ReviewLeads for the development of neuroprotective treatment in Parkinson's disease and brain imaging methods for estimating treatment efficacy
Introduction
Idiopathic Parkinson's disease is a progressive neurodegenerative disorder which manifests itself by bradykinesia in combination with rigidity, tremor and a postural imbalance. In addition, autonomic nervous system dysfunctions such as micturition problems, orthostatic hypotension and seborrhea as well as subtle cognitive dysfunctions and depression occur. Parkinson's disease affects approximately 0.15% of the total population but 0.5% of people older than 50 years. The disease is neuropathologically characterized primarily by degeneration of dopamine-containing neurons in the ventral mesencephalon.
Dopaminergic neurons in the ventral mesencephalon are distributed over different cell groups, including the substantia nigra pars compacta (A9 cell group), the ventral tegmental area (A10 cell group) and the retrorubral area (A8 cell group). Recent neuroanatomical and functional studies have revealed that the dopaminergic projection is just one of the neuronal elements integrated in the basal ganglia-thalamocortical circuits which are involved in the regulation of motor and complex behavioral activity (Alexander et al., 1990; Groenewegen et al., 1990, Groenewegen et al., 1993).
The following brief description of the functional neuroanatomy of these basal ganglia-thalamocortical circuits is useful in understanding the symptomatology of Parkinson's disease and the pharmacotherapy that is currently used.
The basal ganglia consist of four main structures: the striatum (caudate nucleus, putamen and nucleus accumbens), the pallidum (external and internal segments of the globus pallidus and ventral pallidum), the subthalamic nucleus and the substantia nigra (pars compacta and pars reticulata). The striatum is the input structure of the basal ganglia, receiving afferents, in a strict topographical way, from the entire cerebral cortex (including `cortical-like' nuclei of the amygdala and the hippocampal formation), the midline and intralaminar thalamic nuclei, and midbrain serotonergic and dopaminergic cell groups. The output structure of the basal ganglia consists of the internal segment of the globus pallidus and the pars reticulata of the substantia nigra which project, also in a topographical manner, to different medial and ventral thalamic nuclei, the deep layers of the superior colliculus and the reticular formation of the mesencephalon. The various thalamic nuclei that are innervated by these output structures of the basal ganglia project to different cortical areas of the frontal lobe, including motor, premotor and prefrontal cortical areas.
The topography in the projections from different frontal cortical areas through the basal ganglia and the thalamus by subsequent corticostriatal, striatopallidal (or striatonigral), pallidothalamic (or nigrothalamic), and thalamocortical projections is organised in such a way that a number of parallel, functionally segregated basal ganglia-thalamocortical circuits can be discriminated. Whereas sensorimotor functions are dealt with in the circuit that originates in and returns to the (pre)motor cortex (and that at the striatal level, receives also inputs from the somatosensory cortex), other circuits are involved in complex motor/behavioral, cognitive and affective processes (Alexander et al., 1990; Bhatia and Marsden, 1994; Marsden and Obeso, 1994).
The input (striatum) and output structures (internal segment of the globus pallidus and pars reticulata of the substantia nigra) of the basal ganglia are connected with each other by means of two pathways, i.e., a `direct' and an `indirect' pathway. The direct pathway consists of the γ-aminobutyric acid (GABA)/substance P/dynorphin-containing striatopallidal (internal segment of the globus pallidus) and striatonigral (pars reticulata of the substantia nigra) projections. The indirect pathway is constituted by the sequence of the GABA/enkephalin-containing striatopallidal (external segment of the globus pallidus), the GABA-ergic pallido-subthalamic, and the glutamatergic subthalamo-pallidal (internal segment of the globus pallidus) and subthalamo-nigral (pars compacta of the substantia nigra) projections. At the level of the output structures of the basal ganglia, these direct and indirect pathways have opposite effects on the GABA-ergic neurons that project to the thalamic nuclei, the superior colliculus and the reticular formation. A `balance' between these two striatal output pathways appears to be essential for the normal regulation of movement. Although recent data show a more complex picture of the distribution of dopamine receptors, it has previously been suggested that dopamine, acting through different dopamine receptors, has opposing effects on the direct and indirect pathways (Stoof and Kebabian, 1981; Alexander and Crutcher, 1990; Gerfen, 1992): via dopamine D1 receptors a stimulatory effect on the direct pathway, whereas via dopamine D2 receptors an inhibitory effect on the indirect pathway. The consequence of the loss of dopaminergic input to the striatum as occurs in Parkinson's disease is therefore thought to be an increase in the output from the internal segment of the globus pallidus and the pars reticulata of the substantia nigra to the thalamus (DeLong, 1990), ultimately (supposedly at about 75% depletion of striatal dopamine) resulting in a reduction of cortical activation which accounts for (most of) the Parkinsonian signs, including bradykinesia, rigidity, tremor and postural imbalance.
