Motor response to a dopamine D3 receptor preferring agonist compared to apomorphine in levodopa-primed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys

The profile of dopamine receptor subtype activation contributing to the therapeutic efficacy and motor response complications of levodopa (nonselective pro-agonist) in Parkinson's disease remains unclear. Potent, selective, short-acting dopamine D2 receptor subfamily agonists show good antiparkinsonian efficacy but produce dyskinesias comparable to levodopa. Nonetheless, agonists displaying higher affinity for dopamine receptors other than the D2 subtype may have a better therapeutic index. To clarify this issue, we compared the nonselective dopamine D1/D2 receptor subfamilies agonist apomorphine to the dopamine D3 receptor preferring agonist [R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4 , 3-b]-1,4-oxazin-9-ol] (PD 128,907) in 6 levodopa-primed , 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian monkeys with reproducible dyskinesias. Single s.c. dosing with the lowest fully effective dose of apomorphine (averaging 27.9 +/- 4.5 microg/kg) and PD 128,907 (averaging 41.7 +/- 4.4 microg/kg) yielded equivalent antiparkinsonian efficacy on the behavioral scale and portable activity monitoring used. A comparable significant dose-dependent increase in the response magnitude and duration was seen with two higher doses. The severity of dyskinesia was also similar between the two drugs. When the lower dose for each drug was administered six times at a fixed 90-min interval, both drugs remained efficacious with no significant tolerance observed. The D3 receptor preferring antagonist U-99194A significantly reduced the motor effects of both apomorphine and PD 128,907. Thus, increased D3 receptor tone does not acutely ameliorate dyskinesias in levodopa-primed parkinsonian monkeys. Given the reported lack of affinity of PD 128,907 for central D1 receptors, our data support the concept that the pharmacological activation of D1 receptors is not mandatory for relief of parkinsonism and production of dyskinesia.     

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreases glutamate uptake in cultured astrocytes

The deleterious effect of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on dopaminergic neurons of the substantia nigra is well established. In addition, increased glutamatergic drive to basal ganglia output nuclei is considered a likely contributor to the pathogenesis of Parkinson's disease. One possibility for the increased excitatory tone may be related to an impairment in glutamate uptake. As astrocytes possess efficient transport mechanisms for both MPTP and glutamate, we have examined the effect of this agent on D-aspartate uptake into these cells. Treatment of cultures with 50 microM MPTP for 24 h decreased uptake by 39%. Kinetic analysis revealed that this effect was due to a 35% decrease in Vmax with no change in the Km. Treatment with deprenyl, a monoamine oxidase B inhibitor, produced a complete reversal of MPTP-induced uptake inhibition, but was ineffective following exposure of cells to the MPTP metabolite, 1-methyl-4-phenylpyridinium (MPP+). Removal of MPTP from cultures resulted in a complete restoration of glutamate uptake after 24 h. These results show that MPTP reversibly compromises glutamate uptake in cultured astrocytes, which is dependent on the conversion of MPTP to MPP+. Such findings suggest that the glutamate transporter in astrocytes plays an important role in MPTP-induced neurotoxicity and possibly in parkinsonism.     

Effects of ageing on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxic effects on striatum and brainstem in the rat

In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), noradrenaline (NA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the striatum and/or in the brainstem 24 h after single injections of MPTP (12-35 mg/kg i.p.). Aged rats had lower baseline levels of AA and GSH, compared to young rats. In aged rats, MPTP 35 mg/kg induced a 70% death rate and a decrease in striatal DOPAC/DA ratio which was significantly correlated to MPP+ concentrations (r = -0.840, P < 0.005); in addition, MPTP did not increase AA oxidation. In the brainstem, the MPTP-induced decrease in NA levels and increase in uric acid levels were significantly correlated to the MPP+ concentrations (r = -0.709, P < 0.05, and r = +0.888, P < 0.001, respectively). In conclusion, evidence is given of a mechanism of toxicity of MPTP involving oxidative stress produced by xanthine oxidase; in addition, in aged rats the neuronal antioxidant system (levels of AA and GSH) is considerably lower than in young rats and may play an enabling role in the MPTP age-related neurotoxic effects on striatum and brainstem.     

