N-methyltetrahydro-beta-carboline analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin are oxidized to neurotoxic beta-carbolinium cations by heme peroxidases

2-Methyl-1,2,3,4-tetrahydro-beta-carboline (2-Me-THbetaC) and 2,9-dimethyl-1,2,3,4-tetrahydro-beta-carboline (2,9-diMe-THbetaC) are naturally occurring analogs of the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), whereas their corresponding aromatic 2-methyl-beta-carbolinium cations resemble 1-methyl-4-phenylpyridinium (MPP(+)) and are considered potential toxins involved in Parkinson's disease (PD). To become toxicants, 2-methyltetrahydro-beta-carbolines need to be oxidized (aromatized) by human metabolic enzymes to pyridinium-like (beta-carbolinium) cations as occur with MPTP/MPP(+) model. In contrast to MPTP, human MAO-A or -B were not able to oxidize 2-Me-THbetaC to pyridinium-like cations. Neither, cytochrome P-450 2D6 or a mixture of six P450 enzymes carried out this oxidation in a significant manner. However, 2-Me-THbetaC and 2,9-diMe-THbetaC were efficiently oxidized by horseradish peroxidase (HRP), lactoperoxidase (LPO), and myeloperoxidase (MPO) to 2-methyl-3,4-dihydro-beta-carbolinium cations (2-Me-DHbetaC(+), 2,9-diMe-DHbetaC(+)) as the main products, and detectable amount of 2-methyl-beta-carbolinium cations (2-Me-betaC(+), 2,9-diMe-betaC(+)). The apparent kinetic parameters (k(cat), k(4)) were similar for HRP and LPO and higher for MPO. Peroxidase inhibitors (hydroxylamine, sodium azide, and ascorbic acid) highly reduced or abolished this oxidation. Although MPTP was not oxidized by peroxidases; its intermediate metabolite 1-methyl-4-phenyl-2,3-dihydropyridinium cation (MPDP(+)) was efficiently oxidized to MPP(+) by heme peroxidases. It is concluded that heme peroxidases could be key catalysts responsible for the aromatization (bioactivation) of endogenous and naturally occurring N-methyltetrahydro-beta-carbolines and related protoxins to toxic pyridinium-like cations resembling MPP(+), suggesting a role for these enzymes in toxicological and neurotoxicological processes.     

Toxicity and metabolism of the chloral-derived mammalian alkaloid 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) in PC12 cells

Chloral-derived beta-carbolines, which are structurally similar to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 5), are discussed to contribute to neuronal cell death in idiopathic Parkinson's disease. The cytotoxicity of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo, 4) to neuronal-like clonal pheochromocytoma PC12 cells was examined by the determination of lactate dehydrogenase (LDH) release. After incubation for 48 h, 4 showed a strong dose-dependent cytotoxic activity towards PC12 cells with an ED50 value of 230 microM. In PC12 cells reductive dehalogenation of 4 was observed giving rise to the formation of 1-dichloromethyl-1,2,3,4-tetrahydro-beta-carboline (6) as a main TaClo metabolite exhibiting a cytotoxic potential comparable to that of TaClo. An X-ray structure analysis, performed for the trifluoroacetyl derivative of 6, revealed the N-substituent of such a highly chlorinated agent to be dramatically pushed out of the beta-carboline ring 'plane' due to the high steric demand of the huge dichloromethyl group at C(1).     

Modification of tyrosine hydroxylase activity by chloral derived beta-carbolines in vitro

Beta-carbolines have been suggested to be involved in the pathogenesis of Parkinson's disease as a result of their structural similarity to the neurotoxin N -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The chloral-derived beta-carboline derivative 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) causes cell loss in neuronal and glial cell cultures and induces a slowly developing neurodegenerative process in rats. In our experiments, effects of TaClo and its derivatives 2-methyl-TaClo (2-Me-TaClo), and 1-dichloromethylene-1,2,3,4-tetrahydro-beta-carboline (1-CCl(2) -THbetaC) on tyrosine hydroxylase (TH) activity were investigated in TH assays using homogenate preparations of the rat nucleus accumbens and recombinant human TH (hTH1). TH activity was determined in vitro by measuring l-DOPA production with HPLC-ECD. Using homogenate preparations, TaClo, 2-Me-TaClo, and 1-CCl(2) -THbetaC inhibited TH in concentrations of 0.1 mm, while 1-CCl(2) -THbetaC in low concentrations enhanced TH activity. When TH was activated by PACAP-27, TaClo, 2-Me-TaClo, or 1-CCl(2) -THbetaC also inhibited activated enzyme activity in high concentrations. However, in the case of 2-Me-TaClo and 1-CCl(2) -THbetaC a biphasic effect was observed with a marked increase of TH activity in the nanomolar range. In our experiments using recombinant hTH1, TaClo, 2-Me-TaClo, or 1-CCl(2) -THbetaC did not modify enzyme activity. After activation of hTH1 by PKA all the tetrahydro-beta-carbolines investigated in this study decreased l-DOPA formation. We suggest that these beta-carbolines modulate dopamine synthesis by interacting with a protein kinase TH-activating system.     

