CNS & Neurological Disorders - Drug Targets, 2012, 11, 251-263
251
Role of Catechol-O-Methyltransferase (COMT)-Dependent Processes in Parkinson’s Disease and L-DOPA Treatment Stefano Espinoza, Francesca Managò, Damiana Leo, Tatyana D. Sotnikova and Raul R. Gainetdinov* Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Morego 30, Genova, Italy Abstract: One of the most important enzymes in the catecholamine cycle, catecholamine-O-methyltransferase (COMT), plays a critical role in the extracellular metabolism of dopamine and norepinephrine both in the periphery and the central nervous system. COMT has attracted strong interest in regards to its role in dopamine-related pathologies, particularly Parkinson’s disease. There are several mechanisms for the potential involvement of COMT-related processes in the pathophysiology of Parkinson’s disease or the consequences of L-DOPA treatment. COMT-mediated metabolism of LDOPA in the periphery influences brain dopamine levels, while the product of central COMT-mediated dopamine metabolism, 3-methoxytyramine, can affect movement via interaction with Trace Amine-Associated Receptor 1 (TAAR1). COMT inhibitors have a long history of clinical use in the treatment of Parkinson’s disease. Several clinical genetic studies have shown that variants of COMT gene contribute to the manifestations or treatment responses of this disorder. Here, we review the basic molecular mechanisms that could be involved in COMT-dependent processes in Parkinson’s disease, the pharmacological properties of COMT inhibitors used in the treatment of this disorder and the clinical genetic observations involving COMT gene variants as modulators of pathological processes and responses to dopamine replacement therapies used in the treatment of the disorder.
Keywords: Dyskinesia, 3-methoxytyramine, trace amines, TAAR1, tolcapone, entacapone, nebicapone INTRODUCTION Parkinson’s disease (PD) is a devastating neurodegenerative disorder of unknown etiology that develops primarily in aged populations. It has been estimated that the average age of onset of this disorder is approximately 55 years, and its incidence increases 6-fold after 70 years of age. In the vast majority of cases, the disease is not caused by genetic factors (sporadic PD), although in a small percentage of cases the illness is hereditary (familial PD) [1]. This pathology is characterized by the progressive loss of dopamine-containing neurons of the Substantia Nigra pars compacta (SNc), which project axons primarily to the Caudate/Putamen (CPu), and by the presence of intraneuronal proteinaceous inclusions defined as Lewy bodies [2]. The onset of the clinical symptoms occurs as a consequence of a loss of approximately 70-80% of the dopamine levels in the CPu and the degeneration of approximately 60-70% of the SNc neurons [3]. So far, very little is known about why and how the neurodegenerative processes causing PD begin and develop; however, it has been hypothesized that, in most cases, PD could have a multifactorial etiology, including the interaction of external or environmental factors with a genetic predisposition to the illness in certain individuals [4, 5]. Variations in several genes of interest have been identified as potential contributors to the pathology; however, these variants are generally found in a very limited number of patients and, despite an enormous amount of research during the past decade, the molecular mechanisms of their involvement in PD largely remain a mystery.
*Address correspondence to this author at the Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Morego 30, Genova, Italy; Tel: +39 010 71781513; E-mail:
[email protected]
1 -/12 $58.00+.00
Although the mechanisms of PD development are not yet understood, the symptoms of this disorder have been well known for many years and have been fully characterized. PD is essentially a motor disorder, with symptoms consisting of akinesia (absence of movement), bradikinesia (slowness of movements), muscular rigidity, resting tremor and facial masking [6]. PD can also manifest as cognitive deficits, such as deficits in attention, memory and decision-making [7-12]. Pharmacologic treatment of PD was minimally effective and essentially non-existent until the 1960s, when the discovery of dopamine deficiency in PD led to the introduction of Ldihydroxyphenylalanine (L-DOPA) into clinical use as an effective approach to manage the core motor symptoms of the disorder [13-16]. L-DOPA, the immediate biosynthetic precursor of dopamine, has the ability to easily cross the blood-brain barrier, whereas dopamine does not. L-DOPA has had an impressive history of success in PD therapy for over 60 years because of its unprecedented pharmacological effectiveness that can improve motor disability even in the quite severe late stages of the illness [17, 18]. Nevertheless, L-DOPA does not cure the underlying pathology, and its effectiveness may decrease with time. In early-stage PD patients, relatively low L-DOPA doses are able to give a long-lasting beneficial effect in controlling motor symptoms. However, at later stages, higher L-DOPA doses are needed, and its therapeutic window narrows over time [19]. Furthermore, chronic L-DOPA therapy leads to motor complications, with nearly 50% of patients being affected by several years of treatment [20-22]. Wearing-off phenomena, changes in the ON-OFF time and dyskinesia are the most common motor complications of L-DOPA therapy in PD [23, 24]. At the end of the 1970s, the first direct dopamine agonist was developed for PD treatment, thus leading to a second generation of dopaminergic antiparkinsonian drugs © 2012 Bentham Science Publishers
252
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 3
Espinoza et al.