`Restoring the balance' at the level of the output structures of the basal ganglia in order to decrease the inhibition of the thalamic nuclei can be achieved neurosurgically, by lesioning the subthalamic nucleus, a posteroventral pallidotomy and/or venterolateral thalamotomy (Marsden and Obeso, 1994). However, this therapeutic intervention is only rarely applied. In general, Parkinson's disease patients are treated pharmacologically, by suppletion and/or substitution of dopamine with the dopamine precursor l-DOPA or with dopamine receptor agonists (Wolters, 1992). In the late sixties, shortly after it became apparent that patients with Parkinson's disease were suffering from a dopamine deficit in the basal ganglia, the dopamine precursor l-DOPA (soon afterwards in combination with a peripheral decarboxylase inhibitor) was successfully given to supplete the empty dopamine stores. Currently, this treatment is still considered to be the most effective way to control the symptoms of Parkinson's disease. Unfortunately, however, long-term treatment with l-DOPA frequently results in fading of the therapeutic effect (wearing-off), in the development of serious motor side-effects such as on–off motor oscillations and dyskinesias and, although less often, in psychiatric complications. Under those conditions, increasing the dose of l-DOPA to compensate for the loss of therapeutic efficacy gives rise only to more side-effects without adding any beneficial effect. The mechanisms underlying this `narrowing of the therapeutic window' are still largely a matter of speculation. Lately, the hypothesis has been put forward that long-term treatment with l-DOPA might accelerate the degeneration of dopaminergic neurons by enhanced generation of cytotoxic reactive oxygen species as a consequence of dopamine and/or l-DOPA auto-oxidation (see also below).
From the 1980's onwards, the introduction of dopamine D2 receptor agonists has extended the therapeutic armamentarium for Parkinson's disease. Although various compounds, such as lisuride, bromocriptine, 4-propyl-9-hydroxynaphtoxazine (PHNO) and pergolide have been clinically tested, it seems that bromocriptine and pergolide are now the most frequently prescribed dopaminomimetics. Both drugs have a high affinity as an agonist for the dopamine D2 receptor. Moreover, it has been claimed that pergolide in higher concentrations displays agonistic activity at the dopamine D1 receptor. However, given the plasma levels during therapy, it is very doubtful if this phenomenon plays any substantial role in the therapeutic effects of the compound. Although long-term treatment with dopamine D2 receptor agonists results in less dyskinesias, the therapeutic efficacy is likewise less dramatic as compared to the initial effects of l-DOPA. Furthermore, increasing the dose of dopaminergic agonists gives rise to other serious side-effects, such as psychotic reactions. Based on the above-described insights into the clinical action of the drugs, a now generally accepted therapeutic protocol consists of the combination of a low dose of l-DOPA together with one of the dopamine D2 receptor agonists. This treatment regime in general results in optimal control of the symptoms with fewer side-effects, at least in the early stages of the disease. Nevertheless, in the medium to long-run also this therapeutic strategy is doomed to failure.