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) and related derivatives: chemistry and biochemical effects on catecholamine biosynthesis

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo, 2) is a mammalian alkaloid that readily originates in the human organism, by Pictet-Spengler condensation of endogenously present tryptamine (Ta) and the non-natural hypnotic agent trichloroacetaldehyde (chloral, Clo). Due to its structural analogy to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 1), TaClo is discussed to possibly contribute to the pathogenesis of Parkinson's disease acting as an environmental toxin. Previous investigations on rats and neuronal cell cultures revealed 2 to be capable of inducing severe disturbances on the dopamine metabolism. In this paper, we report on the effects of 2 on the activity of tyrosine hydroxylase [L-tyrosine, tetrayhydropteridine/oxygen oxidoreductase (3-hydroxylating), EC 1.14,16.2; TH] in vitro using rat brain homogenates prepared from the TH-rich nucleus accumbens. TaClo (2) dose-dependently inhibited basal TH activity (IC(50)=3 microM), and after enzyme activation by pituitary adenylate cyclase-activating polypeptide (PACAP-27), it also reduced L-DOPA formation (IC(50)=15 microM). Moreover, two presumable TaClo metabolites, 2-methyl-TaClo (N-Me-TaClo, 3) and 1-dichloromethylene-1,2,3,4-tetrahydro-beta-carboline (1-CCl(2)-TH beta C, 4), which were synthesized in good yields, also proved to be potent inhibitors of TH, with the strongest effect on basal activity (similar to TaClo) being observed for 3 (IC(50)=3 microM). In contrast to TaClo, however, 3 and 4 showed biphasic effects after TH activation with PACAP-27, inducing a marked increase of enzyme activity in the nanomolar range (<0.1 microM), while TH activity was nearly completely blocked at high concentrations (IC(100)=0.1mM). An X-ray diffraction investigation on the 3-dimensional structure of the 1-CCl(2)-TH beta C-derived trifluoroacetamide 7 revealed the voluminous and quite rigid dichloromethylene substituent to be only moderately twisted out of the beta-carboline ring 'plane', thus resulting in an increased ring strain of the partially hydrogenated pyrido moiety accompanied by a strong steric hindrance of Cl(1), Cl(2), C(13), and N(2), which pushes the N-trifluoroacetyl group upwards to an even higher extent than for the TaClo-related trifluoroacetamide 8.     

Visualisation of messenger RNA directing peptide synthesis by in situ hybridisation using a novel single-stranded cDNA probe. Potential for the investigation of gene expression and endocrine cell activity

Recently (Pecci Saavedra et al. 1982; Brusco et al. 1982, 1983) we have showed that the actual specificity of the rabbit anti-5-HT antibodies, is for the beta-carboline derivatives of 5-HT as a result of cyclization of the lateral chain. We explained this as resulting from the use of formaldehyde which acted both as a fixative in the preparation of the tissues, and as the coupling agent in the preparation of the immunogen. Following this line we have fixed several brain stem specimens with 0.5% p-benzoquinone; 3% glutaraldehyde; 4% paraformaldehyde plus 0.25% glutaraldehyde and compare the results with tissues fixed in 4% paraformaldehyde. Glutaraldehyde and p-benzoquinone do not produce cyclization of 5-HT but immobilize monoamines in situ. As expected, the antibodies applied according to the PAP technique did not stain the neuronal bodies of the raphe system, known to contain 5-HT when 3-4% glutaraldehyde or 0.5% p-benzoquinone were used. Good staining was obtained with 4% paraformaldehyde alone or with 4% paraformaldehyde plus 0.25% glutaraldehyde. A quantitative assay of the spot test of Larsson (1981) was devised for measuring in vitro the inhibitory effects of 5-HT, of the 5-HT-BSA complex and of the cyclic derivative, 6-OH-1,2,3,4-tetrahydro-beta-carboline. The results confirmed that the avidity of the antiserum is much greater for the cyclic derivatives contained in the 5-HT-BSA complex and for 6-OH-1,2,3,4-tetrahydro-beta-carboline than for 5-HT. It is concluded that the formation of a new ring by the lateral chain of 5-HT is responsible of the in-vitro and in the tissue immunoreactivity of the anti-5-HT-antibodies.     

