Antidepressant stimulation of CDP-diacylglycerol synthesis does not require monoamine reuptake inhibition

Background

Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of brain CDP-diacylglycerol synthase - the enzyme that catalyzes the physiological synthesis of CDP-diacylglycerol.

Results

Imipramine, paroxetine, and maprotiline concentration-dependently increased the levels of CDP-diacylglycerol and phosphatidylinositides in PC12 cells. Rat forebrain tissues depleted of serotonin by pretreatment with p-chlorophenylalanine showed responses to imipramine or maprotiline that were comparable to respective responses from saline-injected controls. With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished. Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues.

Conclusion

Antidepressants probably induce the activity of CDP-diacylglycerol synthase leading to increased production of CDP-diacylglycerol and facilitation of downstream phosphatidylinositol synthesis. Phosphatidylinositol-dependent signaling cascades exert diverse salutary effects in neural cells, including facilitation of BDNF signaling and neurogenesis. Hence, the present findings should strengthen the notion that modulation of brain phosphatidylinositide signaling probably contributes to the molecular mechanism of diverse antidepressant medications.

     

Convulsant bicuculline modifies CNS muscarinic receptor affinity

Background  

Previous work from this laboratory has shown that the administration of the convulsant drug 3-mercaptopropionic acid (MP), a GAD inhibitor, modifies not only GABA synthesis but also binding of the antagonist [³H]-quinuclidinyl benzilate ([³H]-QNB) to central muscarinic receptors, an effect due to an increase in affinity without modifications in binding site number. The cholinergic system has been implicated in several experimental epilepsy models and the ability of acetylcholine to regulate neuronal excitability in the neocortex is well known. To study the potential relationship between GABAergic and cholinergic systems with seizure activity, we analyzed the muscarinic receptor after inducing seizure by bicuculline (BIC), known to antagonize the GABA-A postsynaptic receptor subtype.     

NMR Studies of Drugs. Applications of Achiral and Chiral Wthanide Shift Reagents to Bupropion

Abstract

The ¹H NMR spectra of racemic samples of the antidepressant drug, bupropion, 1, have been studied in CDCl₃ solution at 60 and 200 MHz with the achiral lanthanide shift reagent (LSR), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium (III), 2, and the chiral reagent, tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III), 3. Both LSR produced substantial lanthanide induced shifts consistent with ¹H assignments, but the bound complexes of 1 with 2 versus 3 may not be isostructural. With 3, substantial enantiomeric shift differences were observed for the t-butyl, CH ₃CH, NCH, and the aryl H-2 and H-6 signals, which should permit potential direct determination of enantiomeric excess.     

Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology

Background  

Calcium (Ca²⁺) has recently been shown to selectively increase the activity of monoamine oxidase-A (MAO-A), a mitochondria-bound enzyme that generates peroxyradicals as a natural by-product of the deamination of neurotransmitters such as serotonin. It has also been suggested that increased intracellular free Ca²⁺ levels as well as MAO-A may be contributing to the oxidative stress associated with Alzheimer disease (AD).     

Visible laser spectroscopy of cobalt monofluoride

The laser-induced fluorescence excitation spectrum of jet-cooled CoF molecules has been studied in the range of 18 800–22 000 cm⁻¹. Ten observed vibronic bands have been classified into three transitions with the 0–0 band at 18 909, 19 236, and 20 654 cm⁻¹, assigned as the [18.8]³Φ₄–X³Φ₄, [19.2]³Φ₄–X³Φ₄, and [20.6]³Γ₅–X³Φ₄ transition, respectively, the two ³Φ states, [18.8]³Φ and [19.2]³Φ, are consistent with Adam’s results (10). The previously unanalyzed [20.6] state is identified in the current work. A rotational analysis of [20.6]³Γ₅–X³Φ₄ transition has been performed and effective equilibrium molecular constants have been determined for the first time. In addition, lifetime measurements of the three electronic transitions were carried out under the collision-free condition. From the lifetime analysis, we consider that the V=1, 2, and 3 vibrational levels of [18.8]³Φ state are perturbed by another state.     

13C NMR and 2D (H,H and H,C COSY) Spectra of Triazolo-triazino-indole Derivatives and the Conformational Analysis of the Respective C-Nucleoside Analogues

¹³C NMR and 2D (H,H and H,C COSY) spectra of selected examples of sugar (5H-1,2,4-triazino[5,6-b]-indol-3-yl) hydrazones, peracetylated sugar-1-acetyl -1- (5-acetyl-1,2,4-triazino[5,6-b]indol-3-yl)hydrazones, and 10-acetyl-3-(per-0-acetylalditol-1-yl)-1,2,4-triazolo[4′, 3′:2,3][1,2,4]triazino[5,6-b]indole have been reported. The conformation of the latter C-nucleoside analogues have been determined by analysis of their ¹H NMR spectra. The D-galacto, D-manno and L-arabino isomers are preponderantly existing in the planar zigzag arrangement of carbon atoms.     

