Dopamine D3 receptor agonists for protection and repair 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
References (46)
Dopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugs
Pharmacol Ther
(2001)- et al.
Dopamine agonist monotherapy in Parkinson's disease
Lancet
(2002) - et al.
Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease
Prog Neurobiol
(2001) - et al.
The cellular repair of the brain in Parkinson's disease-past, present and future
Transpl Immunol
(2004) - et al.
Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model
Brain Res
(2000) - et al.
Comparison of the capability of GDNF, BDNF, or both, to protect nigrostriatal neurons in a rat model of Parkinson's disease
Brain Res
(2005) - et al.
Dopamine D3 receptor antagonists as therapeutic agents
Drug Discov Today
(2005) - et al.
Dopamine in neurotoxicity and neuroprotection: what do D2 receptors have to do with it?
Trends Neurosci
(2006) - et al.
Neuroprotective effects of the novel D3/D2 receptor agonist and antiparkinson agent S32504, in vitro against 1-methyl-4-phenylpyridinium (MPP+)and in vivo against 1-methyl- 4-phenyl-1,2,2,6-tetrahydropyridine (MPTP): a comparison to ropinirole
Exp Neurol
(2003) - et al.
Pramipexole inhibits MPTP toxicity in mice by dopamine D3 receptor dependent and independent mechanisms
Eur J Pharmacol
(2003)
Neuroprotective effects of pramipexole in young and aged MPTP-treated mice
Brain Res
Inhibiting BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons
Exp Neurol
Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase
J Biol Chem
Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D3 receptor stimulation
Eur J Neurosci
Dopamine D3 receptor agonist delivery to a model of Parkinson's disease restores the nigrostriatal pathway and improves locomotor behavior
J Neurosci
Etiology of Parkinson's disease
Neurology
Does levodopa slow or hasten the rate of progression of Parkinson's disease?
J Neurol
Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP
Cell Tissue Res
Animal models of Parkinson's disease: an empirical comparison with the phenomenology of the disease in man
J Neural Transm
The pathogenesis of cell death in Parkinson's disease
Neurology
Comparison of embryonic stem cell-derived dopamine neuron grafts and fetal ventral mesencephalic tissue grafts: morphology and function
Cell Transplant
Chronic supranigral infusion of BDNF in normal and MPTP-treated common marmosets
J Neural Transm
Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys
Brain
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