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1.
Br J Pharmacol ; 160(5): 1105-18, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20590604

ABSTRACT

BACKGROUND AND PURPOSE: Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity. EXPERIMENTAL APPROACH: In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (1-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one). KEY RESULTS: WAY-318068 is a potent and effective inhibitor of the NET with a K(i) of 8.7 nM in a binding assay, and an IC(50) of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits. CONCLUSIONS AND IMPLICATIONS: Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.


Subject(s)
Adrenergic Uptake Inhibitors/administration & dosage , Adrenergic Uptake Inhibitors/pharmacology , Depression/drug therapy , Disease Models, Animal , Indoles/administration & dosage , Indoles/pharmacology , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Pain Measurement/methods , Administration, Oral , Adrenergic Uptake Inhibitors/pharmacokinetics , Animals , Cell Line, Transformed , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Indoles/pharmacokinetics , Male , Mice , Mice, Inbred Strains , Norepinephrine/metabolism , Pain , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology
2.
Exp Neurol ; 203(2): 512-20, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17049515

ABSTRACT

Parkinson's disease (PD) is associated with loss of total glutathione (GSH) which may contribute to progressive cell death. Peripheral GSH administration has been used clinically with reported benefits. Despite this, there is little specific information to characterize its cellular uptake or clearance, brain elevation with peripheral delivery or neuroprotective efficacy in PD models. The current study was carried out to provide this information using in vitro and in vivo approaches. In rat mesencephalic culture, the monoethyl ester of GSH (GEE), but not GSH (1-10 mM, 24 h) produced a dose-dependent elevation in GSH. The half-life for clearance was 10.14 h and was not different in cells depleted of GSH prior to loading. Elevation of GSH with GEE protected neurons from oxidative stress with H2O2 or metabolic stress with the complex I and II inhibitors MPP+ and malonate, respectively. To determine if peripheral administration of GEE could elevate brain GSH levels, rats were administered 0.1-50 mg/kg/day GEE via osmotic minipump either subcutaneously (sc) or via a cannula placed into the left cerebral ventricle (icv) for 28 days. Only central delivery of GEE resulted in significant elevations of brain GSH. Elevation of brain GSH by icv infusion of GEE was examined for its neuroprotective effects against chronic central delivery of MPP+. Infusion of 0.142 mg/kg/day MPP+ for 28 days caused a selective ipsilateral loss of striatal dopamine. Co-infusion of MPP+ with 10 mg/kg/day GEE significantly protected against striatal dopamine loss. These findings show that the ethyl ester of GSH but not GSH per se can elevate intracellular GSH, that brain elevation of GSH requires central delivery of the ethyl ester and that this elevation provides neuroprotection against oxidative stress or chronic mitochondrial impairment.


Subject(s)
Brain Chemistry/drug effects , Glutathione/analogs & derivatives , Glutathione/metabolism , Glutathione/pharmacology , Neurons/metabolism , Parkinson Disease/metabolism , Animals , Cell Count , Cell Membrane/drug effects , Cell Membrane/metabolism , Cells, Cultured , Chromatography, High Pressure Liquid , Dopamine/metabolism , Female , Half-Life , Injections, Intraventricular , Mitochondria/drug effects , Mitochondria/metabolism , Neurons/drug effects , Oxidative Stress/drug effects , Pregnancy , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Tyrosine 3-Monooxygenase/metabolism , gamma-Aminobutyric Acid/metabolism
3.
Exp Neurol ; 200(1): 172-83, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16546169

ABSTRACT

Mitochondrial dysfunction is observed in sporadic Parkinson's disease (PD) and may contribute to progressive neurodegeneration. While acute models of mitochondrial dysfunction have been used for many years to investigate PD, chronic models may better replicate the cellular disturbances caused by long-standing mitochondrial derangements and may represent a better model for neurotherapeutic testing. This study sought to develop a chronic model of PD that has the advantages of continuous low level toxin delivery, low mortality, unilateral damage to minimize aphagia and adipsia as well as minimal animal handling to reduce stress-related confounds. Infusion by osmotic minipump of the complex I toxin, 1-methyl-4-phenylpyridinium (MPP+), for 28 days into the left cerebral ventricle in rats caused a selective ipsilateral loss of nigral tyrosine hydroxylase immunoreactive somata (35% loss). In animals that were sacrificed 14 days after the chronic MPP+ administration, there was an even greater loss of nigral tyrosine hydroxylase cells (65% loss). Lewy-body-like structures that stained positive for ubiquitin and alpha-synuclein were found in striatal neurons near the infusion site but were not observed in nigral neurons. At the electron microscope level, however, swollen and abnormal mitochondria were observed in the nigral dopamine neurons, which may represent the early formation of an inclusion body. There were no animal deaths with the chronic treatment regimen that was utilized, and the magnitude of nigrostriatal neuronal loss was relatively consistent among the animals. This model of progressive neurodegeneration of nigrostriatal dopamine neurons may be useful for studying neuroprotective therapeutic agents for PD.


