2330 Current Medicinal Chemistry, 2007, 14, 2330-2334 0929-8673/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. Noradrenaline in Parkinson's Disease: From Disease Progression to Current Therapeutics Francesco Fornai* ,1,2 , Adolfo Bandettini di Poggio 1 , Antonio Pellegrini 1 , Stefano Ruggieri 2 and Antonio Paparelli 1 1 Department of Human Morphology and Applied Biology University of Pisa, Italy 2 Lab of Neurobiology of Movement Disorders I.N.M., I.R.C.C.S., Neuromed Pozzilli (IS) Abstract: The loss of the neurotransmitter noradrenaline occurs constantly in Parkinson’s disease. This is supposed to worsen disease progression, either by increasing the vulnerability of dopamine-containing neurons or by reducing the recovery once they are damaged. Novel data also show that the loss of noradrenergic innervation facilitates the onset of dyskinesia occurring in Parkinsonian patients dur- ing dopamine replacement therapy. In the first part of the manuscript we review the evidence showing the loss of the noradrenergic system as an early event in the natural history of Parkinsonism. This evidence is discussed in light of novel reports showing the deleterious effects produced by the noradrener- gic deficit on the survival of nigral dopamine neurons. In particular, we analyze the biochemical and morphological changes produced in the nigrostriatal system by the loss of endogenous noradrenaline. In a dedicated paragraph we specifically evaluate the cross affinity be- tween dopamine and noradrenaline systems. In fact, this is critical during dopamine/noradrenaline replacement therapy in Parkinson’s disease. In the last part, we overview novel therapeutic approaches aimed at restoring the activation of noradrenaline receptors to reduce the dy- skinesia occurring in the treatment of Parkinson’s disease. Keywords: Neurodegeneration, dyskinesia, locus coeruleus, L-DOPA, DA agonists, D 1 receptors, alpha receptors. 1. NOVEL EVIDENCE INDICATES THAT SEVERE LOSS OF NORADRENALINE OCCURS EARLY IN THE PRO- GRESSION OF PARKINSON’S DISEASE Although the anatomical connection between the locus coer- uleus (LC) and the substantia nigra pars compacta (SNpc) or the striatum are still poorly understood, a strong functional influence between these areas exists. The role of the LC in Parkinson’s dis- ease (PD) was first recognized at the beginning of the past century. In fact, ranging from earliest pathological findings of Tretiakoff [1] to the biochemical data of Oleh Hornykiewicz and co-workers [2], the loss of noradrenaline (NA)-containing neurons joined with a severe decrease in NA content in a variety of brain areas was clearly established. Nonetheless, these finding were not further explored for several decades. In particular, the relevance of such NA deficiency was never translated into any major clinical out- come, including drug development. However, in the last two dec- ades several reports focused on the need to design novel antiparkin- sonian drugs aimed at restoring NA levels in PD [3,4]. In fact, pathological reports confirmed the relevance of NA degeneration and added the concept of a disease-specific pattern of LC damage [5]. In order to evaluate the potential significance of NA loss in parkinsonism we studied the modulation of alpha 2 -NA receptors on central catecholamine systems [6] and their role in the onset of experimental parkinsonism induced by the neurotoxin 1-methyl, 4- phenyl, 1,2,3,6-tetrahydropyridine (MPTP) [7]. As reviewed in the last part of the article, this sub-class of NA receptors is now under clinical evaluation in PD. The loss of the NA system arising from the LC received a spe- cial attention when a variety of pre-clinical studies demonstrated the deleterious influence of such a loss on the survival of DA neu- rons. This evidence was first shown in primates by Mavridis et al. [8], who suggested that a previous damage to NA neurons impaired the recovery of the nigrostriatal DA pathway following a neurotoxic lesion produced by MPTP. Further studies, using catecholamine assay or nigral cell counts confirmed this detrimental effect [9,10] respectively. These studies led to hypothesize that, the detrimental influence of NA loss consisted in increasing the susceptibility, *Address correspondence to this author the Department of Human Morphology and Applied Biology, University of Pisa, Via Roma, 55, 56126, Pisa, Italy; Tel: +39-050- 2218611; Fax: +39-050-2218606; E-mail: f.fornai@med.unipi.ut rather then decreasing the recovery of DA neurons belonging to the SNpc. In fact, in 1997, we found that, the damage to LC-NA neurons did not alter the spontaneous recovery of nigral DA cells following MPTP, but instead, it produced an increased vulnerability for nigral DA neurons [11]. This concept was strengthened by the evidence that, an increased NA stimulation was neuroprotective against MPTP toxicity [12]. A few years before, it was found that an increased DA vulnerability was not dependent on the specific neurotoxin (i.e. MPTP), but it was rather a general effects extending to a variety of conditions. Thus, we found that, in the absence of the physiological NA innervation, the DA damage produced by the drug of abuse methamphetamine was magnified [13]. This phe- nomenon was shown to be the consequence of an increased vulner- ability which develops within DA neurons in the absence of NA [14]. More recently, increased DA vulnerability was demonstrated for the neurotoxin 6-hydroxydopamine, when it was administered to LC-lesioned rodents [15]. The strength of these pre-clinical findings led investigators to re-assess the natural history of PD, and to evaluate in humans the role of LC in the progression of the disor- der. Thus, based on pioneer studies, showing that the LC was im- paired very early in the course of the disorder, it was suggested that such a lesion plays a causative role in the natural progression of PD (for a review, see Gesi et al. [16]). Such working hypothesis is now substantiated by facts, as shown very recently in humans by an extensive biochemical analysis carried out by Tong and co-workers [4], who consistently found a negative correlation between the rich- ness of NA innervation and the occurrence of DA loss in a variety of brain areas. These findings led the authors to hypothesize a fa- cilitating effect of LC damage to the subsequent DA degeneration, as postulated in the experimental models reported above. Thus, the loss of NA is now a critical point in the natural history of PD. This is also confirmed by recent neuropathological findings obtained in a large number of newly autopsied PD patients joined with retrospec- tive cases. Altogether these cases demonstrated that the loss of NA neurons of the LC is at least as severe, as the death of DA cells in the SNpc [17]. This was in line with the extensive neuropathologi- cal re-assessment of the PD by Braak and co-workers [18,19,20]. These authors found that, in a number of PD patients, disease pro- gression starts from lower brainstem regions (including the LC) and later extends to more rostral areas including the mesencephalic SNpc. Altogether, findings obtained within pre-clinical settings, and in PD patients, by using a neuropathological and biochemical