Effects of melatonin and 6-methoxy-tetrahydro-beta-carboline in light induced retinal damage: a computerized morphometric method

The effects of melatonin and a related 5-methoxy-indole, 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeO-THBC) were investigated in rats on the development of retinal degeneration in presence of high intensity illumination (HII). A morphometric method is used in which the degree of degeneration was evaluated by a computer-coupled graphical analyzer. Instead of measuring individual thicknesses of different retinal layers at various loci we measured large areas of retinal light microscopic sections. Thus the influence of sporadic artefactual and other fluctuations in the thickness of various layers of the retina can be essentially reduced. Continuous light produced significant degeneration of the retina and the degree of degeneration was further increased by both studied compounds and even more by 6-MeO-THBC. The role of melatonin and 6-MeO-THBC in retinal physiology is discussed.     

Endogenous alkaloids in man. XXXVIII. "Chiral" and "achiral" determination of the neurotoxin TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) from blood and urine samples by high-performance liquid chromatography--electrospray ionization tandem mass spectrometry

An improved sensitive assay for the determination of the dopaminergic and serotonergic neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) is presented, based upon on-line coupling of high-performance liquid chromatography with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS-MS). Applying synthetic [D4]TaClo as a fourfold deuterated internal standard, TaClo was detected and reliably quantified as a trace constituent of blood samples (0.5 up to 70 ng g(-1) of clot) obtained from six patients orally treated with the hypnotic chloral hydrate. Unambiguous identification of this tricyclic "endogenous alkaloid" was achieved by selected reaction monitoring (SRM) experiments. The molecular ion peaks of TaClo, m/z 289 (for [35Cl3]TaClo) and m/z 291 (for its [37Cl35Cl2]isotopomer), were both monitored to undergo a retro-Diels-Alder fragmentation by loss of a CH2=NH portion (-29 u) as typical of a tetrahydropyrido ring system of tetrahydro-beta-carbolines. Detection of the resulting fragments, m/z 260 and m/z 262, with the expected statistical chlorine isotopic intensities of 100:96 confirmed the identity of the TaClo molecule. In addition, an enantiomer-specific device was developed for TaClo, by employing a chiral reversed-phase HPLC column in combination with circular dichroism (CD) spectroscopy and MS-MS analysis (LC-CD and LC-MS-MS coupling). In a human clot sample, both TaClo enantiomers were found in equimolar concentration (i.e., as a racemate) corroborating a spontaneous, non-enzymatic formation of TaClo from biogenic tryptamine and therapeutically administered chloral. In urine samples of TaClo-treated rats, by contrast, the (S)-antipode was found to predominate, hinting at an enantiomer-differentiating metabolism of the compound.     

Identification of the dopaminergic neurotoxin 1-trichloromethyl-1,2, 3,4-tetrahydro-beta-carboline in human blood after intake of the hypnotic chloral hydrate.

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a potent toxin toward dopaminergic neurons, readily originates in vitro from the biogenic amine tryptamine and the unnatural aldehyde chloral. For this reason, this heterocycle has been postulated to be formed endogenously in humans after administration of the hypnotic chloral hydrate or after exposure to the industrial solvent trichloroethylene by a spontaneous chemical ring closure reaction. In this paper, we report on the first identification of TaClo in blood samples of patients treated orally with chloral hydrate. Using a specific and sensitive gas chromatographic screening procedure based upon electron-capture and mass-selective detection, TaClo was determined after conversion to its volatile trifluoroacetyl derivative. The identity of TaClo in humans was clearly demonstrated by GC-MS analysis in selected-ion-monitoring mode, by the characteristic chlorine isotopic pattern of the molecular ion.     

Reduced peptide bond cyclic somatostatin based opioid octapeptides. Synthesis, conformational properties and pharmacological characterization.

