development , Pituitary Gland/growth & development , Adrenal Cortex/drug effects , Adrenal Cortex/metabolism , Adrenalectomy , Adrenocorticotropic Hormone/metabolism , Animals , Animals, Newborn/physiology , Blood Glucose/metabolism , Corticosterone/metabolism , Corticotropin-Releasing Hormone/metabolism , Corticotropin-Releasing Hormone/pharmacology , Feedback , Hypothalamus/drug effects , Hypothalamus/metabolism , Kinetics , Male , Pituitary Gland/drug effects , Pituitary Gland/metabolism , RatsABSTRACT
The pituitary neural lobe of homozygous Brattleboro rats has high rates of glucose utilization not affected by chronic treatment with exogenous vasopressin, despite attenuation of polydipsia and polyuria. We evaluated whether this effect may result from the inability of vasopressin to affect the hypothalamo-neurohypophysial metabolism or from the development of resistance to chronic vasopressin treatment. We used the [14C]deoxyglucose method to compare 28-h effects of vasopressin treatment (5 U/kg, i.m., twice a day) with that of desmopressin (100 micrograms/kg, i.p., once a day), a long-lasting antidiuretic hormone, on glucose utilization of the hypothalamo-neurohypophysial system and related structures in conscious homozygous Brattleboro rats. Vasopressin and desmopressin reduced water intake, plasma osmolality and plasma Na+ concentration similarly. Vasopressin decreased glucose utilization in the supraoptic nucleus, subfornical organ and median preoptic nucleus, but did not alter activity in the paraventricular nucleus and neural lobe. Desmopressin decreased glucose utilization in all these structures. The results indicate that desmopressin has a more potent inhibitory action on the hypothalamo-neurohypophysial system than vasopressin over this short duration of treatment. The lack of response in the neural lobe from chronic treatment with vasopressin seems to be due to its inability to affect the paraventricular nucleus metabolism. The maintenance of metabolic activity in the paraventricular nucleus of vasopressin-treated Brattleboro rats suggests that this structure contributes importantly to the metabolism of neural lobe.
Subject(s)
Deamino Arginine Vasopressin/pharmacology , Deoxy Sugars/metabolism , Deoxyglucose/metabolism , Hypothalamus/metabolism , Pituitary Gland, Posterior/metabolism , Vasopressins/pharmacology , Animals , Blood , Drinking/drug effects , Hypothalamus/drug effects , Male , Osmolar Concentration , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/metabolism , Pituitary Gland, Posterior/drug effects , Rats , Rats, Brattleboro , Sodium/bloodABSTRACT
To study whether the central nervous system in the perinatal fetal rat can operate during maternal cooling and warming, we examined the 2-deoxy-D-[14C]glucose ([14C]DG) uptake in the fetal brain. Full-term pregnant rats were placed at three different ambient temperatures of 35-37 degrees C, 24-25 degrees C and 0-10 degrees C. Saline containing 20 microCi/100 g of [14C]DG was injected into the superior caval vein in the pregnant rats. Forty-five min after the injection, the mother rats were decapitated and the fetal brains were taken out for autoradiography. The [14C]DG uptake was significantly influenced by maternal thermal stimulation in the hypothalamus and not in other brain regions examined such as the cerebral cortex, the basal ganglia and the limbic nuclei. Glucose utilization in the fetal anterior hypothalamus, paraventricular hypothalamus and dorsomedial hypothalamus significantly increased when the mother rat was exposed to heat compared to when the mother rat was in the thermoneutral condition. During maternal cooling, glucose utilization in the ventromedial hypothalamus and dorsomedial hypothalamus significantly decreased. There was no area activated by cooling and/or inhibited by warming. Compared to a similar study in adult rats (Am. J. Physiol., 248 (1985) R84-92), the present results suggest that although the perinatal fetal brain does not respond to thermal stimulation in terms of glucose utilization as fully as the adults, a few hypothalamic nuclei have already acquired thermal responses, which might be a possible neuronal basis for the thermoregulatory responses just after birth in rats.
Subject(s)
Body Temperature Regulation , Deoxy Sugars/pharmacokinetics , Deoxyglucose/pharmacokinetics , Fetus/metabolism , Hypothalamus/metabolism , Maternal-Fetal Exchange/physiology , Animals , Cold Temperature , Female , Fetus/physiology , Gestational Age , Hot Temperature , Hypothalamus/embryology , Hypothalamus/physiology , Pregnancy , Rats , Rats, Inbred StrainsABSTRACT
Autoradiography with [14C]2-deoxyglucose (2-DG) was used to map functional differences in activation of the central auditory pathway in adult tree shrews during presentation of particular acoustic stimuli (low frequency, LFS, and high frequency, HFS, pure sinus tones; social calls, SC). Individuals stimulated with broadband-noise (BBN) were used as controls. Stimulus-specific labelling was found in autoradiographs of cochlear nucleus, superior olivary complex, inferior colliculus and auditory cortex. These findings imply a tonotopic organization at least in these auditory brain areas and indicate differences in the processing of sounds with different functional significance.