Subject(s)
1-Methyl-4-phenylpyridinium/administration & dosage , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/pathology , 1-Methyl-4-phenylpyridinium/toxicity , Animals , Chronic Disease , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Injections, Intraventricular , Male , Parkinson Disease, Secondary/mortality , Rats , Rats, Sprague-Dawley , Survival Rate
4.
J Neurochem ; 79(1): 152-60, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11595767

ABSTRACT

The neurotoxic actions of methamphetamine (METH) may be mediated in part by reactive oxygen species (ROS). Methamphetamine administration leads to increases in ROS formation and lipid peroxidation in rodent brain; however, the extent to which proteins may be modified or whether affected brain regions exhibit similar elevations of lipid and protein oxidative markers have not been investigated. In this study we measured concentrations of TBARs, protein carbonyls and monoamines in various mouse brain regions at 4 h and 24 h after the last of four injections of METH (10 mg/kg/injection q 2 h). Substantial increases in TBARs and protein carbonyls were observed in the striatum and hippocampus but not the frontal cortex nor the cerebellum of METH-treated mice. Furthermore, lipid and protein oxidative markers were highly correlated within each brain region. In the hippocampus and striatum elevations in oxidative markers were significantly greater at 24 h than at 4 h. Monoamine levels were maximally reduced within 4 h (striatal dopamine [DA] by 95% and serotonin [5-HT] in striatum, cortex and hippocampus by 60-90%). These decrements persisted for 7 days after METH, indicating effects reflective of nerve terminal damage. Interestingly, NE was only transiently depleted in the brain regions investigated (hippocampus and cortex), suggesting a pharmacological and non-toxic action of METH on the noradrenergic nerve terminals. This study provides the first evidence for concurrent formation of lipid and protein markers of oxidative stress in several brain regions of mice that are severely affected by large neurotoxic doses of METH. Moreover, the differential time course for monoamine depletion and the elevations in oxidative markers indicate that the source of oxidative stress is not derived directly from DA or 5HT oxidation.


Subject(s)
Biomarkers/analysis , Brain/drug effects , Brain/metabolism , Lipid Peroxidation , Methamphetamine/pharmacology , Nerve Tissue Proteins/metabolism , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Biogenic Monoamines/metabolism , Cerebellum/drug effects , Cerebellum/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Hydroxyindoleacetic Acid/metabolism , Male , Mice , Oxidation-Reduction , Oxidative Stress , Reactive Oxygen Species/metabolism , Serotonin/metabolism , Thiobarbituric Acid Reactive Substances/analysis
5.
J Pharmacol Exp Ther ; 298(3): 925-33, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11504786

ABSTRACT

Disturbance in phosphorylation/dephosphorylation can trigger apoptosis. Little is known as to its effects on mesencephalic dopamine neurons, the major neurons lost in Parkinson's disease. In this study, okadaic acid (OKA), a phosphatase 1 and 2A inhibitor, with greater potency toward 2A, was toxic to mesencephalic dopamine and gamma-aminobutyric acid (GABA) neurons, however, dopamine neurons were 4-fold more sensitive. The EC(50) for dopamine versus GABA toxicity was 1.5 versus 6.5 nM, respectively, and was consistent with an inhibition of phosphatase 2A. Dopamine neurons were also more sensitive to calyculin-A, a phosphatase inhibitor equipotent toward 1 and 2A. OKA-methyl-ester, which lacks phosphatase inhibitory activity, was without effect. DNA laddering typical of apoptosis was observed in cultures at a concentration that was specifically toxic to dopamine neurons (5 nM). In contrast to the sensitivity of mesencephalic neurons to phosphatase inhibition, inhibition of protein kinase activity with staurosporine or K252a showed little toxicity and protected neurons from OKA. Consistent with in vitro findings, infusion of 32 to 320 pmol of OKA into the left striatum of rats caused a dose-dependent loss of striatal dopamine without any loss of GABA 1 week following infusion. Acutely, OKA increased tyrosine hydroxylase activity, a phosphatase 2A substrate, and increased dopamine turnover. The above-mentioned findings demonstrate that dysregulation of phosphatase activity is detrimental to mesencephalic neurons, with dopamine neurons, in vitro and in vivo, being relatively more sensitive to phosphatase 2A inhibition. Disturbances in the phosphorylation control of proteins unique to dopamine neurons may contribute to their enhanced vulnerability to OKA exposure.