The conformational and pharmacological properties that result from peptide bond reduction as well as the use of secondary amino acids in a series of cyclic peptides related to the mu opioid receptor selective antagonist D-Phe1-Cys2-Tyr3-D-Trp4-Orn5-Thr6-Pen7+ ++-Thr8-NH2 (IV), have been investigated. Peptide analogues that contain [CH2NH] and [CH2N] pseudo-peptide bonds (in primary and secondary amino acids, respectively) were synthesized on a solid support. Substitution of Tyr3 in IV by the cyclic, secondary amino acid 1,2,3,4-tetrahydroisoquinoline carboxylate (Tic) and of D-Trp4 with D-1,2,3,4-tetrahydro-beta-carboline(D-Tca4), gave peptides 4 and 1, respectively. Both analogues displayed reduced affinities for mu opioid receptors. Conformational analysis based on extensive NMR investigations demonstrated that the backbone conformations of 1 and 4 are similar to those of the potent and selective analogue D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (I), while the conformational properties of the side chains of Tic3 (4) and D-Tca4 (1) resulted in topographical properties that were not well recognized by the mu opioid receptor. Peptide bond modifications were made including (Tyr3-psi[CH2NH]-D-Trp4), 3; (Tyr3-psi[CH2N]-D-Tca4), 2; and (Cys2-psi[CH2N]-Tic3), 6. These analogues showed decreases in their mu opioid receptor affinities relative to the parent compounds IV, 1, and 4, respectively. 1H NMR based conformational analysis in conjunction with receptor binding data led to the conclusion that the reduced peptide bonds in 2, 3, 5, and 6 do not contribute to the process of discrimination between mu and delta opioid receptors, and in spite of their different dynamic behaviors (relative to 1 and 4), they are still capable of attaining similar receptor bound conformations, possibly due to their increased flexibility.     

Synthesis and antibacterial activity of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones

A novel series of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones has been designed and synthesized in which the heterocyclic side chain is attached to the quinolone core through a carbon–carbon linkage. The antibacterial activity of the compounds was determined against a panel of Gram-positive and Gram-negative pathogens. Compounds 1b and 1e, bearing an 8-methoxy group as well as unsubstituted and (3S)-methyl substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl side chains, respectively, demonstrated notable activity against ciprofloxacin-resistant clinical isolates of Streptococcus pneumoniae.     

High-performance liquid chromatography of tetrahydro-beta-carbolines extracted from plasma and platelets

A fast method for extraction and concentration of tryptamine (TA), 5-hydroxy-TA, and 5-methoxy-TA was developed using reverse-phase C-18 sample preparation columns in combination with an ion-pairing reagent. Using this method, 1,2,3,4-tetrahydro-beta-carboline (THBC), 6-hydroxy-THBC, and 6-methoxy-THBC, the respective reaction products formed after reaction of formaldehyde with the primary amines mentioned above, and beta-carboline (BC, norharman) and 1-methyl-beta-carboline (1-Me-BC, harman) could also be extracted from human and rat platelets and platelet-poor plasma (PPP). A HPLC method combined with fluorometric detection was developed for the quantitative determination of these compounds in the picomole range. The formation of beta-carbolines during the extraction procedure was below the limit of detection of the assay procedure. 6-OH-THBC, THBC, 1-Me-BC, and 5-HT were identified as normal constituents of human platelets, whereas only 5-hydroxytryptamine (5-HT) and 6-OH-THBC could be identified in human PPP. In rat platelets and PPP 5-HT, but no THBCs, could be detected.     

Synthesis and in vitro binding studies of substituted piperidine naphthamides. Part II: Influence of the substitution on the benzyl moiety on the affinity for D2L, D4.2, and 5-HT2A receptors

In continuation of our work on N-(piperidin-4-yl)-naphthamides, the effect of substituted benzyl groups on D(2L), D(4.2), and 5-HT(2A) receptor affinity was evaluated. In the 1-naphthamide series most compounds were highly selective for D(4.2) over D(2L) and 5-HT(2A) receptors. Halogen and methyl substitution in position 3 or 4 of the benzyl group increased D(4.2) affinity. In the 2-naphthamide series a similar high D(4.2) over D(2L) selectivity was retained while 5-HT(2A) affinity was increased. 3-Methoxy, 3-methyl, and 4-methyl substituents were favorable for D(4.2) affinity while halogens reduced affinity. 2-Naphthamides with a 3-bromo- or a 3-methyl group were mixed D(4.2)/5-HT(2A) ligands similar to their unsubstituted parent compound. All compounds from both series with significant affinity for D(4.2) and 5-HT(2A) receptors were antagonists.     

