Dopamine D3 receptor agonists for protection and repair in Parkinson's disease

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Parkinson's disease is a severe, age-related neurodegenerative disorder in which a loss of substantia nigra-derived dopaminergic pathways to the striatum triggers profound motor perturbation, as well as cognitive, sensory and mood deficits. Although the dopamine precursor, L-dopa, is effective in the short-term in relieving motor dysfunction, it does not stop the progressive disappearance of dopaminergic neurons, encouraging interest in alternative therapeutic strategies. Dopaminergic agonists, such as pramipexole, appear to have neuroprotective and neurorestorative actions based on clinical and, most convincingly, experimental work. The role of specific dopaminergic receptor subtypes is an important issue, especially with respect to new drug development. Of particular interest, dopamine D3 receptors contribute to the beneficial influence of dopaminergic agonists for the protection and restoration of dopaminergic pathways in Parkinson's disease.

Introduction

Parkinson's disease (PD) is an age-related movement disorder affecting approximately 2% of the population over the age of 65 years. It is characterized by bradykinesia, rigidity, resting tremor and postural instability. The neuropathologic hallmarks of PD are the loss of dopaminergic neurons in the substantia nigra (SN) and the presence of intraneuronal cytoplasmic inclusions known as Lewy bodies [1]. Although the significance of a generalized disruption of cerebral monoaminergic transmission should not be neglected, the clinical manifestations of PD are primarily the consequence of progressive and selective degeneration of dopaminergic neurons in the pars compacta of the SN that give rise to the nigrostriatal pathway; disappearance of this tract provokes a depletion of dopamine (DA) in the striatum, where it is required for normal motor (and cognitive) function. Correspondingly, PD has long been treated by administration of the dopaminergic precursor, L-dopa, which is transformed in residual dopaminergic neurons, as well as in serotonergic terminals and glia, into DA. However, despite conflicting data, L-dopa is suspected to exert neurotoxic properties that can accelerate the loss of dopaminergic neurons [2]. Furthermore, the pharmacokinetic profile of L-dopa is highly variable, leading to abrupt transitions between ‘on’ (active) and ‘off’ (inactive) phases. In addition, it elicits marked dyskinesia, and its therapeutic efficacy gradually wanes over years of exposure [3]. The complementation of L-dopa as the mainstay of (first-line) clinical management of PD with direct dopaminergic agonists has accelerated in recent years with the introduction of two highly effective agents: pramipexole (Mirapexin®/Sifrol®/Mirapex®) and ropinirole (Requip®). These agonists are not only clinically active in relieving motor deficits, but they may also slow the loss of dopaminergic terminals upon long-term administration to patients with PD [4]. The mechanisms of action underlying the disease-modifying effects of these and related dopaminergic agonists are the principle subject of the current review.

Section snippets

Neuroprotection and neurorestoration: complementary concepts and therapeutic strategies

Experimental approaches to slowing disease progression in PD have focused on ‘neuroprotective’ and ‘neurorestorative’ actions. Neuroprotection is based on the notion that preventing the death of residual dopaminergic neurons, even after their loss has been sufficient to trigger the clinical symptoms of PD, will impede progression of the disease. This could be achieved with strategies that check cell death or, more specifically, protect dopaminergic neurons. Neurorestorative actions are founded

Dopaminergic agonists and neuroprotection

The effects of DA are mediated by the D1 and D5 receptor subfamily, positively coupled to adenylyl cyclase, and by the D2, D3 and D4 receptor subfamily, which is negatively coupled to adenylyl cyclase [16, 17]. However, it is evident that activation of D2 and/or D3 receptors underlies the anti-parkinsonian (motor) effects of dopaminergic agonists [3]. Even before brain imaging studies indicated that long-term administration of pramipexole and ropinirole to PD patients retards the loss of

Dopaminergic agonists and neurorestoration

Another mode of action for transduction of the therapeutic effects of D3 receptor-preferring agonists has been pursued by Van Kampen and associates [33, 34•, 35••]; that is, induction of neurogenesis leading to the regeneration of dopaminergic pathways. The existence of neural stem cells in the central nervous system of adult mammals has been demonstrated convincingly over the past few years. Cells from the mammalian central nervous system can differentiate into neurons and glia, and they

Regeneration of dopaminergic pathways

In ground-breaking work, two papers in 2004 indicated that, both in vitro [39] and in vivo [33], dopaminergic agonists augment SVZ cell numbers via recruitment of D3 receptors, and that this effect reflects enhanced mitogenesis, not decreased apoptosis. Thus, intrasubventricular (ICV) infusion of the D3 receptor-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) for between 4 days and 2 weeks doubled cell proliferation in the SVZ and the rostral migratory stream (RMS),

Conclusions

On the basis of a broad pattern of complementary in vitro, in vivo and clinical observations, the findings outlined above collectively provide compelling evidence that dopamine D3 receptors play a major role in the expression of the neuroprotective and neurorestorative actions of dopaminergic agonists. Although much work remains to be undertaken to further characterize and mechanistically define their significance (and that of other dopaminergic receptor subtypes), the recruitment of dopamine

Update

Recent work has shown that following the destruction of the nigro-striatal pathway (SN-6-OHDA lesion), some SVZ precursors begin to express TH and neuronal markers (NeuN). Grafting of chromaffin cells into the denervated striatum increases the number of TH+ cells, and these are functional as determined by patch-clamp electrophysiology and DA release [43]. The SVZ receives a topographically organized projection from the SN; this projection is dopaminergic and closely approaches the proliferating

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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