Effects of Catechol-O-methyltransferase Inhibition on the Rates of Uptake and Reversibility of 6-Fluoro-l-Dopa Trapping in MPTP-induced Parkinsonism in Monkeys

doi:10.1016/S0028-3908(97)00017-8

Neuropharmacology

Volume 36, Issue 3, March 1997, Pages 363-371

https://doi.org/10.1016/S0028-3908(97)00017-8 Get rights and content

Abstract

The uptake rate constant and the loss rate constant that expresses the reversibility of the uptake process of 6-[¹⁸F]fluoro-l-Dopa (FDOPA) were measured by positron emission tomography in the striatum of normal rhesus monkeys and in monkeys with unilateral lesions of the dopaminergic nigro-striatal pathway, induced by intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Each animal was studied twice: with and without pretreatment of the catechol-O-methyltransferase (COMT) inhibitor Ro 40-7592, tolcapone. After pretreatment with tolcapone, there was a very significant increase in plasma FDOPA throughout the course of the study, accompanied by a significant decrease in its main metabolite, 3-O-methylfluorodopa. Tolcapone did not induce a significant change in the uptake rate constant in either the normal or the MPTP-treated striatum. However, after tolcapone pretreatment, there was a significant decrease in the loss rate constant in the MPTP-treated striatum (25%) and a smaller, non-significant decrease in the normal striatum (13%). It is concluded that the COMT inhibitor tolcapone exhibits clear peripheral and central activity. As compared to peripheral COMT inhibitors, this central effect may help preserve and stabilize the synaptic levels of DA and, thus, further improve the effects of l-DOPA therapy in parkinsonian patients. © 1997 Elsevier Science Ltd. All rights reserved.

Section snippets

MATERIALS AND METHODS

Twelve rhesus monkeys (Macaca mulatta) were used in this study. Six animals were normal controls. The other six animals had received unilateral intracarotid injections of MPTP 6–7 years prior to the study. The MPTP infusion protocol, including dose and schedule, and early FDOPA PET data from some of these animals were reported elsewhere (Doudet et al., 1993). Motor function of the side of the body contralateral to MPTP administration ranged from normal in four animals to moderately

RESULTS

No significant differences were observed in the plasma metabolite time courses between the normal and MPTP-treated groups, either with or without COMT inhibition and, thus, the data from the two groups were combined for the demonstration of the effects of COMT inhibition (Fig. 1). There was a very significant increase (p < 0.01) in the fraction of plasma FDOPA in the RO condition compared to the CL condition, accompanied by a significant decrease in the fraction of 3-OMFDOPA and a small

DISCUSSION

In this study, we investigated the peripheral and central effects of an acute administration of tolcapone, on the metabolism of FDOPA, a PET tracer specific to the DA presynaptic system. Tolcapone is now being tested in clinical trials as an adjuvant to Parkinson's disease therapy based on its ability to inhibit both peripheral and central O-methylation of l-DOPA and central O-methylation of DA.

Because of the potential risks associated with high doses of tolcapone (30 mg/kg) administration to

Acknowledgements

This work was supported by the Medical Research Council of Canada. We thank Merck, Sharp and Dohme, Canada for their gift of the carbidopa and Hoffman LaRoche, Basel, Switzerland for their gift of tolcapone. The authors thank the staff of the UBC/TRIUMF PET program for their assistance and contribution to this work, especially Dr M. J. Adam and Ms Salma Jivan for tracer synthesis, Ms Teresa Dobko and Ms Carolyn English for data acquisition and processing. Special thanks are due to Dr J. Love