Subject(s)
Enzyme Inhibitors/pharmacology , Mesencephalon/cytology , Mesencephalon/drug effects , Neurons/drug effects , Phosphoprotein Phosphatases/antagonists & inhibitors , Animals , Cell Count , Cells, Cultured , DNA Fragmentation , Dopamine/metabolism , Immunohistochemistry , Injections , Male , Neostriatum/physiology , Okadaic Acid/administration & dosage , Okadaic Acid/pharmacology , Phosphorylation , Protein Phosphatase 1 , Protein Phosphatase 2 , Rats , Rats, Sprague-Dawley , Staurosporine/administration & dosage , Staurosporine/pharmacology , Tyrosine 3-Monooxygenase/metabolism , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/physiology
6.
Exp Neurol ; 161(2): 638-46, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10686083

ABSTRACT

Defects in energy metabolism have been detected in patients with Parkinson's disease and have been proposed as a contributing factor in the disease. Previous in vitro studies showed that NMDA receptors contribute to the loss of dopamine neurons caused by the metabolic inhibitor malonate. In vivo, it is not known whether this interaction occurs through a postsynaptic action on the cell body in the substantia nigra or through a presynaptic action at the dopamine terminal in the striatum. So we could discern the anatomical level of NMDA receptor involvement, rats were infused with malonate, either into the left striatum or into the left substantia nigra. NMDA receptors were locally blocked by an intranigral or intrastriatal coinfusion of malonate plus MK-801 followed by a second infusion of MK-801 3 h later. Animals were examined at 1 week for striatal and nigral dopamine and GABA levels. Intranigral infusion of malonate (0.5 micromol) produced an approximate 50% loss of both nigral dopamine and GABA. MK-801 (0.1 micromol) provided significant protection against both nigral dopamine and GABA loss and against anterograde damage to dopamine terminals in the striatum. Intrastriatal administration of malonate (2 micromol) produced a 68 and 35% loss of striatal dopamine and GABA, respectively. In contrast to intranigral administration, intrastriatal blockade of NMDA receptors did not protect against striatal dopamine loss, although GABA loss was significantly attenuated. Core body temperature monitored several hours throughout the experiment was unchanged. Consistent with a lack of effect of NMDA antagonists on malonate-induced toxicity to dopamine neurons in striatum, intrastriatal infusion of NMDA had a pronounced effect on long-term GABA toxicity with little effect of dopamine loss. These findings are consistent with a postsynaptic action of NMDA receptors on mediating toxicity to dopamine neurons during impaired energy metabolism.


Subject(s)
Corpus Striatum/physiology , Dizocilpine Maleate/pharmacology , Malonates/pharmacology , Neurons/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Substantia Nigra/physiology , Animals , Body Temperature , Corpus Striatum/drug effects , Dizocilpine Maleate/administration & dosage , Dopamine/metabolism , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/pharmacology , Functional Laterality , Infusions, Parenteral , Male , Malonates/administration & dosage , Neurons/cytology , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Substantia Nigra/drug effects , gamma-Aminobutyric Acid/metabolism
7.
Brain Res ; 773(1-2): 223-6, 1997 Oct 31.
Article in English | MEDLINE | ID: mdl-9409726

ABSTRACT

This study examined whether damage to dopamine (DA) nerve terminals via inhibition of energy metabolism in the striatum would result in the retrograde loss of cell bodies in the substantia nigra. Infusion of 2 micromol malonate into the left striatum of rats resulted in a 67% loss of striatal DA and a 40% loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. No change in the number of Nissl-positive-TH-negative neurons was observed. These findings demonstrate the retrograde destruction of DA cell bodies in the substantia nigra resulting from energy impairment at their terminal projection site.


