Locomotor hypoactivity and motor disturbances--behavioral effects induced by intracerebellar microinjections of dopaminergic DA-D2/D3 receptor agonists.
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In the light of recent findings, DA-D3 dopamine receptors with an unclear physiological function are present in the cerebellar cortex. Our preliminary results seem to indicate that bilateral injection of 7-OH-DPAT, a DA-D2/D3 receptor agonist (1 and 10 microg/0.5 microl), to lobule 9/10 of rat cerebellar cortex reduces spontaneous locomotor activity (hypolocomotor effects) and induces balance and motor coordination disturbances, respectively. Similar effects can be observed in the case of analogous microinjection of the DA-D3/D2 agonist pramipexole. In earlier studies, peripheral (ip) injection of nafadotride (0.6 mg/kg), a D3 receptor antagonist, neither affected per se spontaneous motor activity, nor modified the above described effects of 7-OH-DPAT. Participation of cerebellar DA-D3 and DA-D2 receptors in hypolocomotor effects, as well as putative participation of other receptors in the generation of motor disturbances, has been discussed. (+info)
Pramipexole in patients with Parkinson's disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study.
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OBJECTIVE: To compare the tremorlytic properties of pramipexole, a non-ergoline dopamine agonist to those of placebo as add on medication in patients with Parkinson's disease. METHODS: Eighty four patients with early or advanced Parkinson's disease and marked, drug resistant tremor under a stable and optimised antiparkinsonian medication were included in a double blind, randomised, placebo controlled, multicentre study and assigned to add on treatment (7 week dose titration interval, 4 week maintenance period) with either pramipexole (n=44) or placebo (n=40) as adjunct. The primary end point was the absolute change in tremor score, defined as the sum of tremor related items (16, 20, 21) of the unified Parkinson's disease rating scale (UPDRS) in "on" periods. Secondary end points included the percentage change in tremor score, the absolute and percentage changes in long term EMG tremor registration, and the change in tremor self rating scales. Safety and tolerability were assessed on the basis of adverse events, laboratory tests, ECG, and vital signs. RESULTS: Pramipexole was significantly superior to placebo with a difference between treatment groups in the mean absolute change in tremor score of -4.4 (95% confidence interval (95% CI) -6.2 to -2.5) (p<0.0001), corresponding to a difference in the mean percentage change of -34.7% in favour of pramipexole. The secondary end points were consistent with the significant change in tremor score and provided further evidence for the benefit of pramipexole compared with placebo. Long term EMG registration as an objective measure showed a difference in mean absolute change in tremor occurrence of -15.2% (95%CI -21.4 to -9.0) (p<0.0001), and a difference in the mean percentage change of -45.7% in favour of pramipexole. The treatment effects increased during dose titration and remained stable during the 4 week maintenance dose period until the end of the study. The average daily pramipexole dose during maintenance was 4.1 (SD 0.9) mg. Safety analysis showed an increased rate of fatigue, insomnia, nausea, abdominal pain, and headache under pramipexole, comparable with previous studies. CONCLUSION: Pramipexole proved to be an effective agent for patients with Parkinson's disease and drug resistant tremor. (+info)
E3040 sulphate, a novel thromboxane synthase inhibitor, blocks the Cl- secretion induced by platelet-activating factor in isolated rat colon.
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1. E3040 (6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole), is a novel dual inhibitor of 5-lipoxygenase (5-LOX) and thromboxane synthase (Tx synthase). Here, we examined the effects of E3040 sulphate, a sulphate conjugate of E3040, on these enzyme activities in cell-free systems and on the thromboxane A2 (TxA2)-mediated Cl- secretion induced by platelet-activating factor (PAF) in isolated rat colons. 2. E3040 sulphate inhibited Tx synthase activity in a concentration-dependent manner (IC50=0.013 microM), whereas it induced little effects on 5-LOX and cyclo-oxygenase activities (IC50>100 microM) with the cell-free enzyme assay. 3. With isolated rat colonic mucosa, E3040 sulphate in a concentration-dependent manner (IC50=1.8 microM) inhibited the Cl- secretion induced by 10 microM PAF. On the other hand, E3040 sulphate (30 microM) induced no effect on the prostaglandin E2 (0.5 microM)- and leukotriene D4 (1 microM)-induced Cl- secretion in the colon. 4. PAF (10 microM) increased a release of TxB2, a stable metabolite of TxA2, from the colonic mucosa. This increase was significantly inhibited by subsequent addition of E3040 sulphate (30 microM). 5. Probenecid (100 microM), an inhibitor of organic anion transporter, abolished the inhibitory effect of E3040 sulphate on the PAF-induced Cl- secretion. Another inhibitor, sulphobromophthalein (30 microM) partially but significantly attenuated the effect of E3040 sulphate. p-aminohippuric acid (1 mM) had no effect. 6. These findings suggest that E3040 sulphate is a novel Tx synthase inhibitor, and that E3040 sulphate taken up into the colonic cells by organic anion transporters inhibits the PAF-induced Cl- secretion by blocking a release of TxA2. (+info)
Metal ions as potential regulatory factors in the biosynthesis of red hair pigments: a new benzothiazole intermediate in the iron or copper assisted oxidation of 5-S-cysteinyldopa.