Subject(s)
Auditory Cortex/physiology , Auditory Pathways/physiology , Deoxy Sugars/pharmacokinetics , Deoxyglucose/pharmacokinetics , Inferior Colliculi/physiology , Olivary Nucleus/physiology , Tupaiidae/physiology , Acoustic Stimulation , Animals , Audiometry, Pure-Tone , Auditory Cortex/metabolism , Auditory Pathways/metabolism , Cochlear Nerve/physiology , Female , Inferior Colliculi/metabolism , Olivary Nucleus/metabolism , Rhombencephalon/physiology , Vocalization, Animal/physiologyABSTRACT
Regional glucose metabolic rates were measured in affectively disordered patients during the performance of auditory discrimination. Those regions previously observed as abnormal in schizophrenia were examined to see if similar alterations might be associated with affective disorder. The abnormalities observed in the mid-prefrontal cortex, an area that appears to be an important biologic determinant of the sustained attention required of subjects in this task, are similar to those previously observed in schizophrenia. Moreover, the abnormalities do not appear to relate directly to symptomatology or the subject's performance. The authors discuss the possibility that this abnormality may reflect dysfunction in the integrating component of the attention network critical for the maintenance of goal-directed behavior and thus represent a psychosis vulnerability factor in some patients.
Subject(s)
Brain/metabolism , Deoxy Sugars/metabolism , Deoxyglucose/metabolism , Glucose/metabolism , Mood Disorders/metabolism , Schizophrenia/metabolism , Acoustic Stimulation , Adult , Auditory Perception , Bipolar Disorder/metabolism , Brain/diagnostic imaging , Deoxyglucose/analogs & derivatives , Depressive Disorder/metabolism , Female , Fluorine Radioisotopes , Fluorodeoxyglucose F18 , Humans , Male , Mood Disorders/diagnostic imaging , Organ Specificity , Reference Values , Schizophrenia/diagnostic imaging , Tomography, Emission-Computed/methodsABSTRACT
The effects on brain monoamines (norepinephrine, serotonin and the metabolite of dopamine) following administration of d-fenfluramine (10 mg/kg IP) and 2-deoxy-d-glucose (500 mg/kg IP) have been measured by microdialysis from the ventromedial hypothalamus, lateral hypothalamic area and dorsomedial hypothalamus of conscious, unrestrained rats. Following administration of d-fenfluramine there was a significant increase in the concentration of serotonin in the ventromedial hypothalamus and lateral hypothalamic area, but no significant increase in the DMH. 5-HIAA (5-hydroxy-3-indoleacetic acid), the metabolite of serotonin, was increased in the DMH, but not in the other two regions. DOPAC (3,4-dihydroxyphenylacetic acid) was increased following fenfluramine treatment in all three regions examined. An increase in norepinephrine was observed in the VMH, but not in the other two regions, while the concentration of the 3-methoxy-4-hydroxyphenylglycol (MHPG) was increased in both areas. Treatment with 2-deoxy-D-glucose (2DG) was associated with fewer changes. In the lateral hypothalamic area there was a decrease in 5-HIAA and an increase in DOPAC. In the VMH there was an increase in norepinephrine and a decrease in MHPG in the DMH, but otherwise no significant alterations were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Biogenic Monoamines/analysis , Deoxy Sugars/pharmacology , Deoxyglucose/pharmacology , Fenfluramine/pharmacology , Hypothalamus/drug effects , Animals , Dialysis/methods , Hypothalamus/metabolism , Male , Rats , Rats, Inbred StrainsABSTRACT
Autoradiography with [14C]2-deoxyglucose (2-DG) was used to examine the functional activity of the rat auditory system during long- and short-term habituation of the acoustic startle reflex. The data showed that presentation of the acoustic stimulus to long-term habituated rats resulted in a learning-related metabolic enhancement that was significantly greater than the response evoked by the same acoustic stimulus in the inexperienced rats. This enhancement was localized to brainstem and midbrain auditory nuclei and no significant changes occurred at thalamocortical levels of the auditory pathway. The largest difference in 2-DG uptake between long- and short-term habituated rats was in the lateral superior olivary nucleus (LSO). The LSO activation suggests that olivocochlear efferents may operate in a central feedback control of peripheral auditory input during long-term habituation. Findings of enhanced metabolism from the cochlear nuclei to the central nucleus of the inferior colliculus indicated that active processes of neuronal plasticity take place in the lower auditory system during long-term habituation. The results provide the first demonstration of how a nonassociative learning experience such as long-term habituation modifies the metabolic activity of the auditory system. The findings support the conclusion that auditory responses of behaving animals to acoustic stimuli are dependent not only on the physical parameters of a stimulus, but also on its learned behavioral significance.