Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Alzheimer's disease, brain glucose metabolic ratio decreases, whereas the brain lactate metabolic ratio increases. To investigate possible synaptic dysfunction in Alzheimer's disease, we examined the effects of exogenous glucose deprivation and replacement of glucose with lactate on the synaptic transmission, synaptic plasticity, and the morphological integrity of hippocampal neurons. Synaptic activity was estimated by the amplitude of the population spike (PS) recorded in the granular cell layer in the hippocampal slices from guinea pig and rat. Exogenous glucose deprivation caused the immediate depression of PS. Replacement of glucose with lactate induced transient decrease of PS, followed by spontaneous recovery of synaptic transmission. Neural activity recovered from transient glucose deprivation became resistant to the replacement of glucose with exogenous lactate. Glucose-supported synaptic transmission exhibited approximately 140% enhancement of PS (LTP). However, lactate-supported synaptic activity yielded approximately 110% potentiation of PS. Effects of exogenous glucose and lactate on the cell viability were examined by the propidum iodide uptake and LDH release in the organotypic hippocampal slice cultures. Hippocampal slice cultures incubated in medium containing 10 mM lactate suppressed the cell death during 48 h observation as well as those in the 10-30 mM glucose containing medium. These results indicate that lactate can sustain the neural transmission and support the morphological integrity of hippocampal neurons, but failed to induce LTP, which could at least in part, cause the memory impairment in Alzheimer's disease.
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PMID:[Exogenous lactate sustains synaptic activity and neuronal viability, but fails to induce long-term potentiation (LTP)]. 1120 Nov 84

The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-11C] WAY-100635 (WAY), [carbonyl-11C]desmethyl-WAY-100635 (DWAY), p-[18F]MPPF and [11C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT1A receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET.
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PMID:Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system. 1120 45

Our goal was to synthesize with high specific activity R(-)-1-(2,5-Dimethoxy-4-[123I]iodophenyl)-2-aminopropane [R(-)[123I]DOI], an in vitro potent and selective 5-HT(2A/2C) serotonin agonist, and study in vivo its plasma pharmacokinetics and brain distribution in baboon by SPECT. The purpose was to evaluate this radiotracer as a potential tool in discerning the role of the agonist high affinity state of 5-HT(2) receptors in depression and other neurological disorders. The radiotracer was prepared by electrophilic radioiodination of the N-trifluoroacetyl precursor of R(-)-1-(2,5-Dimethoxyphenyl)-2-aminopropane [R(-)DMA-TFA] with high-purity sodium [123I]iodide in the presence of chloramine-T, followed by amino deprotection with KOH in isopropanol (labeling yield: 73%, radiochemical yield: 62%, radiochemical purity: 99%). In vivo studies in baboon showed high accumulation of radioactivity in thalamus, the frontoparietal cortex, temporal, occipital and the striatum regions, with slightly lower accumulation in the midbrain and cerebellum. Ketanserin did not displaced the radioactivity in any of these brain regions. Plasma metabolite analysis was performed using methanol protein precipitation, the methanol fractions contained from 68% to 92% of the mixture of a labeled metabolite and parent compound. The recovery coefficient of unmetabolized R(-)[123I]DOI was 68%. The percent parent compound present in the extracted fraction, measured by HPLC, decreased gradually with time from 99.8% to 0.3% still present after 4.7 hours post injection whereas the percentage of the only one detected metabolite increased conversely. Free fraction determination (f(1)), was 31 +/- 0.9% (n = 3). For comparison purposes, ex-vivo brain distribution, displacement and metabolite analysis was also carried out in rodents. Although R(-)[123I]DOI displayed good brain uptake and localized in serotonergic areas of the brain, its target to non target ratio and its insensitivity to ketanserin displacement suggest high nonspecific uptake, therefore non potentially useful as brain imaging radiotracer for visualization of the agonist high-affinity state of 5-HT(2A) receptors and for visualizing 5-HT(2C) receptors by SPECT.
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PMID:Pharmacokinetics and brain distribution in non human primate of R(-)[123I]DOI, A 5HT(2A/2C) serotonin agonist. 1208 28