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) disrupts social memory/recognition processes in the male mouse

Male mice treated with MPTP or vehicle were tested for their ability to demonstrate a memory-recognition response as evaluated in a habituation-dishabituation task. Treatment with MPTP severely disrupted the male's habituation-dishabituation response profile compared to vehicle treated animals. Administration of L-DOPA at 45 min prior to behavioral testing in MPTP animals restored their performance on the habituation-dishabituation test to levels observed in vehicle treated animals. There was also a tendency for L-DOPA to produce enhanced responsiveness in vehicle treated animals. Mice treated with MPTP had significantly reduced concentrations of norepinephrine within the olfactory bulb and hippocampus. Vehicle treated mice administered L-DOPA had significantly increased dopamine concentrations within the corpus striatum. These results suggest that, in addition to its putative effects upon the nigrostriatal dopaminergic system and motor behavior, MPTP is also exerting substantial effects upon other systems. In particular, the noradrenergic system and its potential involvement with memory/recognition processes in the CD-1 mouse appears to be very sensitive to the neurotoxic effects of MPTP.     

Nullification of a positive correlation between urinary contents of alpha1-microglobulin and ulinastatin with intracerebroventricularly administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) in mice

BACKGROUND: Wolff-Parkinson-White syndrome is thought to be a congenital disease, however, its exact prevalence is not known. This may be because of the intermittent activity of accessory pathways in some cases and fluctuations in autonomic tone. AIMS: To investigate the prevalence of ventricular preexcitation by electrocardiography and reported symptoms in each school age child in Yamanashi prefecture. METHODS: From 1994 to 1996, answers to a questionnaire, results of physical examination, and electrocardiography were obtained from all schoolchildren in Yamanashi prefecture (n = 92,161; total population 880,000) on admission to elementary school (age 6 to 7 years, n = 28,395), junior high school (age 12 to 13 years, n = 31,206), and high school (age 14 to 15 years, n = 32,837). RESULTS: Elementary and junior high school students had a significantly lower prevalence of preexcitation than high school students (0.073% and 0.070% v 0.174%, p < 0.001). The prevalence of left free wall pathway was highest in high school students (n = 27) compared with elementary (n = 6) and junior high school students (n = 5) (p < 0.005). The only symptom noted in the answers to the questionnaire was palpitations. The symptomatic cases were more frequent in high school (n = 13) than in elementary (n = 1) and junior high school (n = 2) children, but not significantly. No student with preexcitation had associated heart disease or family history of Wolff-Parkinson-White syndrome or sudden death. CONCLUSIONS: The prevalence of preexcitation in younger schoolchildren was less frequent than previously reported. The prevalence of preexcitation and left free wall pathways increased with age. The symptoms were few and there was no significant morbidity.     

Dermal application of lisuride on parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset and on cases with Parkinson''s disease

BACKGROUND: Follow-up study of patients with surgical repair of aneurysmal subarachnoidal hemorrhage (SAH), looking for clinical outcome predictors. PATIENTS AND METHODS: Sixty two patients consecutively admitted to a teaching hospital, from January 1992 to December 1995 were included in the study. We studied preoperative, intraoperative and postoperative features looking for their relationship with the outcome. The ultimate outcome was evaluated by means of Glasgow Outcome Scale on discharge and 6 months later. RESULTS: Smoking (p = 0.0001) and arterial hypertension (AHT) (p = 0.0186) were more frequent in these patients than in general population, but without relationship to the outcome as with the age of the clinical status on admission. The greatest statistical relationship was found between the level of consciousness on postoperative awakening (measured by the Hunt and Hess scale), and the outcome (p = 2.53 x 10(-8). From our results we made an algorithm that correctly assigned 92% of studied patients to their outcome. CONCLUSIONS: All patients admitted on with aneurysm SAH deserve intensive care treatment besides their clinical grade. The level of consciousness on postoperative awakening was a good outcome predictor.     

Elevation of antioxidant potency in the brain of mice by low-dose gamma-ray irradiation and its effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced brain damage

The elevation of endogenous thiol-related antioxidants and free radical scavenging enzymes in the brain of C57BL/6 female mice after low-dose gamma-ray irradiation and its inhibitory effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced brain damage were investigated. The brain level of the reduced form of glutathione (GSH) increased soon after irradiation with 50 cGy of gamma-rays, reached a maximum at 3 h post-treatment, and remained elevated until 12 h. Thioredoxin (TRX) was also transiently increased after irradiation. The activities of free radical scavenging enzymes, including Cu/Zn-superoxide dismutase, catalase and glutathione peroxidase, were significantly induced after irradiation as well. Cerebral malondialdehyde was remarkably elevated by MPTP treatment, and this elevation was suppressed by pre-irradiation (50 cGy). The contents of GSH and TRX were significantly decreased by MPTP treatment in comparison with those of the control group. These reductions both seemed to be attenuated by pre-irradiation with gamma-rays. These results suggest that low-dose gamma-ray irradiation induces endogenous antioxidative potency in the brain of mice and might be effective for the prevention and/or therapy of various reactive oxygen species-related neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease.     