Biostimulation and bioaugmentation to enhance dechlorination of polychlorinated dibenzo-p-dioxins in contaminated sediments

Dechlorination of spiked 1,2,3,4-tetrachlorodibenzo-p-dioxin (1,2,3,4-TeCDD) was investigated in sediment microcosms from three polychlorinated dibenzo-p-dioxin and dibenzofuran (CDD/F)-contaminated sites: River Kymijoki, Finland; Gulf Island Pond, Maine; and Lake Roosevelt, Washington. Dechlorination was stimulated by addition of electron donor and halogenated priming compounds, and bioaugmentation by a mixed culture containing Dehalococcoides ethenogenes strain 195. Amendment with 1,2,3,4-tetrachlorobenzene (1,2,3,4-TeCB) promoted rapid dechlorination of 1,2,3,4-TeCDD to 2-monochlorodibenzo-p-dioxin (2MCDD) in Gulf Island Pond and River Kymijoki sediments, however, only slow dechlorination to 1,4-dichlorodibenzo-p-dioxin was observed in Lake Roosevelt sediments. The dechlorination pathway in 1,2,3,4-TeCB-amended microcosms proceeded mainly via 1,3-dichlorodibenzo-p-dioxin, with less production of 2,3-dichlorodibenzo-p-dioxin in comparison with other treatments. Microbial community analyses indicated that Dehalococcoides-like bacteria were enriched with 1,2,3,4-TeCB. Quantitative real-time PCR analysis of Dehalococcoides-specific 16S rRNA genes and the D. ethenogenes strain 195 dehalogenase gene, tceA, showed at least an order of magnitude higher gene copy numbers in the bioaugmented than in the nonbioaugmented microcosms. An active-dechlorinating population is present in the River Kymijoki and biostimulation may enhance both native Dehalococcoides spp. and the bioaugmented D. ethenogenes strain 195.     

Increased Levels of Monoamine-Derived Potential Neurotoxins in Fetal Rat Brain Exposed to Ethanol

Pregnant SD rats were exposed to ethanol (25 % (v/v) ethanol at 1.0, 2.0 or 4.0 g/kg body weight from GD8 to GD20) to assess whether ethanol-derived acetaldehyde could interact with endogenous monoamine to generate tetrahydroisoquinoline or tetrahydro-beta-carboline in the fetuses. The fetal brain concentration of acetaldehyde increased remarkably after ethanol administration (2.6 times, 5.3 times and 7.8 times as compared to saline control in 1.0, 2.0 and 4.0 g/kg ethanol-treated groups, respectively) detected by HPLC with 2,4-dinitrophenylhydrazine derivatization. Compared to control, ethanol exposure induced the formation of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol, Sal), N-methyl-salsolinol (NMSal) and 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (6-OH-MTHBC) in fetal rat brains. Determined by HPLC with electrochemical detector, the levels of dopamine and 5-hydroxytryptamine in whole fetal brain were not remarkably altered by ethanol treatment, while the levels of homovanillic acid and 5-hydroxyindole acetic acid in high dose (4.0 g/kg) of ethanol-treated rats were significantly decreased compared to that in the control animals. 4.0 g/kg ethanol administration inhibited the activity of mitochondrial monoamine oxidase (51.3 % as compared to control) and reduced the activity of respiratory chain complex I (61.2 % as compared to control). These results suggested that ethanol-induced alteration of monoamine metabolism and the accumulation of dopamine-derived catechol isoquinolines and 5-hydroxytryptamine-derived tetrahydro-beta-carbolines may play roles in the developmental dysfuction of monoaminergic neuronal systems.     

Design, synthesis and biological evaluation of new tryptamine and tetrahydro-beta-carboline-based selective inhibitors of CDK4

We present the design, synthesis and biological activity of a library of substituted (biphenylcarbonyl)-tryptamine and (biphenylcarbonyl)-tetrahydro-beta-carboline compounds related to the natural product fascaplysin, as novel inhibitors of CDK4/cyclin D1. We show all these molecules, prepared using the Suzuki-Miyaura reaction, being selective inhibitors of CDK4 over CDK2. The most active compounds have a CDK4 IC(50) in the range 9-11 microM, three of them containing the para-biphenyl plus para-substituents supporting the existence of a pi-stacking pocket within the active site of CDK4.     