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The cynomolgus monkey is a species that is physiologically and pathologically similar to humans and has been used to characterize the pharmacological properties of COMT inhibitors (Bonifácio et al., 2014). In addition, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated monkeys have been used to develop COMT inhibitors as this animal model reproduces symptoms that resemble PD and can be used to evaluate the therapeutic effects of l-DOPA (Filion et al., 1991; Doudet et al., 1997). Repeated oral treatment of 100 mg/kg opicapone reduced soluble COMT (S-COMT) activity in erythrocytes and increased the l-DOPA level systemically and in the dorsal striatum, substantia nigra and prefrontal cortex in cynomolgus monkeys (Bonifácio et al., 2014).
The aim of the study was to clarify the dose response for inhibition of catechol-O-methyltransferase (COMT) by opicapone, a third generation COMT inhibitor, after acute and repeated administration to the cynomolgus monkey with pharmacokinetic evaluation at the higher dose.
Three cynomolgus monkeys were used in the study. In the first experiment, COMT inhibition was evaluated over 24 h after the first and at 24 h after the last of 14 daily oral administrations of vehicle, 1, 10 and 100 mg/kg opicapone using a crossover design. In the second experiment, the effect of the maximally effective dose, 100 mg/kg, was retested under the same conditions with additional monitoring of plasma opicapone levels to explore the relationship between pharmacokinetics and pharmacodynamics.
Opicapone dose-dependently inhibited COMT activity, significantly so at 10 and 100 mg/kg. Maximal inhibition was 13.1%, 76.4% and 93.2% at 1, 10 and 100 mg/kg respectively, and COMT remained significantly inhibited at 24 h after 10 and 100 mg/kg (42.6% and 60.2% respectively). Following repeated administration of opicapone residual COMT inhibition at 24 h was 15–25% greater at all doses. In contrast to its pharmacodynamic effect, opicapone was rapidly absorbed and eliminated, with no accumulation in plasma following repeated administration.
Opicapone showed sustained and dose-dependent COMT inhibition despite being rapidly eliminated from plasma and with no evidence for accumulation in plasma after 14 days administration. Opicapone fills the unmet need for a compound with sustained COMT inhibition which will improve levodopa bioavailability in patients with Parkinson's disease.
Animal Models of Parkinson's Disease to Aid Drug Discovery and Development
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Parkinson's Disease (PD) is the second most common, age-related progressive neurodegenerative disorder. Two events have impacted significantly the discovery and development approaches for novel therapeutics for PD: (a) the discovery of disease-causing mutations in multiple genes and (b) an emerging appreciation that the pathophysiology and associated symptoms of PD are more widespread than those resulting from the progressive loss of the nigrostriatal dopamine projections. Specifically, there has been an emergence of new animal models based on genetic etiology of familial PD and hence a renewed focus on using the new animal models to develop therapeutic strategies aimed at slowing the progression of the disease as well as treating non-motor symptoms of PD. This chapter provides an overview of the current state of the PD research with a special emphasis on animal models that can help therapeutic discovery and development. It focuses on the animal models of disease pathophysiology and resultant symptoms. It presents a summary on the clinical syndrome and current therapies of PD to set the context for the discussion to follow on commonly used animal models, their phenotypes and how they correlate/reproduce disease pathophysiology or specific symptoms of PD. It also addresses the specific utility of animal models in drug discovery and development, paying attention to current challenges or gaps that hinder discovery and development of drugs addressing the unmet medical needs of PD patients. Additionally, the chapter offers some suggestions on the utility of classical animal models as well as emerging models to address these gaps and facilitate development of therapeutic interventions.
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Dopamine (DA) neurons degenerate in Parkinson's disease and dopamine neurotransmission may be affected in psychotic states seen in schizophrenia. Understanding the regulation of enzymes involved in DA metabolism may therefore lead to new treatment strategies for these severe conditions. We investigated mRNA expression of the cytosolic aldehyde dehydrogenase (ALDH1), presumably involved in DA degradation, by in situ hybridization in DA neurons of human postmortem material. Parallel labeling for GAPDH, neuron-specific enolase, tyrosine hydroxylase, dopamine transporter, and dopamine β-hydroxylase was used to ensure suitability of tissue specimen and to identify all dopamine neurons. ALDH1 was found to be expressed highly and specifically in DA cells of both substantia nigra (SN) and the ventral tegmental area (VTA) of controls. A marked reduction of ALDH1 expression was seen in surviving neurons of SN pars compacta but not of those in the VTA in Parkinson's disease. In patients suffering from schizophrenia we found ALDH1 expression at normal levels in DA cells of SN but at significantly reduced levels in those of the VTA. We conclude that ALDH1 is strongly and specifically expressed in human mesencephalic dopamine neurons and that low levels of ALDH1 expression correlate with DA neuron dysfunction in the two investigated human conditions.
Effects of peripheral and central catechol-O-methyltransferase inhibition on striatal extracellular levels of dopamine: A microdialysis study in freely moving rats
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Tolcapone is a mixed (peripheral and central) catechol-O-methyltransferase (COMT) inhibitor, whereas entacapone is a preferential peripheral COMT inhibitor. Both drugs are able to decrease the peripheral conversion of l-DOPA into 3-O-methyl-DOPA and thereby increase plasma and cerebral levels of l-DOPA, the precursor of dopamine (DA). Tolcapone may also impair the extraneuronal catabolism of DA by inhibiting COMT activity in the brain. To evaluate the role played by peripheral and central COMT inhibition, we compared the effects of tolcapone and entacapone on COMT activity in peripheral tissues, and on striatal extracellular levels of l-DOPA and DA in rats. Tolcapone and entacapone, at the dose of 15 mg/kg p.o., were almost equally effective in inhibiting COMT activity in duodenum and liver. Tolcapone decreased striatal extracellular levels of homovanillic acid (HVA), thus confirming its central COMT inhibitory effect, whereas entacapone did not alter HVA efflux. Following l-DOPA/benserazide administration (50/15 mg/kg p.o.), both COMT inhibitors significantly increased striatal levels of l-DOPA and DA compared with saline. The levels of l-DOPA were similar after treatment with either COMT inhibitors, whereas the increase in DA output was significantly greater in rats given tolcapone compared to those given entacapone. We conclude that the blockade of central DA catabolism by tolcapone contributes to the greater increase in striatal DA levels achieved with this drug.
New, selective catechol-O-methyltransferase inhibitors as therapeutic agents in Parkinson's disease
1999, Pharmacology and Therapeutics
Levodopa remains the most effective drug for Parkinson’s disease (PD). However, its benefits are limited owing to extensive metabolism by catechol-O-methyltransferase (COMT), especially if levodopa is used in combination with peripheral dopa-decarboxylase inhibitors. A new generation of potent, orally active, selective, and reversible COMT inhibitors has become available recently. Among these, tolcapone and entacapone have been best characterised. Preclinical and clinical studies have shown that COMT inhibitors markedly enhance levodopa availability and prolong its plasma half-life. In recent large clinical trials they proved to be able to ameliorate motor fluctuations, reduce disability, and decrease levodopa requirements in PD patients. The tolerability profiles of entacapone and tolcapone are good. COMT inhibition promises to become an important means of extending the benefits of levodopa therapy in PD.
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Effects of Catechol-O-methyltransferase Inhibition on the Rates of Uptake and Reversibility of 6-Fluoro-l-Dopa Trapping in MPTP-induced Parkinsonism in Monkeys