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as a substrate of cytochrome P450 2D6: allosteric effects of NADPH-cytochrome P450 reductase

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that produces Parkinsonism symptoms in man, has been examined as a substrate of recombinant human cytochrome P450 2D6. When cumene hydroperoxide is used as an oxygen and electron donor, a single product is formed, identified as 4-phenyl-1,2,3,6-tetrahydropyridine. The K(m) for formation of this product (130 microM) is in agreement with the dissociation constants for MPTP binding to the enzyme determined by optical and nuclear magnetic resonance (NMR) spectroscopy. When the reaction is carried out with nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) and recombinant human NADPH-cytochrome P450 reductase, a second product, identified as 1-methyl-4-(4'-hydroxyphenyl)-1,2,3,6-tetrahydropyridine, is formed in addition to 4-phenyl-1,2,3,6-tetrahydropyridine. The K(m) values for formation of these two products are 19 microM and 120 microM, respectively. Paramagnetic relaxation experiments have been used to measure distances between the protons of bound MPTP and the heme iron, and these have been used to construct models for the position and orientation of MPTP in the active site. For the cytochrome alone, a single mode of binding was observed, with the N-methyl close to the heme iron in a position appropriate for the observed N-demethylation reaction. In the presence of the reductase, the data were not consistent with a single mode of binding but could be explained by the existence of two alternative orientations of MPTP in the active site. One of these, characterized by a dissociation constant of 150 microM, is essentially identical to that observed in the absence of the reductase. In the second, which has a K(d) of 25 microM, the MPTP is oriented so that the aromatic ring is close to the heme iron, in a position appropriate for p-hydroxylation leading to the formation of the product seen only in the presence of the reductase. In the case of codeine, another substrate for cytochrome P450 2D6, the addition of reductase had no effect on the nature of the product formed, the dissociation constant, or the orientation in the binding site. These observations show that NADPH-cytochrome P450 reductase has an allosteric effect on the active site of cytochrome P450 2D6 that affects the binding of some substrates but not others.     

Oxidation of 1-amino-4-phenyl-1,2,3,6-tetrahydropyridine, a 1-amino analog of MPTP, by type A and B monoamine oxidase

A 1-amino analog of MPTP, 1(N)-amino-4-phenyl-1,2,3,6-tetrahydropyridine, was synthesized and the oxidation was examined using human synaptosomal mitochondria as sources of type A and B monoamine oxidase. An oxidation product, 1-amino-4-phenylpyridinium ion, was quantified by high-performance liquid chromatography-fluorometric detection. The amino analog was a substrate of both type A and B monoamine oxidase and the oxidation depended linearly on the enzyme amount and the reaction time with an optimal pH around 7.5. After the systemic injection of the amino analog in C57/black mice for one week, 1-amino-4-phenylpyridinium ion was detected in the brain. 1(N)-Amino-4-phenyl-1,2,3,6-tetrahydropyridine was proved to be cytotoxic to pheochromocytoma PC12 cells, and it may be a new neurotoxin bioactivated through the oxidation by type A and B monoamine oxidase.     

Cytotoxicity of 1-amino-4-phenyl-1,2,3,6-tetrahydropyridine and 1-amino-4-phenylpyridinium ion, 1-amino analogues of MPTP and MPP+, to clonal pheochromocytoma PC12 cells

AIMS: To compare the tolerability and efficacy of a fixed combination solution of dorzolamide/timolol (Cosopt), administered twice daily with the concomitant administration of its components, dorzolamide (Trusopt) twice daily and timolol (Timoptic) twice daily. METHODS: After a 2 week timolol run in, patients with open angle glaucoma or ocular hypertension were randomised (1:1) to receive treatment with either the dorzolamide/timolol combination solution twice daily (combination) or the dorzolamide solution twice daily plus timolol maleate solution twice daily (concomitant) for 3 months. RESULTS: 299 patients were entered and 290 patients completed the study. Compared with the timolol baseline, additional IOP lowering of 16% was observed at trough (hour 0) and 22% at peak (hour 2) at month 3 in both the concomitant and combination groups. The IOP lowering effects of the two treatment groups were clinically and statistically equivalent as demonstrated by the extremely small point differences (concomitant--combination) observed in this study--0.01 mm Hg at trough and 0.08 mm Hg at peak. The safety variables of the concomitant and combination groups were very similar. Both combination and concomitant therapy were well tolerated and few patients discontinued due to adverse effects. CONCLUSIONS: The dorzolamide/timolol combination solution administered twice daily is equivalent in efficacy and has a similar safety profile to the concomitant administration of the components administered twice daily.     

