Parkinson Drug Research Articles

Psychopharmacologist

Psychopharmacologist

Tu2086 The Endocannabinoid System (ECS) and the Hypothalamic-Pituitary-Adrenal (HPA) Axis in Adults With Cyclic Vomiting Syndrome (CVS)

Background: The most commonly used drug for Parkinson disease (PD) therapy, levodopa (L-dopa) induces delayed gastric emptying (GE) in PD patients and healthy controls. We previously reported that ghrelin could prevent L-dopa-inhibited GE in rats. Rikkunshito is a kampo medicine that increases ghrelin in humans and mice and used clinically in Japan to treat functional and chemotherapy-induced dyspepsia, and post-operative gastric ileus. Aim: To investigate whether rikkunshito mimics ghrelin effect to improve gastric motility in L-dopa-treated rats. Methods: In overnight fasted rats, rikkunshito (Gastroenterology 2008, 143:2004), or vehicle (distilled water) was administered by orogastic gavage (og) 170 min before L-dopa/carbidopa (LD/CD, og), 10 min later followed by a meal (methylcellulose/ phenol red or 40% powder meal in water with 50% glass bead, og), and GE was assessed 20 min (non-nutrient solution) or 60 min (nutrient meal) thereafter. The ghrelin antagonist, D-[Lys3]-GHRP-6 was injected IP at the same time as rikkunshito and GE was determined 20 min after og LD/CD or vehicle. Strain gauge transducer was implanted in the rat antrum. After 6 days, overnight food restricted rats were treated with rikkunshito or vehicle and 170 min later with L-dopa or vehicle (IP) and then 10 min later, the powder meal solution was gavaged and antral motility was recorded for 60 min. Food intake was monitored after rikkunshito and LD/CD gavage in overnight fasted rats. Results: LD/CD (15/1.5, 20/2 and 50/5 mg/kg, og) dose-dependently inhibited GE of nutrient meal (58.1±4.1%, 41.9±5.8%*, 28.9±5.6%* vs. vehicle 72.9±5.2%, respectively, *:p,0.05). In vehicle pretreated rats, LD/ CD (20/2 mg/kg, og) decreased GE of a non-nutrient meal compared to vehicles (12.1±7.4% vs. 49.3±7.0%, p,0.05). Rikkunshito (0.5 or 1.0 g/kg, og) prevented dose-dependently the LD/CD inhibitory effect on GE (36.9±7.4% and 46.6±4.8% respectively, p,0.05 vs. vehicle plus LD/CD) while having no effect alone (56.6±8.5%). Likewise, rikkunshito (1.0 g/kg) blocked LD/CD reduced GE of the nutrient meal (61.4±4.1% vs. 43.0±5.0%, p ,0.05) compared to vehicles (71.5±5.0%). L-dopa (15 mg/kg)-induced reduction of antral motility (motility index 78.3±3.4 vs. vehicle 103.3±6.7, p,0.05) was blocked by rikkunshito (1.0 g/kg; motility index 102.0±5.4). D-[Lys3]-GHRP-6 (1 mg/kg) partially reversed rikkunshito effect on LD/CD-inhibited GE. There was no significant difference in cumulative food intake response to a fast at 1, 2, 4 and 24 h after og rikkunshito (1.0 g/kg) plus LD/CD (20/2 mg/ kg). Conclusions: Rikkunshito exerts a gastroprokinetic effect under conditions of levodopainhibited gastric motor function that may be in part mediated by ghrelin. Rikkunshito may have therapeutic application to improve gastric transit in levodopa treated-PD patients. Supported by Tsumura & Co. and NIDDK 41303 (animal core)