Reactions to oral contraceptive therapy tend to be maximal during the first few months of use. They include nausea or epigastric discomfort, malaise, dizziness, nervousness, fatigue, weakness, leg cramps, headache, and depression. The estrogenic component is thought to be the cause. There may also be a psychogenic basis reflecting apprehension. Breast tenderness is an occasional complaint and intermenstrual spotting or breakthrough bleeding is often reported. Increasing dosage has reduced this symptom. Dysmenorrhea prior to treatment may be improved but occasionally it is aggravated. Drug-induced amenorrhea presents a double problem in that failure to resume medication 7 days after completion of a cycle results in a risk of conception. Episodes of severe uterine bleeding in patients discontinuing use after several months or years have been reported. Other side effects include a skin reaction resembling acne, pruritus, hirsutism, thinning of scalp hair, increased skin pigmentation, and weight gain or loss. Serious vascular complications and hepatic dysfunction have been shown and deviation of thyroid function may be shown by increase of serum protein-bound iodine (PBI). Clinical signs of hyperthyroidism have not been described. Oral contraception is associated with elevated plasma cortisol (hydrocortisone) levels and decreased urinary levels of 17-hydroxycorticosteroids (17-OCHS). Suppression of ovarian activity by oral contraceptives is rapidly reversible. Fear of carcinogenesis has caused much alarm but no proof as of the present time. Safety of long term use will require additional years of experience.
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PMID:Side-effects and possible complications of oral contraceptive drugs. 1225 41

We have studied the modulatory effects of cholinergic agonists on excitatory postsynaptic currents (EPSCs) in nucleus accumbens (nAcb) neurons during postnatal development. Recordings were obtained in slices from postnatal day 1 (P1) to P27 rats using the whole cell patch-clamp technique. EPSCs were evoked by local electrical stimulation, and all experiments were conducted in the presence of bicuculline methchloride in the bathing medium and with QX-314 in the recording pipette. Under these conditions, postsynaptic currents consisted of glutamatergic EPSCs typically consisting of two components mediated by AMPA/kainate (KA) and N-methyl-D-aspartate (NMDA) receptors. The addition of acetylcholine (ACh) or carbachol (CCh) to the superfusing medium resulted in a decrease of 30-60% of both AMPA/KA- and NMDA-mediated EPSCs. In contrast, ACh produced an increase ( approximately 35%) in both AMPA/KA and NMDA receptor-mediated EPSCs when administered in the presence of the muscarinic antagonist atropine. These excitatory effects were mimicked by the nicotinic receptor agonist 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) and blocked by the nicotinic receptor antagonist mecamylamine, showing the presence of a cholinergic modulation mediated by nicotinic receptors in the nAcb. The antagonistic effects of atropine were mimicked by pirenzepine, suggesting that the muscarinic depression of the EPSCs was mediated by M(1)/M(4) receptors. In addition, the inhibitory effects of ACh on NMDA but not on AMPA/KA receptor-mediated EPSC significantly increased during the first two postnatal weeks. We found that, under our experimental conditions, cholinergic agonists produced no changes on membrane holding currents, on the decay time of the AMPA/KA EPSC, or on responses evoked by exogenous application of glutamate in the presence of tetrodotoxin, but they produced significant changes in paired pulse ratio, suggesting that their action was mediated by presynaptic mechanisms. In contrast, CCh produced consistent changes in the membrane and firing properties of medium spiny (MS) neurons when QX-314 was omitted from the recording pipette solution, suggesting that this substance actually blocked postsynaptic cholinergic modulation. Together, these results suggest that ACh can decrease or increase glutamatergic neurotransmission in the nAcb by, respectively, acting on muscarinic and nicotinic receptors located on excitatory terminals. The cholinergic modulation of AMPA/KA and NMDA receptor-mediated neurotransmission in the nAcb during postnatal development could play an important role in activity-dependent developmental processes in refining the excitatory drive on MS neurons by gating specific inputs.
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PMID:Muscarinic and nicotinic presynaptic modulation of EPSCs in the nucleus accumbens during postnatal development. 1246 49