Decline in striatal dopamine D1 and D2 receptor activation in aged F344 rats

Aging differentially affects receptor function. In the present electrophysiological study we compared neuronal responsiveness to locally applied dopamine D1 and D2 receptor agonist in the striatum of female Fischer 344 rats aged 3 and 26-27 months. In a subgroup of the old rats, the nigrostriatal dopamine bundle was destroyed unilaterally with 6-hydroxydopamine (6-OHDA) to assess receptor plasticity in response to denervation. Spontaneous firing rate of striatal neurons was higher in aged compared to young rats. Higher doses of the D1 agonist SKF 38393 or the D2 agonist quinpirole were required to elicit a 50% change in firing rate in aged compared to young rats. No difference with SKF 38393 or quinpirole was detected between 6-OHDA denervated and control (nonlesioned) striatum in aged rats. Supersensitivity to D2 agonists has been reported following 6-OHDA lesions in young rats. These observations suggest that D2 receptors in aged rat striatum might not be as plastic as in younger rats.     

Pharmacological and histopathological aspects of 1-methyl-4-phenyl-4-hydroxy-piperidine (MPIP)

The inhibitory effects of Radix Astragali (RA) on hypoxic structural remodeling of intra-acinar pulmonary arteries (IAPA) and pulmonary hypertension (PHT) were studied in rats, which were fed in hypoxic environment under normal atmospheric pressure (10% O2 10 hours/day). 60 rats were divided into 3 groups; hypoxia group, hypoxia+RA group and control group. On the 15th and 30th day of hypoxia, right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RVHI) were measured and pulmonary vessel changes were studies under light and electronic microscopes and morphometric analysis. Compared with the hypoxia+RA group, RA could prevent IAPA wall cell damage and dilate the constricted IPIA induced by hypoxia. RA could also inhibit hypertrophic changes in the tunica media and proliferation of adventitial cells of the IAPA and muscularization of non-muscular arteries. Therefore, preserving the IAPA wall cells and dilating IAPA by RA may play an important role in inhibiting structural remodeling of IAPA and pulmonary hypertension.     

Adenovirus-mediated transduction with human glial cell line-derived neurotrophic factor gene prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopamine depletion in striatum of mouse brain

OBJECTIVE: This study assesses intravascular density produced by ionic and nonionic contrast material and its effect on visualization of stenoses by CT angiography. MATERIALS AND METHODS: CT angiography was performed using a 32-vessel phantom to study grades of luminal stenoses (0-100%), three lengths of stenoses (1, 3, and 5 mm), and two angles of inclination into the stenoses (45 degrees and 75 degrees). Scans were obtained with a slice thickness of 2 mm, a slice interval of 1.5 mm, a pitch of 1.0, a voltage of 120 kV, and a current of both 100 and 200 mA. Vessels were oriented parallel to the z-axis, and opacified with ionic and nonionic contrast material that had densities of 100, 150, 200, 250, 300, and 350 H. Cross-sectional luminal diameters were measured in and out of the stenoses. Edge definition and halo artifact for each vessel were graded by an investigator who was unaware of the contrast material density used. RESULTS: A contrast density of 150 H as revealed by CT angiography yielded the most accurate stenosis measurements with ionic contrast material. For nonionic contrast material, attenuation values of 150 and 200 H produced the best results on CT angiography. A density of 100 H or greater than 250 H significantly increased the error of vessel measurement (p = .001) for both types of contrast material. For the two current levels tested (100 and 200 mA), no statistical difference was found. CONCLUSION: The accuracy of CT angiography in measuring carotid stenosis depends on the luminal attenuation value. An optimum contrast density is 150 H for ionic contrast material; for nonionic contrast material, 150-200 H (at the window and level settings of 300 H and 40 H).     