Dipole bands and multi-quasiparticle excitations in 193Pb

The nucleus ¹⁹³Pb was populated via the ¹⁶⁸Er(³⁰Si,5n) reaction at a beam energy of 159 MeV and studied with the EUROGAM II spectrometer. Five new dipole Δ I = 1 cascades have been found. These structures have been connected to the level scheme which has been considerably extended up to a spin of ? and an excitation energy of about 8 MeV. Angular distribution coefficients, a₂, have been measured and confirm the dipole character of the in-band transitions. B(M1)/B(E2) ratios have been extracted for the two most intense cascades. The ¹⁹³Pb dipole bands are discussed in comparison with those known in odd lead isotopic series and the structure of the band heads is analyzed in terms of microscopic HF+BCS calculations. The proposed configurations are based on a high-K two quasiproton excitation, π ([505]9/2^t? ? [606]13/2⁺)_K=11^t -, coupled to one or three rotation aligned quasineutrons involving the i_13/2, p _3/2, f_5/2 and/or h{9/2} subshells. The main difference, compared with the heavier lead isotopes, is the presence of large Ω orbitals from the ν (i_13/2) shell near the Fermi surface which are responsible for the increasing band-head spin as A decreases.     

Isotope effects in the enzymatic oxidation of tryptamine to 3-indolyl-acetaldehyde

The reaction mechanisms of the enzymatic deamination of tryptamine catalysed by the enzyme monoamine oxidase (MAO, EC 1.4.3.4) were investigated using the kinetic isotope effect and solvent isotope effect methods. The numerical values of these deuterium effects in the (1S) and (1R) positions of tryptamine were determined using the non-competitive spectrophotometry. The deuterium-labelled isotopologue [(1S)-²H]tryptamine was obtained in two steps by enzymatic coupling of indole with S-methyl-l-cysteine in a deuterated medium followed by enzymatic decarboxylation of the resulting [2-²H]-l-tryptophan. [(1R)-²H]tryptamine was obtained by enzymatic decarboxylation of l-tryptophan in the fully deuterated medium.     

Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease

Background  

Predominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T₂ water ¹H relaxation or ¹H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan in vivo brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin.     

1H and 13C NMR Spectra of Alditolyl Derivatives of 3-Hydrazino-5-Methyl[1,2,4]triazino[5,6-b]indole and Their Cyclized Products.

The ¹H and ¹³C NMR spectra of sugar (5-methyl [1, 2, 4]-triazino [5, 6-b] indol-3-yl) hydrazones (1), per-0-acetyl aldehydo sugar 1-acetyl-1-(5-methyl [1, 2, 4] triazino [5, 6-b]-indol-3-yl) hydrazones (2), l- (penta-0-acetyl-pentitol-1-yl)-10-methyl [l, 2, 4] triazolo [3′, 4′:3, 4] [l, 2, 4] triazino [5, 6-b]-indoles (3) have been investigated. The 2 D NMR (H, C COSY) spectrum of 2a has been studied.     

Dipole and quadrupole cascades in the yrast region of 143Gd

The high spin states of ¹⁴³Gd have been studied via the ¹¹¹Cd(³⁵Cl,1p2n) reaction at 170 MeV. One dipole cascade has been newly found and two dipole cascades have been extended to higher spin states. A relatively long E2 cascade consisting of irregular transition energies has been found, which has only weak connections to the other dipole and quadrupole cascades. This resembles the ones recently found in ^142,143,144Eu and ¹⁴⁴Gd. The dipole and quadrupole cascades have been found to appear by turns in an energy increment of about 0.2 MeV above the yrast line. Received: 1 November 1997     

Fluoxetine Hydrochloride的NMR数据解析

由美国Lilly公司开发的第二代抗抑郁症药物盐酸氟西汀（Fluoxetine hydrochloride），属于选择性5-羟色胺再摄取抑制剂（SSRI），除了用于治疗各类抑郁症，包括轻性或重性抑郁症，尤宜用于老年性抑郁症之外，对于强迫症、惊恐发作、贪食症、经前期焦虑等亦有很好疗效. Fluoxetine hydrochloride是一种双环化合物，与传统的三环类、杂环类或单胺氧化酶抑制剂抗抑郁药相比，具有疗效好、不良反应轻而少，安全性高、耐受性好等特点，目前已作为一线的抗抑郁药得到广泛应用. 本文对Fluoxetine hydrochloride进行了¹H NMR和¹³C NMR检测，并通过DEPT和¹H-¹H COSY、HMBC、HSQC等2D NMR技术对其¹H NMR和¹³C NMR数据进行了较为详细的解析和比文献[1]更为全面的NMR归属，为以后的分析鉴定提供更完善的依据.     