Tu2085 Rikkunshito Prevents Levodopa-Inhibited Gastric Motility in Fasted Rats

Background: The most commonly used drug for Parkinson disease (PD) therapy, levodopa (L-dopa) induces delayed gastric emptying (GE) in PD patients and healthy controls. We previously reported that ghrelin could prevent L-dopa-inhibited GE in rats. Rikkunshito is a kampo medicine that increases ghrelin in humans and mice and used clinically in Japan to treat functional and chemotherapy-induced dyspepsia, and post-operative gastric ileus. Aim: To investigate whether rikkunshito mimics ghrelin effect to improve gastric motility in L-dopa-treated rats. Methods: In overnight fasted rats, rikkunshito (Gastroenterology 2008, 143:2004), or vehicle (distilled water) was administered by orogastic gavage (og) 170 min before L-dopa/carbidopa (LD/CD, og), 10 min later followed by a meal (methylcellulose/ phenol red or 40% powder meal in water with 50% glass bead, og), and GE was assessed 20 min (non-nutrient solution) or 60 min (nutrient meal) thereafter. The ghrelin antagonist, D-[Lys3]-GHRP-6 was injected IP at the same time as rikkunshito and GE was determined 20 min after og LD/CD or vehicle. Strain gauge transducer was implanted in the rat antrum. After 6 days, overnight food restricted rats were treated with rikkunshito or vehicle and 170 min later with L-dopa or vehicle (IP) and then 10 min later, the powder meal solution was gavaged and antral motility was recorded for 60 min. Food intake was monitored after rikkunshito and LD/CD gavage in overnight fasted rats. Results: LD/CD (15/1.5, 20/2 and 50/5 mg/kg, og) dose-dependently inhibited GE of nutrient meal (58.1±4.1%, 41.9±5.8%*, 28.9±5.6%* vs. vehicle 72.9±5.2%, respectively, *:p,0.05). In vehicle pretreated rats, LD/ CD (20/2 mg/kg, og) decreased GE of a non-nutrient meal compared to vehicles (12.1±7.4% vs. 49.3±7.0%, p,0.05). Rikkunshito (0.5 or 1.0 g/kg, og) prevented dose-dependently the LD/CD inhibitory effect on GE (36.9±7.4% and 46.6±4.8% respectively, p,0.05 vs. vehicle plus LD/CD) while having no effect alone (56.6±8.5%). Likewise, rikkunshito (1.0 g/kg) blocked LD/CD reduced GE of the nutrient meal (61.4±4.1% vs. 43.0±5.0%, p ,0.05) compared to vehicles (71.5±5.0%). L-dopa (15 mg/kg)-induced reduction of antral motility (motility index 78.3±3.4 vs. vehicle 103.3±6.7, p,0.05) was blocked by rikkunshito (1.0 g/kg; motility index 102.0±5.4). D-[Lys3]-GHRP-6 (1 mg/kg) partially reversed rikkunshito effect on LD/CD-inhibited GE. There was no significant difference in cumulative food intake response to a fast at 1, 2, 4 and 24 h after og rikkunshito (1.0 g/kg) plus LD/CD (20/2 mg/ kg). Conclusions: Rikkunshito exerts a gastroprokinetic effect under conditions of levodopainhibited gastric motor function that may be in part mediated by ghrelin. Rikkunshito may have therapeutic application to improve gastric transit in levodopa treated-PD patients. Supported by Tsumura & Co. and NIDDK 41303 (animal core)

Multiple controls exerted by 5-HT2C receptors upon basal ganglia function: from physiology to pathophysiology

Serotonin2C (5-HT2C) receptors are expressed in the basal ganglia, a group of subcortical structures involved in the control of motor behaviour, mood and cognition. These receptors are mediating the effects of 5-HT throughout different brain areas via projections originating from midbrain raphe nuclei. A growing interest has been focusing on the function of 5-HT2C receptors in the basal ganglia because they may be involved in various diseases of basal ganglia function notably those associated with chronic impairment of dopaminergic transmission. 5-HT2C receptors act on numerous types of neurons in the basal ganglia, including dopaminergic, GABAergic, glutamatergic or cholinergic cells. Perhaps inherent to their peculiar molecular properties, the modality of controls exerted by 5-HT2C receptors over these cell populations can be phasic, tonic (dependent on the 5-HT tone) or constitutive (a spontaneous activity without the presence of the ligand). These controls are functionally organized in the basal ganglia: they are mainly localized in the input structures and preferentially distributed in the limbic/associative territories of the basal ganglia. The nature of these controls is modified in neuropsychiatric conditions such as Parkinson's disease, tardive dyskinesia or addiction. Most of the available data indicate that the function of 5-HT2C receptor is enhanced in cases of chronic alterations of dopamine neurotransmission. The review illustrates that 5-HT2C receptors play a role in maintaining continuous controls over the basal ganglia via multiple diverse actions. We will discuss their interest for treatments aimed at ameliorating current pharmacotherapies in schizophrenia, Parkinson's disease or drugs abuse.