Subject(s)
Corpus Striatum/metabolism , Dopamine/metabolism , Energy Metabolism/physiology , Malonates/toxicity , Substantia Nigra/pathology , Animals , Corpus Striatum/drug effects , Corpus Striatum/pathology , Energy Metabolism/drug effects , Functional Laterality , Infusions, Parenteral , Male , Malonates/administration & dosage , Nerve Endings/drug effects , Nerve Endings/physiology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Rats , Rats, Sprague-Dawley , Substantia Nigra/drug effects , Tyrosine 3-Monooxygenase/analysis
8.
Eur J Pharmacol ; 320(2-3): 111-9, 1997 Feb 12.
Article in English | MEDLINE | ID: mdl-9059843

ABSTRACT

In vitro studies indicate that mesencephalic dopamine neurons are more vulnerable than other neurons to impairment of energy metabolism. Such findings may have bearing on the loss of dopamine neurons in Parkinson's disease, in which mitochondrial deficiencies have been identified, but would only be relevant if the selective vulnerability were maintained in vivo. To examine this, rats were stereotaxically administered various concentrations of the succinate dehydrogenase inhibitor, malonate (0.25-4 mumol), either into the left substantia nigra or striatum. One week following injection, dopamine and gamma-aminobutyric acid (GABA) levels in the mesencephalon and striatum were measured. Intranigral injection of malonate caused nigral dopamine and GABA to be comparably reduced at all doses tested. The 50% dose level for malonate vs. dopamine and GABA loss was 0.39 and 0.42 mumol, respectively. Tyrosine hydroxylase immunocytochemistry of the midbrains of rats which received an intranigral injection of malonate showed normal staining with 0.25 mumol malonate, but almost complete loss of tyrosine hydroxylase positive nigral pars compacta cells with 1 mumol malonate. Intrastriatal injection of malonate produced a loss of both tyrosine hydroxylase activity and dopamine. In contrast to what was seen in substantia nigra, there was a greater loss of dopamine than GABA in striatal regions nearest the injection site. In striatal regions most distal to the injection site, and which received the lowest concentration of malonate due to diffusion, dopamine levels were significantly reduced with all doses of malonate (0.5-4 mumol), whereas GABA levels were unaffected. Intrastriatal coinfusion of succinate along with malonate completely prevented the loss of dopamine and GABA indicating that succinate dehydrogenase inhibition was the cause of toxicity. These findings indicate that dopamine terminals in the striatum of adult rats are selectively more vulnerable than are the GABA neurons to a mild energy impairment.


Subject(s)
Corpus Striatum/metabolism , Dopamine/metabolism , Malonates/pharmacology , Neurons/metabolism , Substantia Nigra/metabolism , Animals , Axons/drug effects , Axons/metabolism , Corpus Striatum/cytology , Corpus Striatum/drug effects , Energy Metabolism/drug effects , Male , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Sensitivity and Specificity , Substantia Nigra/cytology , Substantia Nigra/drug effects , gamma-Aminobutyric Acid/metabolism
9.
Neurology ; 44(8): 1432-6, 1994 Aug.
Article in English | MEDLINE | ID: mdl-8058144

ABSTRACT

We report a patient with Meige syndrome (segmental cranial dystonia) who had neuropathologic changes of Parkinson's disease on postmortem examination. Neuropathologic examination showed typical and atypical Lewy bodies in the pigmented nuclei of the brainstem (substantia nigra, locus ceruleus), the nucleus basalis of Meynert, and the nucleus ambiguus. Neurochemical analysis of postmortem brain tissue showed evidence for decreased dopamine turnover in the substantia nigra, striatum, and nucleus accumbens. We propose that some cases of Meige syndrome may be included in the spectrum of Lewy body disease.


Subject(s)
Meige Syndrome/pathology , Parkinson Disease/pathology , Biogenic Amines/metabolism , Brain/metabolism , Brain/pathology , Dopamine/metabolism , Homovanillic Acid/metabolism , Humans , Male , Meige Syndrome/etiology , Meige Syndrome/metabolism , Middle Aged , Parkinson Disease/complications , Parkinson Disease/metabolism
10.
J Neurochem ; 58(5): 1979-982, 1992 May.
Article in English | MEDLINE | ID: mdl-1560247