[25]. However, although dopaminergic agonists interact directly with dopamine receptors and do not depend on enzymatic conversion, none of them shows the same potency and efficacy of L-DOPA treatment [26]. Interestingly, longacting dopamine agonists, such as ropirinole, pramipexole and pergolide, do not cause pronounced dyskinesia and in fact may reduce their development [27].
toxic catechols, including catecholamines, catecholestrogens, ascorbic acid and many pharmaceutical compounds [32, 33]. The COMT gene encodes two different protein isoforms: a soluble form (S-COMT) and a membrane bound form (MBCOMT) [34, 35]. Both isoforms have been found in a variety of tissues: S-COMT is mainly expressed in the periphery and particularly abundant in the liver and kidney [36] and MBCOMT is present in liver, kidneys and in the brain, where it is the predominant isoform expressed [37]. In the brain, COMT is localized in the intracellular compartments in both neuronal and non-neuronal cells, mainly close to postsynaptic sites [38, 39]. However, under physiological conditions, the main route by which catecholamines are cleared from the synaptic cleft is the neuronal reuptake transporter. In fact, many studies have demonstrated that COMT inhibition does not alter the extracellular level of dopamine in areas of the brain highly expressing the dopamine transporter, such as the striatum [33]. The effect of COMT inhibition on extracellular dopamine levels in the striatum is evident only under conditions in which the function of the dopamine transporter is blocked [40, 41]. However, in the prefrontal cortex, a significant increase in the extracellular levels of dopamine was found following COMT inhibition [42]. In this area, the dopamine transporter is expressed at low levels; thus, other systems become predominantly involved in the elimination of dopamine from the synapse, namely the norepinephrine transporter and COMT. Accordingly, although no changes in the extracellular levels of dopamine have been found in the striatum or hypothalamus of COMT knockout (COMT-KO) mice, a 2- to 3-fold increase has been reported for male mice in the prefrontal cortex [43]. In a fast scan cyclic voltammetry study by Yavich et al. [44], it has been shown that a lack of COMT produces a slower removal of extracellular dopamine in the prefrontal cortex by approximately 2-fold, with no difference found in the striatum. Similarly, in vivo microdialysis experiments have demonstrated that extracellular dopamine levels are higher in the prefrontal cortex of COMT-KO animals and that the dopamine transporter has no role in the clearance of dopamine in this area because its inhibition does not induce any additional increase in the concentration of dopamine [45].
It has been hypothesized that the adverse events of chronic L-DOPA treatment might be due to the pulsatile, non-physiological dopaminergic stimulation caused by repeated L-DOPA treatment; however, other mechanisms could also be involved [28, 29]. It is possible that at early stages of the disease, there are enough dopaminergic terminals remaining that can buffer the pulsatile L-DOPA concentrations, but with the progressive degeneration, this property wanes and motor complications appear [19]. In fact, continuous infusion of L-DOPA results in a reduced probability of both OFF time and dyskinesia in comparison to standard L-DOPA formulations [30]. Therefore, strategies aimed at stabilizing L-DOPA plasma levels could be helpful in the management of these motor complications. The first approach to decrease peripheral L-DOPA degradation was the co-administration of aromatic L-amino acid decarboxylase (L-AADC) inhibitors, such as carbidopa or benserazide, thus leading to a reduction of peripheral dopaminergic side-effects and increased levels of L-DOPA reaching the brain. However, the majority of plasma LDOPA could still be metabolized by another ubiquitous enzyme, catechol-O-methyltransferase (COMT), to form 3O-methyldopa (3-OMD). In the brain, COMT can also metabolize extracellular dopamine to 3-methoxytyramine (3MT) and, consequently, to homovanillic acid (HVA) via monoamine oxidase (MAO)-mediated oxidation (Fig. 1). In fact, combined treatment of L-DOPA/carbidopa with a COMT inhibitor results in improved pharmacokinetics of LDOPA with an increased half-life in the plasma and availability in the brain. Thus, COMT inhibitors have a clinical application in PD as an effective adjunct therapy in the management of L-DOPA-related motor complications, and therefore COMT has become a valuable target for drug development. Similarly, selective MAO-B inhibitors have been used in PD pharmacotherapy presumably due to their ability to enhance the effects of dopamine by slowing its metabolism in the brain [31]. In this review, we focus on the role played by COMT and related processes in the pathophysiology and pharmacology of PD. In particular, we discuss the critical mechanisms affected by COMT that may influence the therapeutic or side effects of L-DOPA treatment, the recent progress in the development and clinical use of COMT inhibitors and the genetic studies highlighting the role of this enzyme in PD pathogenesis and treatment. BASIC MECHANISMS OF COMT INVOLVEMENT IN PARKINSON’S DISEASE AND L-DOPA TREATMENT
Alternatively, L-DOPA pharmacokinetics are strongly affected by alterations in COMT activity. Normally, LDOPA is decarboxylated by L-AADC to dopamine mainly in the periphery, and only a small portion reaches the brain. When L-AADC is inhibited, COMT becomes the main enzyme responsible for the peripheral degradation of LDOPA to 3-OMD, thereby indicating the potential of COMT as a target for therapeutic strategies aimed at increasing LDOPA half-life in the brain. In fact, based on this strategy of peripheral COMT inhibition, several COMT inhibitors were introduced into clinical practice to increase the brain availability of L-DOPA in PD (see other sections of this review).