To obtain an effective iodine solution, the use of 2-hydroxypropyl-alpha-cyclodextrin (2-HP-alpha-CD) as solubilizer was examined in comparison with alpha-cyclodextrin (alpha-CD), beta-cyclodextrin (beta-CD), potassium iodide (KI), and polyvinylpyrrolidone (PVP). The stability constants for inclusion of iodine with cyclodextrin and KI were ascertained by the solubility method. The apparent stability constants increased in the following order: KI < beta-CD < alpha-CD < 2-HP-alpha-CD. This order was nearly in accordance with that of the stabilization ability. The largest volatile depression effect was exhibited by 2HP-alpha-CD. The measurement of the minimum inhibitory concentration (MC) using Escherichia coli NIH-J-2 and Staphylococcus aureus FDA209P suggested that the bactericidal activity of the iodine/2-HP-alpha-CD system was the same as that of the iodine/alpha-CD, iodine/beta-CD, and iodine/PVP systems. The present results suggest that the combination of 2-HP-alpha-CD and iodine is useful for a stable and effective iodine solution.
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PMID:Interaction of iodine with 2-hydroxypropyl-alpha-cyclodextrin and its bactericidal activity. 1247 76

Blood samples from lizards (Gallotia galloti) collected from two agricultural areas (Las Galletas and Punta del Hidalgo) and two reference areas on the Island of Tenerife (Canary Islands, Spain) were analyzed for butyrylcholinesterase (BChE) activity. Serum BChE activity was characterized first by in vitro experiments using selective substrates and inhibitors. Of the total cholinesterase (ChE) activity, 74% could be attributed to BChE activity. This portion of the total ChE activity was inhibited dose dependently by tetraisopropyl pyrophosphoramide and hydrolyzed the substrate butyrylthiocholine iodide. No enzyme inhibition was observed at high substrate concentration. Twenty-one lizards collected from agricultural sampling sites showed significant inhibition (p < 0.001) of BChE activity (mean +/- standard deviation [SD] of 4.66 +/- 2.63 micromol/min/ml for lizards from Las Galletas and 5.13 +/- 1.48 for lizards from Punta del Hidalgo) compared with BChE activity for lizards from the reference sites (6.35 +/- 1.75 micromol/min/ ml). Las Galletas had the highest number of lizards (22%) with significantly inhibited BChE activity. In vitro assays showed that 10(-4) M pyridine-2-aldoxime methochloride (2-PAM) reactivated dichlorvos- or paraoxon-inhibited BChE activity within a 60-min incubation period. Almost all serum samples with depressed BChE activity that were collected from lizards from agricultural areas responded to 2-PAM reactivation of enzyme activity (8-60% increase in enzyme activity). Reactivation by treatment with 2-PAM confirmed that the depression of BChE activity was attributable to organophosphorus (OP) compounds. Evaluation of BChE activity levels and the chemical reactivation of serum BChE activity in G. galloti using 2-PAM was found to be a sensitive indicator of G. galloti exposure to OP compounds.
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PMID:Evaluating reptile exposure to cholinesterase-inhibiting agrochemicals by serum butyrylcholinesterase activity. 1255 60