Surface,micellar, and thermodynamic properties of antidepressant drug nortriptyline hydrochloride with TX‐114 in aqueous/urea solutions

This paper deals with a comprehensive study of the mixed micellization and adsorption behavior of mixed systems enclosing an amphiphilic antidepressant drug nortriptyline hydrochloride (NOT) and Triton X‐114 (TX‐114) (nonionic surfactant) in aqueous/urea (500 mmol·kg^?1 and 1000 mmol·kg^?1) solutions by tensiometric method. The NOT is used for the cure of depression. For comparison purpose cmc value of pure drug NOT was also evaluated by conductimetric technique. Different theoretical models like Clint, Rubingh, and Rosen were used to get information about the nature of interaction between the components in bulk and at the interface. Because of the occurrence of urea increase in the surface charge of the micelles was obtained resulting a delay of the micelles formation. The cmc values of the mixed systems of NOT and TX‐114 were found to be in between the cmc values of pure components, which signify nonideal mixed system having attractive interactions in the absence and presence of urea. Various parameters such as micellar mole fractions of TX‐114 (X₁^m, X₁^σ) in solution and at interface, interaction parameter (β^m/β^σ) in solution and at interface, and activity coefficient in solution and at interface were evaluated and discussed using Rubingh's and Rosen's models. Surface excess (Γ_max) increases that means minimum area per head group (A_min) decreases as mole fraction (α₁) of TX‐114 increases in the absence/presence of urea. Different thermodynamic parameters have been calculated and discussed. The ?G⁰_m values achieved are all negative both in the absence and occurrence of urea.     

Photoinduced electron‐transfer reactions of tris(2,2′‐bipyridine)ruthenium(II)‐based carbonic anhydrase inhibitors tethering plural binding sites

Tris(2,2′‐bipyridine)ruthenium(II) complex‐based carbonic anhydrase (CA) inhibitors, [Ru(bpy)₂(bpydbs)]²⁺ {bpy = 2,2′‐bipyridine and bpydbs = 2,2′‐bipyridinyl‐4,4′‐dicarboxilic acid bis[(2‐{2‐[2‐(4‐sulfamoylbenzoylamino)ethoxy]ethoxy}ethyl)amide]} and [Ru(bpydbs)₃]²⁺, tethering plural benzenesulfonamide groups have been prepared. The CA catalytic activity was effectively suppressed by these synthetic [Ru(bpy)₂(bpydbs)]²⁺ and [Ru(bpydbs)₃]²⁺ inhibitors, and their dissociation constants at pH = 7.2 and at 25°C were determined to be K_I = 0.93 ± 0.02 μM and K_I = 0.24 ± 0.03 μM, respectively. Next, 2 photoinduced electron‐transfer (ET) systems comprising a Ru²⁺‐CA complex and an electron acceptor, such as chloropentaamminecobalt(III) ([CoCl(NH₃)₅]²⁺) or methylviologen (MV²⁺) were studied. In the presence of CA and a sacrificial electron acceptor, such as pentaamminechlorocobalt(III) complex, the photoexcited triplet state of ³([Ru(II)]²⁺)* was quenched through an intermolecular photoinduced ET mechanism. In case of the [Ru(bpydbs)₃]²⁺‐CA‐MV²⁺ system, the photoexcited triplet state of ³([Ru(bpydbs)₃]²⁺)* was quenched by sacrificial quencher through an intermolecular photoinduced ET mechanism, giving the oxidized [Ru(bpydbs)₃]³⁺. Then the following intramolecular ET from the amino acid residue, Tyr6, near the active site of CA proceeded. We observed a transient absorption around at 410 nm, arising from the formation of a Tyr^?+ in the [Ru(bpydbs)₃]²⁺‐CA‐MV²⁺ system. These artificial Ru(II)‐CA systems may clearly demonstrate both intermolecular and intramolecular photoinduced ET reactions of protein and could be one of the interesting models of the ET proteins. Their photophysical properties and the detailed ET mechanisms are discussed in order to clarify the multistep ET reactions.     

Dipole bands and multi-quasiparticle excitations in193Pb

The nucleus¹⁹³Pb was populated via the¹⁶⁸Er(³⁰Si,5n) reaction at a beam energy of 159 MeV and studied with the EUROGAM II spectrometer. Five new dipoleΔI=1 cascades have been found. These structures have been connected to the level scheme which has been considerably extended up to a spin of 61/2? and an excitation energy of about 8 MeV. Angular distribution coefficients,α ₂, have been measured and confirm the dipole character of the in-band transitions. B(M1)/B(E2) ratios have been extracted for the two most intense cascades. The¹⁹³Pb dipole bands are discussed in comparison with those known in odd lead isotopic series and the structure of the band heads is analyzed in terms of microscopic HF-BCS calculations. The proposed configurations are based on a high-K two quasiproton excitation,π([505]9/2^??[606]13/2⁺) _K =11^?, coupled to one or three rotation aligned quasineutrons involving thei _13/2,p _3/2,f _5/2 and/orh _9/2 subshells. The main difference, compared with the heavier lead isotopes, is the presence of largeΩ orbitals from theν (i _13/2) shell near the Fermi surface which are responsible for the increasing band-head spin as A decreases.     