Abstract

Section snippets

MATERIALS AND METHODS

RESULTS

DISCUSSION

Acknowledgements

Life Sci.

Appl. Radiat. Isot.

Appl. Radiat. Isot.

Eur. J. Pharmacol.

Brain Res.

The relationship between locomotor disability, autonomic dysfunction and the integrity of the striatal dopaminergic system in patients with multiple system atrophy, pure autonomic failure and Parkinson's disease, studied with PET

Brain

Effects of selective monoamine oxidase inhibitors on the in vivo release and metabolism of dopamine in the rat striatum

J. Neurochem.

OR-462 inhibits 3-O-methyldopa formation in monkeys (Abstract)

Neurology

Improved therapy of Parkinson's disease with tolcapone, a central and peripheral COMT inhibitor with an S-Adenosyl-l-Methionine-sparing effect

Clin. Neuropharmacology

Effects of inhibition of catechol-O-methyltransferase (COMT) on the rates of uptake (Ki) and reversibility (kloss) of 6-fluoro-l-dopa (FDOPA) in the MPTP-primate model of Parkinson's disease (Abstract)

Can. J. Neurol. Sci.

6-[18F]Fluoro-l-DOPA and cerebral blood flow in unilaterally MPTP-treated monkeys

J. Neur. Transplant. Plast.

Influence of selective inhibition of monoamine oxidase A or B on striatal metabolism of l-DOPA in hemiparkinsonian rats

J. Neurochem.

Side effects of the catechol-O-methyltransferase inhibitor Ro 40-7592 in rabbits

Clin. Neuropharmacol.

6-[¹⁸F]Fluoro-l-DOPA and cerebral blood flow in unilaterally MPTP-treated monkeys