ABSTRACT

Previous studies from this laboratory demonstrated that (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), an N-methyl-D-aspartate (NMDA) receptor antagonist, did not prevent neurotoxicity to dopaminergic neurons in mice produced by systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, Turski et al. [Nature 349, 414-418 (1991)] reported that extended treatment of rats with NMDA receptor antagonists (six injections at 4-h intervals) did prevent the loss of nigral dopaminergic neurons resulting from an intranigral infusion of 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of MPTP. The present studies examined if a similar extended treatment with MK-801 would protect mice from the neurotoxicity of systemically administered MPTP. Six intraperitoneal injections of MK-801 given at 4-h intervals did not protect mice against the MPTP-induced neostriatal dopamine loss measured 1 week after treatment. In other experiments, designed to replicate and expand on the results of Turski et al. (1991), the extended treatment of rats with MK-801 did not prevent MPP(+)-induced cell loss in the infused substantia nigra pars compacta or the dopamine depletion in the ipsilateral neostriatum at 7-11 days after MPP+ infusion. These results do not support the hypothesis that NMDA receptors are involved with MPTP/MPP(+)-induced neurodegeneration.


Subject(s)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , 1-Methyl-4-phenylpyridinium , Dizocilpine Maleate/pharmacology , Dopamine/physiology , Nervous System Diseases/prevention & control , Substantia Nigra/physiology , Animals , Male , Mice , Mice, Inbred Strains , Nervous System Diseases/chemically induced , Nervous System Diseases/pathology , Rats , Rats, Inbred Strains
13.
J Pharmacol Exp Ther ; 247(1): 180-5, 1988 Oct.
Article in English | MEDLINE | ID: mdl-2971797

ABSTRACT

In rats with a unilateral lesion of the nigrostriatal dopaminergic pathway, the ipsilateral rotation produced by the enhanced actions of endogenous dopamine (DA) on the nonlesioned side, induced by either the DA-releasing drug amphetamine or the DA uptake inhibitor GBR 13069, was blocked effectively by pretreatment with either the selective D1 DA receptor antagonist, SCH 23390, or the D2 selective antagonist, haloperidol. In contrast, contralateral rotation produced by apomorphine or I-dihydroxyphenylalanine, which lead to the preferential activation of D1 and D2 receptors on the lesioned side, was effectively prevented only when both receptor subtypes were inhibited. The results of these experiments demonstrate that the interaction between D1 and D2 receptors in the lesioned side differs from that in the nonlesioned side. Whereas the simultaneous stimulation of both DA receptor subtypes in the normally innervated basal ganglia is required for the production of turning behavior, the stimulation of either subtype alone in the dopaminergic denervated side can produce rotation. However, the concurrent administration of the D1 agonist, SKF 38393, with the D2 agonist, LY 171555, produced a synergistic effect on contralateral rotation. These results suggest that there is preservation of at least some functional interaction between D1 and D2 receptors in the lesioned basal ganglia but that there may be in addition a mechanism by which the two receptor subtypes can function independently of each other. The unilaterally lesioned rat appears to be a very good model in which to study the interaction between D1 and D2 receptors under conditions of both normal innervation and of DA denervation.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Corpus Striatum/physiology , Receptors, Dopamine/physiology , Substantia Nigra/physiology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine , Animals , Basal Ganglia/physiology , Benzazepines/pharmacology , Denervation , Dextroamphetamine/pharmacology , Ergolines/pharmacology , Female , Flunarizine/analogs & derivatives , Flunarizine/pharmacology , Functional Laterality , Haloperidol/pharmacology , Levodopa/pharmacology , Neural Pathways/physiology , Parkinson Disease/drug therapy , Quinpirole , Rats , Rats, Inbred Strains , Receptors, Dopamine/drug effects , Receptors, Dopamine D1 , Receptors, Dopamine D2 , Rotation
14.
Clin Neuropharmacol ; 11(3): 212-20, 1988 Jun.
Article in English | MEDLINE | ID: mdl-3401857

ABSTRACT

In eight dogs, a 20 cm section of isolated jejunum with intact blood supply was externalized to the abdominal wall and used as a device for levodopa (LD) administration. Overall, Sinemet tablets and LD suspension produced similar plasma levodopa concentrations with oral and pouch administration. The most ideal plasma concentration curves were obtained for CR-3, a sustained release Sinemet preparation, given through the jejunal pouches. Plasma LD concentrations rose within the first hour after administration of CR-3 and remained constant for the next 3 h, before falling slowly. Isolated jejunal pouches may therefore be an effective, simple means of maintaining constant plasma LD concentrations in parkinsonian patients with motor fluctuations and may diminish the deleterious effects of erratic gastric emptying and competition with food-derived amino acids at the gut/blood transport system.