Apart from dopamine D2 receptors, also dopamine D1 receptors are targets for the action of dopamine in the striatum. Especially, the (medium spiny) output neurons projecting to the internal segment of the globus pallidus, forming the so-called `direct route', are known to express significant numbers of dopamine D1 receptors, whereas the cells of the `indirect route' are supposed to contain predominantly dopamine D2 receptors (Gerfen and Young, 1988; Gerfen, 1992). Dopamine, by simultaneously facilitating the activity of the `direct' pathway (via stimulation of dopamine D1 receptors) and inhibiting the activity of the `indirect' pathway (via stimulation of dopamine D2 receptors), keeps these pathways in a delicate balance which, as noted above, is thought to be essential for the normal regulation of movement. Moreover, this concept provides also a rationale for the observed requirement of both dopamine D1 and dopamine D2 receptor stimulation to restore the complete repertoire of motor activity in animal models for Parkinson's disease (Waddington and O'Boyle, 1989). The fact that dopamine D2 receptor agonists mediate therapeutic effects on their own, especially in the early phases of Parkinson's disease, could mean that in that stage residual dopamine released from surviving dopaminergic neurons is still sufficient to stimulate the `direct' pathway (Strange, 1993). Thus, one would expect selective dopamine D1 receptor agonists to be of additional therapeutic value later on in the course of Parkinson's disease. However, in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-lesioned monkey model of Parkinson's disease, the partial dopamine D1 receptor agonist SKF 38393, which was developed in the late seventies, failed to stimulate motor behavior (Barone et al., 1987; Bedard and Boucher, 1989). Recently, it was demonstrated that at least in primates, this compound's lack of therapeutic effect is most likely due to its very low intrinsic activity at the dopamine D1 receptor (Pifl et al., 1992; Vermeulen et al., 1994). Subsequently, full dopamine D1 receptor agonists became available and animal studies have now definitely proven that stimulation of dopamine D1 receptors affects motor behavior, especially in those animals in which the nigrostriatal dopaminergic system has been lesioned (Taylor et al., 1991; Kebabian et al., 1992; Vermeulen et al., 1993). However, careful analysis of this behavioral stimulation casts doubt on the anti-Parkinsonian nature of the effects of dopamine D1 receptor agonists. For example, the claim that dopamine D1 receptor stimulation activates motor behavior without inducing dyskinesias cannot be generally confirmed (Blanchet et al., 1996; Andringa et al., 1998). In fact, long-term stimulation seems to induce significant dyskinesias. Another drawback of long-term treatment with dopamine D1 receptor agonists appears to be the poorly sustained action of these drugs because of receptor desensitisation (Blanchet et al., 1996), and last but not least, the occurrence of seizures (Starr and Starr, 1993; Shiosaki et al., 1996; Andringa et al., 1999a, Andringa et al., 1999b). Thus, contrary to expectation, dopamine D1 receptor stimulation, even with selective high efficacy agonists, in our opinion, will not substantially improve the pharmacotherapy of Parkinson's disease.
One of the mechanisms likely to underly the occurrence of wearing-off and the development of serious side-effects upon long-term treatment with dopaminergic compounds in Parkinson's disease is the progression of the pathologic process. Thus, the ongoing degeneration of dopaminergic neurons might not only prohibit efficient decarboxylation of the administered l-DOPA but could also be responsible for changes in (postsynaptic) dopamine receptor sensitivity, resulting in the aforementioned problems. Therefore, as of late, much effort has been invested in the development of neuroprotective agents that will be able slow down the degenerative process. In order to design an optimal causal treatment regime for Parkinson's disease, two lines of investigation are of crucial importance. First, in-depth knowledge about the whole cascade of events that leads to the degeneration of the dopaminergic cells, i.e., the etiopathogenesis of Parkinson's disease, is required (Section 2), since such knowledge is indispensable for the rational development of neuroprotective agents. Secondly, in order to assess the effectiveness of such compounds in longitudinal studies, a brain imaging technique that visualizes the striatal dopaminergic innervation and is able to estimate the rate of degeneration of the dopaminergic system in the course of Parkinson's disease (Section 3) should be available.
Section snippets
Oxidative stress hypothesis
As noted already, at the cellular level Parkinson's disease is characterized foremost by a loss of the neurotransmitter dopamine in the striatum due to degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra (Gibb and Lees, 1991). In addition, also other neuronal systems, in particular noradrenergic neurons originating in the locus coeruleus, are affected by the disease process albeit to a substantially smaller extent (Jellinger, 1991). Despite large scale
SPECT studies with []β-CIT, []FP-CIT and other dopamine transporter ligands
Possibilities to determine the integrity of the dopaminergic system in vivo emerged by the recent finding that cocaine analogues are very selective and efficient ligands for the so-called dopamine transporters, which are expressed in the striatal dopaminergic projections (Kaufman and Madras, 1991). Thus, it was proposed that labeling of the dopamine transporter in vivo with ligands that can be visualized by brain imaging techniques could provide a valuable tool to investigate the extent of
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