Corticosteroids regulate a variety of essential physiological functions, such as mineral balance and stress. The great interest in these steroids, especially the glucocorticoids, stems from roles they are thought to play in neuropsychiatric disorders, such as severe depression and anxiety.The development of glucocorticoid receptor (GR) ligands which are appropriately labeled with short-lived positron-emitting radioisotopes would allow the non-invasive in-vivo imaging and mapping of brain GRs by means of positron emission tomography (PET). In this context we have synthesized a series of novel arylpyrazolo steroids exhibiting different substitution patterns at the D-ring of the steroid skeleton, as ligands for brain GRs. Special attention was given to 4-fluorophenyl pyrazolo steroids, which are known to display high binding affinity toward the GR. The compounds were evaluated in a competitive radiometric receptor binding assay to determine their relative binding affinities (RBA) to the GR. Some compounds show good binding affinities of up to 56% in comparison to dexamethasone (100%). In initial experiments, selected candidates were labeled with the positron emitter fluorine-18 and in one case with the gamma-emitter iodine-131.
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PMID:Synthesis of novel arylpyrazolo corticosteroids as potential ligands for imaging brain glucocorticoid receptors. 1260 9

There is an increasing prevalence of high levels of thyroid stimulating hormone (TSH) with age - particularly in postmenopausal women - which are higher than in men. The incidence of thyroid disease in a population of postmenopausal women is as follows: clinical thyroid disease, about 2.4%; subclinical thyroid disease, about 23.2%. Among the group with subclinical thyroid disease, 73.8% are hypothyroid and 26.2% are hyperthyroid. The rate of thyroid cancer increases with age. The symptoms of thyroid disease can be similar to postmenopausal complaints and are clinically difficult to differentiate. There can also be an absence of clinical symptoms. It is of importance that even mild thyroid failure can have a number of clinical effects such as depression, memory loss, cognitive impairment and a variety of neuromuscular complaints. Myocardial function has been found to be subtly impaired. There is also an increased cardiovascular risk, caused by increased serum total cholesterol and low-density lipoprotein cholesterol as well as reduced levels of high-density lipoprotein. These adverse effects can be improved or corrected by L-thyroxine replacement therapy. Such treatment has been found to be cost-effective. With time, overt hypothyroidism can develop. Therefore, routine screening of thyroid function in the climacteric period to determine subclinical thyroid disease is recommended. Hormone replacement therapy (HRT) in women with hypothyroidism treated with thyroxine causes changes in free thyroxine and TSH. Increased binding of thyroxine to elevated thyroxine-binding globulin causes an elevation of TSH by feedback. Since adaptation is insufficient, there is an increased need for thyroxine in these women taking HRT. TSH levels should be controlled at 12 weeks after the beginning of therapy. At higher age the need for iodine and thyroxine is decreased. Therefore, therapy has to be controlled. For bone metabolism thyroid hormones play a dominant role. While there are only marginal differences between hypothyroid patients and euthyroid controls, there are large differences for hyperthyroid patients. Previous thyrotoxicosis and subsequent long-lasting L-thyroxine treatment are together associated with reduction in femoral and vertebral bone density in postmenopausal women. In these cases HRT is important for the control of bone loss.
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PMID:Thyroid function and postmenopause. 1272 22

Four chick bioassays were conducted to quantify iodine (I) toxicity and its amelioration in young chicks. A supplemental I level from KI of 600 mg/kg depressed growth in chicks fed methionine-deficient diets but not in those fed methionine-adequate diets. An I dose level >or= 900 mg/kg was required to cause growth depression in chicks fed a methionine-adequate corn-soybean meal diet. Iodine intoxicated chicks also displayed neurological symptoms and extreme malaise, but dose levels up to 1200 mg I/kg had no effect on blood hemoglobin or hematocrit. Supplemental I levels of 1000-1500 mg/kg caused severe growth depressions that could be totally reversed by dietary addition of 50 or 100 mg/kg bromine provided as NaBr. Nuclear accidents or terrorist actions that result in I toxicity and thyroid cancer or goiter may benefit from use of NaBr as a therapeutic agent.
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PMID:Oral iodine toxicity in chicks can be reversed by supplemental bromine. 1284 Jan 98


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