Subject(s)
Jejunum/physiology , Levodopa/administration & dosage , Parkinson Disease/drug therapy , Animals , Dietary Proteins/metabolism , Dogs , Drug Implants , Levodopa/blood , Levodopa/therapeutic use , Tablets
16.
Eur J Pharmacol ; 131(2-3): 199-209, 1986 Nov 19.
Article in English | MEDLINE | ID: mdl-3493157

ABSTRACT

The regional uptake and subsequent dopaminergic toxicity, receptor proliferation, and rotational behavior pharmacology following intracerebral 1-methyl-4-phenylpyridine (MPP+) administration was determined in the rat. [3H]MPP+ was transported by the high-affinity dopamine uptake system equally in the caudate-putamen (CP), nucleus accumbens (NA) and olfactory tubercle (OT), and to a lesser extent in the substantia nigra. Consistent with the equivalent uptake of [3H]MPP+ by mesostriatal and mesolimbic dopamine neurons, dopamine concentrations of the ipsilateral CP and NA were decreased equally (83-98%) following a 10, 17.5 or 25 microgram injection of MPP+ along the left medial forebrain bundle (MFB). At four weeks after a 25 microgram injection of MPP+ into the MFB, the concentration (Bmax) of D2 receptors in the left CP was increased by 42% compared with the intact hemisphere. D2 receptors did not proliferate in the denervated nucleus accumbens. The affinity (Kd) of D2 receptors was not affected in either the CP or NA. The MPP+ injection, which was restricted to the region of striatonigral efferent fibers, also produced a 60% decrease in the GABA content of the substantia nigra. Ipsiversive rotational behavior was induced in MPP+-treated rats by systemic injections of d-amphetamine. Systemic injections of neither the dopamine agonist apomorphine nor agonist prodrug formulation of 1-DOPA and carbidopa induced contraversive rotation. These behavioral and neurochemical results are identical to those observed following concomitant destruction of striatonigral GABA and mesostriatal dopamine projections, and indicate that MPP+ may be toxic to GABAergic as well as to A10 and A9 dopaminergic neurons.


Subject(s)
Dopamine/physiology , Neurons/metabolism , Pyridinium Compounds/toxicity , Receptors, Dopamine/drug effects , Stereotyped Behavior/drug effects , 1-Methyl-4-phenylpyridinium , Animals , Autoradiography , Basal Ganglia/metabolism , Brain , Dopamine/metabolism , Injections , Male , Neurons/drug effects , Pyridinium Compounds/administration & dosage , Pyridinium Compounds/metabolism , Rats , Rats, Inbred Strains , Spiperone , gamma-Aminobutyric Acid/metabolism
17.
J Neurochem ; 45(4): 1049-54, 1985 Oct.
Article in English | MEDLINE | ID: mdl-3928814

ABSTRACT

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a chemical that, after injection into experimental animals, including mice and monkeys, causes a degeneration of the nigrostriatal pathway. We carried out experiments designed to study the in vitro oxidation of MPTP by mouse brain mitochondrial preparations. MPTP was actively oxidized by the mitochondrial preparations, with Km and Vmax values very similar to those of benzylamine, a typical substrate for MAO-B. MPTP was oxidized considerably better than many of its analogs, even those with relatively minor structural changes. Several monoamine oxidase inhibitors (MAOI) were potent inhibitors of MPTP oxidation, and there was a highly significant correlation between the capacity of the MAOI tested to inhibit MPTP oxidation and benzylamine oxidation. There was no correlation between the capacity of the MAOI to inhibit MPTP oxidation and their capacity to inhibit the oxidation of tryptamine, a substrate for MAO-A. In other experiments, MPTP was an excellent substrate for pure MAO-B, prepared from bovine liver. All of these data, combined with the fact that MAO-B inhibitors can protect against MPTP-induced dopaminergic neurotoxicity in vivo, point to an important role for MAO-B in MPTP metabolism in vivo.


