CommentaryNorepinephrine: The redheaded stepchild of Parkinson's disease
Introduction
Parkinson's disease (PD) is one of the most common diseases among the aging and affects approximately 1% of the population worldwide [1]. Although PD is characterized by the degeneration of nigrostriatal dopamine (DA) neurons, PD pathology also involves the serotinergic and cholinergic systems as well as a profound loss of neurons from the locus coeruleus (LC), the major noradrenergic nucleus in the brain [2], [3], [4], [5]. Other brain regions may be relevant to pathology and treatment of PD, this review will focus on the relationship between the dopaminergic and noradrenergic systems in PD. The cardinal symptoms of PD include resting tremor, bradykinesia, rigidity, and postural instability. These motor impairments do not become apparent until ∼80% of the DA terminals have been lost, which suggests the existence of an impressive compensatory mechanism in the earlier stages of disease. Several independent investigators have found that experimental lesions of the LC exacerbate PD pathology and behavioral symptomology in animal models, indicating that NE may play a key role in this compensation [6], [7], [8]. Postmortem examinations have shown that the LC in PD patients almost always demonstrates either cell loss or Lewy body inclusions, and most often both [9]. In fact, degeneration of the LC may precede and ultimately even surpass DA neuron degeneration in the substantia nigra par compacta (SNc) [2], [10], [11], [12], [13], [14]. NE has profound effects on brain inflammation, oxidative stress, and the function of other proteins implicated in PD, and in general confers potent neuroprotective properties. The first part of this review weighs the evidence that LC loss contributes directly to the demise of DA neurons in PD.
Apart from its importance for the survival of DA neurons, NE could also play an independent role in the behavioral symptoms of PD. Despite the popularity and utility of animal models of PD, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced DA neuron degeneration, it has proved difficult to simultaneously recapitulate the neuropathological and behavioral symptoms of PD, especially in mice. One limitation of these techniques is that they tend to model PD as a pure DA deficit, rather than as a multisystem disorder involving both the NE and DA systems. However, when researchers have lesioned both DA and NE neurons, the behavioral manifestations reminiscent of PD become more apparent, suggesting that NE loss exacerbates the motor deficits of PD. In addition to the spectrum of movement abnormalities, many PD patients experience neuropsychiatric symptoms, such as depression and sleep disturbances, which may be related to LC degeneration [15]. For example, PD patients with comorbid depression tend to exhibit more pronounced PD symptoms, and their depression can be alleviated by the selective NE transporter (NET) blocker reboxetine [16], [17]. Finally, the death of NE neurons may modulate the plastic changes and behavioral pathology associated with long-term l-dihydroxyphenylalanine (l-DOPA) therapy. Although DA replacement with l-DOPA remains one of the most effective treatments for PD, long-term treatment results in the development of dyskinesias (unwanted choreic involuntary movements), which complicate rather than alleviate the PD symptoms [18]. Human and animal studies have shown that α2-adrenoreceptor (α2AR) antagonists provide relief from l-DOPA-induced dyskinesias (LID) [19], [20]. While the mechanism of LID and the basis of the relief provided by blockade of α2ARs remains unknown, the data imply that NE continues to function in modulating the plasticity and activity of the basal ganglia during the progression of PD with l-DOPA treatment. The second part of this review will focus on the role of NE in the motor symptoms of PD.
To elucidate the way NE could modulate DA system function and survival directly and play a role in the progression and expression of PD, it is critical to summarize the intimate molecular, functional, and anatomical relationships between NE and DA. First, NE and DA share a biosynthetic pathway, and DA is in fact the direct precursor of NE [21]. In DA neurons, tyrosine is converted to l-DOPA by tyrosine hydroxylase (TH), which is subsequently converted to DA by aromatic acid decarboxylase (AADC), whereupon the DA is transported into synaptic vesicles by the vesicular monoamine transporter (VMAT). In NE neurons dopamine β-hydroxylase (DBH) acts within the synaptic vesicles to convert DA to NE. Second, noradrenergic neurons directly innervate midbrain DA neurons and the striatum. Stimulation of the LC facilitates burst firing of SNc neurons, while administration of the α1AR antagonist prazosin attenuates firing [22]. DBH, NE, and NET can be detected in the midbrain and striatum [23], [24], [25], [26] and, as in other regions of the brain, striatal NE release is controlled by both NET and α2AR autoreceptors [27], [28], [29]. Finally, either lesions of the LC or chronic NE depletion decrease striatal DA release [30], [31] and result in the compensatory upregulation of striatal D2 receptors [32], [33]. Combined, these results establish a functional connection between the noradrenergic and dopaminergic systems, which may form the basis for the influence of NE on PD neuropathology and motor deficits.
Section snippets
The neuroprotective properties of NE in PD
The first hints that NE promotes DA neuron survival came from MPTP studies in nonhuman primates and mice. Both Mavridis et al. [7] and Fornai et al. [34] noticed that the MPTP-induced damage to nigrostriatal DA neurons was potentiated by pretreatment with DSP4, which is a selective LC neurotoxin. Later, Kilbourn and colleagues found that the tottering mouse, which has noradrenergic hyperinnervation and increased levels of NE throughout the forebrain, was protected from MPTP toxicity [35]. We
The role of NE in motor function in PD
Animal models of PD have been established in an attempt to recapitulate the salient features of human PD. MPTP treatment is considered the gold-standard PD model, because of its abilities to faithfully produce SN neuronal death and motor impairments in nonhuman primates and to cause PD in humans [90], [91]. Although MPTP used in mouse models has successfully created the characteristic nigrostriatal loss seen in PD, its ability to induce PD-like behavioral symptoms has been inconsistent, at best
Future directions
Understanding the physiological interactions between NE and DA pathology in PD could lead to novel co-therapies with the potential to preserve and protect nigrostriatal DA neurons, improve l-DOPA efficacy, and prevent LID. Many issues will first need to be addressed in order to move forward with testing noradrenergic drugs as potential PD treatments.
Summary
There is no known cure for PD, and understanding the cause and progression of the neurodegenerative process is as challenging as it is necessary. Historically, DA has been the focus of most PD research, which led to the current first-line treatment for PD, l-DOPA. However, l-DOPA treatment does not slow the degeneration of DA neurons, and its benefits are temporary, because of an eventual loss of efficacy and the development of LID. In addition, l-DOPA does not reverse some motor symptoms such
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