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In the presence of iron or copper ions, the course of the oxidation in air of 5-S-cysteinyldopa (1), the main biosynthetic precursor of pheomelanins and trichochromes, was markedly changed affording two main products. One of these was identified as the oxobenzothiazine 8, previously obtained under nonphysiologically relevant conditions, while the other was characterized as the novel hydroxybenzothiazole 9. Besides 8 and 9, carboxylated and noncarboxylated benzothiazine products were obtained by persulfate oxidation of 1 in the presence of iron or copper ions. The ratio of formation yields of carboxylated/noncarboxylated benzothiazines, determined after reduction of the mixture, was lower than that of the control reaction run in the absence of metal ions, and much lower than that of the oxidation carried out in the presence of zinc ions, in agreement with a recent report. Notably, 8 and 9 were formed in variable yields under different oxidation conditions including tyrosinase/O(2), peroxidase/hydrogen peroxide, and the hydrogen peroxide/or (9E,11Z,13S)-13-hydroperoxyoctadeca-9,11-dienoic acid/Fe(III) systems. Mechanistic routes to 8 and 9 were proposed based on the results of experiments involving in situ generation of labile benzothiazine intermediates. Overall, these results allow to formulate an improved biosynthetic scheme in which metal ions act as critical regulatory factors determining pheomelanin vs. trichochromes formation. (+info)
Fluorescence lifetime spectroscopy in multiply scattering media with dyes exhibiting multiexponential decay kinetics.
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To investigate fluorescence lifetime spectroscopy in tissue-like scattering, measurements of phase modulation as a function of modulation frequency were made using two fluorescent dyes exhibiting single exponential decay kinetics in a 2% intralipid solution. To experimentally simulate fluorescence multiexponential decay kinetics, we varied the concentration ratios of the two dyes, 3,3-diethylthiatricarbocyanine iodide and indocynanine green (ICG), which exhibit distinctly different lifetimes of 1.33 and 0.57 ns, respectively. The experimental results were then compared with values predicted using the optical diffusion equation incorporating 1) biexponential decay, 2) average of the biexponential decay, as well as 3) stretched exponential decay kinetic models to describe kinetics owing to independent and quenched relaxation of the two dyes. Our results show that while all kinetic models could describe phase-modulation data in nonscattering solution, when incorporated into the diffusion equation, the kinetic parameters failed to likewise predict phase-modulation data in scattering solutions. We attribute the results to the insensitivity of phase-modulation measurements in nonscattering solutions and the inaccuracy of the derived kinetic parameters. Our results suggest the high sensitivity of phase-modulation measurements in scattering solutions may provide greater opportunities for fluorescence lifetime spectroscopy. (+info)
Two advances in the management of Parkinson disease.
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Levodopa should generally be avoided early in the course of Parkinson disease; dopamine agonists, particularly second-generation agents such as ropinirole (Requip) and pramipexole (Mirapex), carry a smaller long-term risk of dyskinesia and should be used instead. Deep brain stimulation is remarkably effective in refractory cases and may well usher in a new era in the treatment of chronic neurologic disease. (+info)
Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay.
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Preventing the formation of insoluble polyglutamine containing protein aggregates in neurons may represent an attractive therapeutic strategy to ameliorate Huntington's disease (HD). Therefore, the ability to screen for small molecules that suppress the self-assembly of huntingtin would have potential clinical and significant research applications. We have developed an automated filter retardation assay for the rapid identification of chemical compounds that prevent HD exon 1 protein aggregation in vitro. Using this method, a total of 25 benzothiazole derivatives that inhibit huntingtin fibrillogenesis in a dose-dependent manner were discovered from a library of approximately 184,000 small molecules. The results obtained by the filter assay were confirmed by immunoblotting, electron microscopy, and mass spectrometry. Furthermore, cell culture studies revealed that 2-amino-4,7-dimethyl-benzothiazol-6-ol, a chemical compound similar to riluzole, significantly inhibits HD exon 1 aggregation in vivo. These findings may provide the basis for a new therapeutic approach to prevent the accumulation of insoluble protein aggregates in Huntington's disease and related glutamine repeat disorders. (+info)
Inhibition of muscle carbonic anhydrase slows the Ca(2+) transient in rat skeletal muscle fibers.
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A countertransport of H(+) is coupled to Ca(2+) transport across the sarcoplasmic reticulum (SR) membrane. We propose that SR carbonic anhydrase (CA) accelerates the CO(2)-HCO reaction so that H(+) ions, which are exchanged for Ca(2+) ions, are produced or buffered in the SR at sufficient rates. Inhibition of this SR-CA is expected to reduce the rate of H(+) fluxes, which then will retard the kinetics of Ca(2+) transport. Fura 2 signals and isometric force were simultaneously recorded in fiber bundles of the soleus (SOL) and extensor digitorum longus (EDL) from rats in the absence and presence of the lipophilic CA inhibitors L-645151, chlorzolamide (CLZ), and ethoxzolamide (ETZ), as well as the hydrophilic inhibitor acetazolamide (ACTZ). Fura 2 and force signals were analyzed for time to peak (TTP), 50% decay time (t(50)), and their amplitudes. L-645151, CLZ, and ETZ significantly increased TTP of fura 2 by 10-25 ms in SOL and by 5-7 ms in EDL and TTP of force by 6-30 ms in both muscles. L-645151 and ETZ significantly prolonged t(50) of fura 2 and force by 20-55 and 40-160 ms, respectively, in SOL and EDL. L-645151, CLZ, and ETZ also increased peak force of single twitches and amplitudes of fura fluorescence ratio (R(340/380)) at an excitation wavelength of 340 to 380 nm. All effects of CA inhibitors on fura 2 and force signals could be reversed. ACTZ did not affect TTP, t(50), and amplitudes of fura 2 signals or force. L-645151, CLZ, and ETZ had no effects on myosin-, Ca(2+)-, and Na(+)-K(+)-ATPase activities, nor did they affect the amplitude and half-width of action potentials. We conclude that inhibition of SR-CA by impairing H(+) countertransport is responsible for deceleration of intracellular Ca(2+) transients and contraction times. (+info)