Subject(s)
Monoamine Oxidase/metabolism , Pyridines/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Allylamine/analogs & derivatives , Allylamine/pharmacology , Animals , Benzylamines/metabolism , Brain/ultrastructure , Clorgyline/pharmacology , Indans/pharmacology , Kinetics , Mice , Mice, Inbred C57BL , Mitochondria/enzymology , Oxidation-Reduction , Selegiline/pharmacology , Tryptamines/metabolism
18.
Neurosci Lett ; 58(1): 133-7, 1985 Jul 04.
Article in English | MEDLINE | ID: mdl-3876523

ABSTRACT

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a recently discovered neurotoxin, caused extensive losses of dopamine and its major metabolites after its administration to male Swiss-Webster mice. In contrast, under identical conditions, several MPTP analogues, even those with relatively minor structural changes, were without toxicity. These include compounds with a 1-ethyl and 1-propyl substituent rather than the 1-methyl, the compound lacking the double bond in the tetrahydropyridine ring, as well as the compound with no phenyl substituent. It follows that each part of the MPTP molecule is important in determining its neurotoxic activity.


Subject(s)
Corpus Striatum/physiology , Dopamine/metabolism , Pyridines/pharmacology , Substantia Nigra/physiology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Corpus Striatum/metabolism , Male , Mice , Mice, Inbred Strains , Neural Pathways/drug effects , Neural Pathways/metabolism , Substantia Nigra/metabolism
19.
Res Commun Chem Pathol Pharmacol ; 47(3): 333-43, 1985 Mar.
Article in English | MEDLINE | ID: mdl-3922020

ABSTRACT

The rates of decomposition of 3H-dopamine (3H-DA), 3H-apomorphine and 3H-ADTN were determined in Tris buffer at pH 7.4 and in a Tris buffer containing a neostriatal membrane preparation representative of that used in binding experiments. In both the Tris buffer alone and in the neostriatal membrane preparation, 3H-DA was the most stable, 3H-ADTN was intermediate and 3H-apomorphine was the least stable. In the Tris buffer, the extent of decomposition of all three 3H-catechols was greatly retarded by sodium ascorbate. In contrast, in the neostriatal membrane preparation pronounced inhibitory effects of ascorbate were obtained only with 3H-ADTN. Even in the presence of high concentrations of sodium ascorbate (i.e., 0.5 mM), there was an extensive decomposition of 3H-apomorphine in the neostriatal membrane preparation. The data suggest that one exercise great caution in choosing appropriate conditions for binding experiments with these unstable ligands.


Subject(s)
Apomorphine , Ascorbic Acid , Dopamine , Edetic Acid , Naphthalenes , Tetrahydronaphthalenes , Animals , Apomorphine/metabolism , Ascorbic Acid/pharmacology , Brain/metabolism , Buffers , Dopamine/metabolism , Drug Stability , Edetic Acid/pharmacology , Male , Membranes/metabolism , Naphthalenes/metabolism , Rats , Temperature , Tetrahydronaphthalenes/metabolism , Time Factors
20.
J Neurochem ; 44(1): 310-3, 1985 Jan.
Article in English | MEDLINE | ID: mdl-3871120

ABSTRACT

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is known to cause a destruction of the dopaminergic nigrostriatal pathway in certain animal species including mice. MPTP and some structurally related analogs were tested in vitro for their capacity to inhibit the uptake of [3H]3,4-dihydroxyphenylethylamine-([3H]DA), [3H]5-hydroxytryptamine ([3H]5-HT), and [3H]gamma-aminobutyric acid [( 3H]GABA) in mouse neostriatal synaptosomal preparations. MPTP was a very potent inhibitor of [3H]5-HT uptake (IC50 value 0.14 microM), a moderate inhibitor of [3H]DA uptake (IC50 value 2.6 microM), and a very weak inhibitor of [3H]GABA uptake (no significant inhibition observed at 10 microM MPTP). In other experiments, MPTP caused some release of previously accumulated [3H]DA and [3H]5-HT, but in each case MPTP was considerably better as an uptake inhibitor than as a releasing agent. The 4-electron oxidation product of MPTP, i.e., 1-methyl-4-phenyl-pyridinium iodide (MPP+), was a very potent inhibitor of [3H]DA uptake (IC50 value 0.45 microM) and of [3H]5-HT uptake (IC50 value 0.78 microM) but MPP+ was a very weak inhibitor of [3H]GABA uptake. These data may have relevance to the neurotoxic actions of MPTP.


Subject(s)
Corpus Striatum/metabolism , Dopamine/metabolism , Pyridines/pharmacology , Serotonin/metabolism , Synaptosomes/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Corpus Striatum/drug effects , Dose-Response Relationship, Drug , Male , Mice , Synaptosomes/drug effects , gamma-Aminobutyric Acid/metabolism
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