1,25(OH)2-vitamin D3 mediated changes in mRNA for c-myc and 1,25(OH)2D3 receptor in HL-60 cells and related subclones

The aim of this study was to clarify the change of the gastric mucosa following inoculation with Helicobacter pylori (H. pylori). Two pairs of cynomolgus monkeys received either H. pylori of human origin (group A) or H. pylori of monkey origin (group B) by intragastric inoculation at a dose of 10(9) CFU. After inoculation, endoscopical observation and biopsies were done every 7 days for one month. The bacteria in the biopsy samples were cultured quantitatively. The content of intracellular PAS-AB positive substance was quantitatively analyzed with the image analyzing system. Results were as follows: 1) Before inoculation, the gastric mucosa was endoscopically normal and free from H. pylori. 2) The quantity of H. pylori varied from 0 to 10(3) CFU/0.1 g tissue in group A and from 10 to 10(6) CFU/0.1 g tissue in group B. 3) Severe erosion was seen in group B, while mild mucosal erythema and erosion were observed in group A. 4) There was a correlation between the quantity of H. pylori and histological activity (Rauws' gastritis score). 5) The PAS-AB positive substance in H. pylori-positive mucosa was less than that in H. pylori-negative mucosa. In conclusion, gastric mucosal changes of varying degrees were brought about after inoculation of H. pylori depending on the quantity of bacilli in the gastric tissue.     

Implication of dopamine transporter system on 1-methyl-4-phenylpyridinium and rotenone effect in striatal synaptosomes

Absorption and endogenous excretion of P by male broiler chicks (14-29 d old) were quantitatively evaluated at different Ca:P ratios (1, 1:1; 2, 1.5:1; 3, 2:1; 4, 2.5:1) in four groups given experimental diets ad lib. The P content was the same in all diets. An isotope-dilution technique was used to determine endogenous faecal and renal excretion. Ca and P retentions in the whole body were estimated according to the comparative slaughter technique. P absorption was calculated from retention and endogenous excretion. Absorption and endogenous excretion of P amounted to (mg P/d per chick): 304, 270, 160 and 158; and 135, 109, 31 and 30 in groups 1, 2, 3 and 4 respectively. Widening of the Ca:P ratio in the feed limited the P absorption. Availability of feed P amounted to (%): (1) 66, (2) 57, (3) 32 and (4) 30, and the amounts of absorbed P retained were (%): (1) 56, (2) 60, (3 and 4) 81. The increasing Ca concentration in the feed showed a greater effect on P absorption than on P retention. The ratios of relative retention to relative endogenous excretion of absorbed P were: (1) 1.27, (2) 1.50, (3 and 4) 4.26.     

Selective full dopamine D1-like (SKF-82958) and D2-like (N-0923) agonist combination in the MPTP monkey model of hemiparkinsonism

OBJECTIVE: Fluoxetine is widely prescribed for depressed patients. Hyponatremia secondary to inappropriate secretion of antidiuretic hormone has been reported in a few cases associated with routine use of fluoxetine, especially in elderly patients. The mechanism has been postulated to be linked to the inappropriate secretion of antidiuretic hormone. Serum concentrations of antidiuretic hormone and fluoxetine have not been reported in previously published reports. CASE REPORT: We report two new cases of severe and reversible hyponatremia associated with routine use of fluoxetine therapy in two elderly women. Fluoxetine-induced inappropriate secretion of antidiuretic hormone was confirmed by elevated serum concentrations of antidiuretic hormone and fluoxetine.     

用1—苯基—3—甲基—4—苯甲酰基吡啉唑酮—5（PMBP）从高氯酸介质中萃取钯机理研究

研究了用1－苯基－3－甲基－4－苯甲酰基吡啉唑酮－5（PMBP）的氯仿溶液,从高氯酸介质中萃取钯的机理。采用斜率法测得萃合物组成为（Pd.L)ClO4,萃取反应方程式为：HL（o）＋Pd^2 (a) ClO4^-(a)＝（Pd.L)ClO4(o)^ (a)。     

Synthesis and dopamine transporter affinity of 2-(methoxycarbonyl)-9-methyl-3-phenyl-9-azabicyclo[3.3.1]nonane derivatives

A series of 9-methyl-3 beta-phenyl-2-substituted-9-azabicyclo[3.3.1]nonane derivatives were synthesized and evaluated as cocaine-binding site ligands at the dopamine transporter (DAT). The conformation of the bicyclic structures and the stereochemistry of the substituents were determined by NMR and X-ray crystallography. The in vitro binding affinity (Ki) of the 9-azabicyclo[3.3.1]nonane derivatives was measured in rat caudate-putamen tissue, and they were found to be 100-fold (Ki = 2-14 microM) less potent than cocaine and other tropane analogs. From these results it is evident that the cocaine-binding site at the DAT is very sensitive to structural modifications of the unsubstituted methylene bridge [C(6)-C(7)] of cocaine and cocaine-like compounds.