COMT-Mediated Control of Brain Dopamine Dynamics COMT is a Mg++-dependent enzyme that catalyzes the transfer of a methyl group of S-adenosyl-L-methionine (SAM) to a hydroxyl group of a catechol substrate [32]. Its physiological role is to metabolize biologically active or
COMT-Dependent Metabolites as Novel Neuromodulators The role of COMT-related processes in the brain following L-DOPA treatment has received significantly less attention. In the brain, dopamine is metabolized
COMT and Parkinson’s Disease
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 3
Periphery
253
Brain
3-O-METHYLDOPA
DOPAC COMT MAO
COMT
L-AADC
L-DOPA L-AADC
L-DOPA
HVA
DOPAMINE COMT
MAO
3MT DOPAMINE
Fig. (1). Major neurochemical mechanisms of COMT involvement in L-DOPA and dopamine metabolism in the periphery and brain. For details, please see description in the text.
intraneuronally by MAO to yield 3, 4-dihydroxyphenylacetic acid (DOPAC) and extraneuronally by COMT to yield 3methoxytyramine (3-MT). A large portion of DOPAC is then metabolized to HVA by COMT, whereas 3-MT is metabolized to HVA by MAO (Fig. 1). Both DOPAC and HVA are then eliminated from the brain via specific transporters [46, 47]. Although 3-MT has generally been considered as an inactive metabolite and merely a reflection of dopamine release, growing evidence suggests that it has a specific physiological role. Over the years, several groups have noted that 3-MT infusion into the brain at high concentrations can induce certain behavioral manifestations such as tremor, stereotypies, hyperactivity and even hypoactivity [48-51]. In a recent study, unbiased screening for potential motor activity among endogenous monoaminergic compounds, such as trace amines and monoamine metabolites, under conditions of absolute dopamine deficiency in dopamine-deficient dopamine transporter knockout mice (DDD mice) revealed a role of 3MT as a novel neuromodulator that could affect striatal signaling mechanisms and induce behavioral alterations. It has been observed that 3-MT infused i.c.v. was able to induce a complex set of abnormal movements in a dopamine-independent manner in DDD mice [52]. In normal mice, a similar central administration of 3-MT caused temporary mild hyperactivity with a concomitant set of abnormal movements, including stereotypies, head bobbing, backward walking and prominent abnormal orofacial and whole body involuntary movements. Furthermore, 3-MT induced significant ERK and CREB phosphorylation in the mouse striatum, leading to signaling events generally related to PKA-mediated cAMP accumulation and indicating the involvement of G protein-coupled receptors (GPCRs). Intriguingly, recent biochemical investigations have
suggested that 3-MT could be a ligand for the newly discovered GPCR Trace Amine-Associated Receptor 1 (TAAR1), as it can stimulate cAMP and induce ERK and CREB signaling via this receptor in cellular assays [52-54]. Most importantly, in mice lacking TAAR1, both the behavioral and signaling effects of 3-MT were partially attenuated. Taken together, these observations indicate that 3-MT is not just an inactive metabolite of DA but a novel neuromodulator that, in certain situations, may be involved in movement control. It would be important to explore whether other COMT-dependent metabolites of catecholamines, such as 4-methoxytyramine, metanephrine and normetanephrine, which are also known to activate TAAR1 [54], could also play independent neuromodulatory roles in the brain. It should be noted, however, that the concentrations of 3-MT required to activate TAAR1 are in the high nanomolar range, which is substantially higher than that observed under normal physiological conditions (