Optical Fabry–Perot filter based on photonic band gap quasi-periodic one-dimensional multilayer according to the definite Rudin–Shapiro distribution

In this work, a new type of optical filter using photonic band gap materials has been suggested. Indeed, a combination of periodic H(LH)^J and Rudin–Shapiro quasi-periodic one-dimensional photonic multilayer systems (RSM) were used. SiO₂ (L) and TiO₂ (H) were chosen as two elementary layers with refractive indexes n_L = 1.45 and n_H = 2.30 respectively. The study configuration is H(LH)^J[RSM]^PH(LH)^J, which forms an effective Fabry–Perot filter (FPF), where J and P are respectively the repetition number of periodic and (RSM) stacks. We have numerically investigated by means of transfer-matrix approach the transmission properties in the visible spectral range of FPF system. We show that the number and position of resonator peaks are dependent on the (RSM) repetition number P and incidence angle of exciting light. The effect of these two parameters for producing an improved polychromatic filter with high finesse coefficient (F) and quality factor (Q) is studied in details.     

Protonic mobility in acidic colloids

Colloidal monoclinic zirconia ZrO₂ particles have been synthesized by hydrothermal treatment from acetate solutions. To increase their surface acidity, they have been treated by aqueous solutions of phosphoric acid, sulfophenylphosphonic acid (SPPA, (HO)₂(O)–C₆H₆–SO₃H) and sulfodifluoromethylphosphonic acid (SFPA, (HO)₂(O)P–CF₂–SO₃H). This leads to the covalent bonding of phosphoric or sulfonic acid groups onto the surface of the particles. Solid state NMR (³¹P, ¹H) studies show the covalent grafting of the phosphate and phosphonates groups and qualitatively illustrate the fast proton dynamics of these surface conducting materials as compared with that of crystalline α-Zr(HPO₄)₂. H₂O. But, water adsorption is still necessary to increase the long distance proton mobility. Then, the macroscopic conductivity remains low (between 10^− 4 S cm^− 1 and 10^− 3 S cm^− 1 25 °C, RH 70%) and shows a strong hysteresis while cycling the relative humidity. The mechanism limiting the conductivity seems to be interparticle transfer.     

Chronologically overlapping occurrences of nicotine-induced anxiety- and depression-related behavioral symptoms: effects of anxiolytic and cannabinoid drugs

Background  

Anxiety and depression are among the most frequently-observed psychiatric symptoms associated with nicotine (NC). In addition to the similarity to other addictive drugs, these NC-induced symptoms are characteristic in that the opposite behavioral effects, i.e. anxiolytic and antidepressant effects, which may reinforce the habitual use of NC, have also been reported. In the present study, the time course of anxiety- and depression-related behavioral alterations was examined in mice. Furthermore, based on the reported similarity in the mechanisms responsible for NC-induced anxiety- and depression-related symptoms, as well as the contribution of brain cannabinoid (CB) receptors to these behavioral symptoms, the effects of anxiolytics and CB receptor ligands (CBs) against these behavioral symptoms were investigated.     

De novo design of N-(pyridin-4-ylmethyl)aniline derivatives as KDR inhibitors: 3D-QSAR, molecular fragment replacement, protein-ligand interaction fingerprint, and ADMET prediction

Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 or kinase insert domain receptor (KDR) have been identified as promising targets for novel anticancer agents. To achieve new potent inhibitors of KDR, we conducted molecular fragment replacement (MFR) studies for the understanding of 3D-QSAR modeling and the docking investigation of arylphthalazines and 2-((1H-Azol-1-yl)methyl)-N-arylbenzamides-based KDR inhibitors. Two favorable 3D-QSAR models (CoMFA with q ², 0.671; r ², 0.969; CoMSIA with q ², 0.608; r ², 0.936) have been developed to predict the biological activity of new compounds. The new molecular database generated by MFR was virtually screened using Glide (docking) and further evaluated with CoMFA prediction, protein?Cligand interaction fingerprint (PLIF) and ADMET analysis. 44 N-(pyridin-4-ylmethyl)aniline derivatives as novel potential KDR inhibitors were finally obtained. In this paper, the work flow developed could be applied to de novo drug design and virtual screening potential KDR inhibitors, and use hit compounds to further optimize and design new potential KDR inhibitors.