大沙鼠在中国的地理分布

搜集了大沙鼠在中国的分布资料，运用地理信息系统（ＧＩＳ）的叠加和空间分析功能，结合生境，利用１：４００００００比例尺中国植被图和１：１００００００比例尺中国草地资源图，对我国大沙鼠的地理分布进行了系统研究。根据大沙鼠对梭梭和盐爪爪盐漠，梭梭、红砂培漠，梭梭在乐漠，沙拐枣沙漠，茺漠盐生草 盐地要柳灌丛和柽柳包，极稀疏地柽柳沙漠，红砂砾漠、禾草拐枣沙漠，荒漠盐生草甸的盐地柽柳灌丛和柽柳包，极稀疏的柽柳     

1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline-induced apoptosis in the human neuroblastoma cell line SK-N-SH

Trichloroethylene, a common industrial solvent and a metabolic precursor of chloral hydrate, occurs widely in the environment. Chloral hydrate, which is also used as a hypnotic, has been found to condense spontaneously with tryptamine, in vivo, to give rise to a highly unpolar 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) that has a structural analogy to the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Earlier studies have revealed the relative permeability of the molecule through the blood-brain barrier and its ability to induce Parkinson-like symptoms in rats. In this study, we report that TaClo induces an apoptotic pathway in the human neuroblastoma cell line, SK-N-SH, involving the translocation of mitochondrial cytochrome c to the cytosol and activation of caspase 3. TaClo-induced apoptosis shows considerable differences from that mediated by other Parkinson-inducing agents such as MPTP, rotenone and manganese. Although it is not clear if the clinically administered dosage of chloral hydrate or the relatively high environmental levels of trichloroethylene could lead to an onset of Parkinson's disease, the spontaneous in vivo formation of TaClo and its pro-apoptotic properties, as shown in this report, should be considered.     

Evaluation of neurotoxicity of TIQ and MPTP and of parkinsonism-preventing effect of 1-MeTIQ by in vivo measurement of pre-synaptic dopamine transporters and post-synaptic dopamine D(2) receptors in the mouse striatum.

Parkinsonism-inducing neurotoxicity of 1,2,3,4-tetrahydroisoquinoline (TIQ), as contrasted to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and parkinsonism-preventing effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) have been investigated in mice by measuring their effects on the in vivo binding of radioligand to pre-synaptic dopamine transporters (DATs) or to dopamine D(2) receptors (D2R) in the striatum. A significant reduction of the ligand-DATs binding was found in the mice treated with MPTP, but not with TIQ, under the dosage inducing behavioral abnormality and loss of tyrosine hydroxylase-positive cells in the substantia nigra. A slight decrease in the ligand-DATs binding was observed in the mice given a larger dose of TIQ. Compensatory up-regulation in the post-synaptic D2Rs was found in the MPTP-treated mice. Pre-treatment with (S)-enantiomer, but not (R)-enantiomer, of 1-MeTIQ prevented the degeneration of DATs to some extent. We concluded that the TIQ-induced parkinsonism model is different from the MPTP-induced model as evaluated by the radioligand-DATs binding and that (S)-1-MeTIQ has a preventing effect for the degeneration of the DATs to a certain extent.     

Side reactions in the preparation of 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid

Summary During a study on the preparation of the conformationally restricted analogue of tryptophan into 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid1 by a Pictet-Spengler condensation with formaldehyde, two site products were detected:N-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid2 and a dimer3 of two 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid units linked by a methylene group. Their structures were determined by HPLC-MS and 2D NMR spectroscopy. By changing the isolation procedure, theN-hydroxymethyl compound was removed. Treatment of the mixture with TFA in water converted the dimer into 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid1.     

民勤绿洲人工梭梭林退化现状、特征与恢复对策

民勤全县共有人工梭梭林近3．5万hm^2,占人工林总面积的51．5％,在民勤固沙林中占主导地位。但目前除水库与环河周围外,人工梭梭林均出现不同程度的退化现象,并表现为建群种梭梭光合强度减弱、群落盖度降低、梭梭种群优势度下降、林地土壤含水率下降、组成群落的物种多样性减少、地表土壤结皮破坏、风蚀作用增强等特征。梭梭林的退化,直接威胁到民勤绿洲的生存与发展,其恢复与重建成为当前一项十分重要而紧迫的任务,为此提出控制梭梭林密度、人工集雨、布设粘土或新型材料沙障、引进与培育抗旱新品种、特殊区域应用喷灌技术补水、补充水源不断恢复民勤地区的地下水位等措施,以期达到恢复与维持梭梭群落稳定发展的目的。