Protein interacting with C kinase and neurological disorders

Best known for its interaction with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA2 and for its influence on excitatory synapse activity, the protein interacting with C kinase, PICK1, is the focus of considerable attention from neurobiologists. Indeed, this PSD-95/DlgA/ZO-1 (PDZ) domain-containing protein has been shown to interact with a wide variety of neurotransmitter receptors, transporters, and enzymes, including glutamate and nicotinic acetylcholine receptors, dopamine and glutamate transporters, and the enzyme serine racemase. Through its lipid binding domain, PICK1 is targeted to the inner surface of the cell membrane where it contributes to anchoring these partners and thereby influences their synaptic localization and function. Under pathological conditions, the regulation of some PICK1-interacting partners is altered, pointing to an involvement of PICK1 in neurological disorders. Also, genetic or pharmacological manipulations of PICK1 expression, localization, or function have been shown to influence several physiological or pathological processes in which putative PICK1 partners are involved. This review will summarize recent experimental observations that highlight the involvement of PICK1 in neurological disorders, including schizophrenia, Parkinson's disease, epilepsy, chronic pain, drug abuse, and amyotrophic lateral sclerosis.

The practical management of cognitive impairment and psychosis in the older Parkinson’s disease patient

Parkinson's disease (PD) has been described as an age-related disease. Ageing significantly increases the risk of psychosis and dementia. Older patients often have a complex mixture of delirium, psychosis, dementia, gait and balance problems and other comorbidities which can cause significant management problems. There are concerns about the safety and tolerability of the treatments for psychosis and dementia. Delirium is common in older Parkinson's patients and must be assessed and managed carefully. The aetiology of psychosis in Parkinson's is complex and often associated with the development of cognitive impairment. Initial adjustments of Parkinson's drugs should be considered if symptoms are intrusive. Where drug therapy is required, evidence suggests that quetiapine may be a safe initial option. There is no contraindication to the use of clozapine in older patients, with the required blood monitoring. Dementia is almost inevitable with very advanced disease and increasing age, and is associated with a marked cholinergic deficit in the brain. Cholinesterase inhibitors may be more effective in PD than in Alzheimer's disease and appear relatively safe with appropriate monitoring of the pulse. There is much less evidence for the use of memantine. There is no current evidence for the use of specific non-pharmacological therapies in the management of psychosis or dementia in PD. Due to the associated gait and balance problems, older Parkinson's patients benefit from comprehensive multi-disciplinary assessment.

Protection of MPTP-induced neuroinflammation and neurodegeneration by Pycnogenol

Oxidative stress and inflammation play a crucial role in Parkinson’s disease (PD) pathogenesis and may represent a target for treatment. Current PD drugs provide only symptomatic relief and have limitations in terms of adverse effects and inability to prevent neurodegeneration. Flavonoids have been suggested to exert human health benefits by its anti-oxidant and anti-inflammatory properties. Therefore, in the present study, using 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-induced mouse model of Parkinsonism, we investigated the neuroprotective potential of bioflavonoid compound Pycnogenol® (PYC), an extract of Pinus maritime bark. MPTP injected mice developed significantly severe oxidative stress and impaired motor coordination at day 1 and day 7 postinjection. This was associated with significantly increased inflammatory responses of astrocyte and microglia as assessed by ionized calcium binding adaptor molecule 1 (Iba 1) and glial fibrillary acidic protein (GFAP) immunohistochemistry, and nuclear transcription factor-κB (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in the striata by Western blot. Additionally, there was significant upregulation of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) expression in the striata of MPTP injected mice compared to saline controls. The MPTP-induced neuroinflammation, neurodegeneration and behavioral impairments were markedly repudiated by treatment with PYC. These results suggest that PYC protects dopaminergic neurons from MPTP-induced toxicity in the mouse model of PD. Thus, the present finding of PYC-induced adaptation to oxidative stress and inflammation could suggest a novel avenue for clinical intervention in neurodegenerative diseases including PD.

Is there room for non-dopaminergic treatment in Parkinson disease?

Although levodopa and dopaminergic drugs remain the mainstay of therapy for the motor symptoms of Parkinson disease (PD), they fail to address many of the non-motor symptoms of PD including orthostatic hypotension, freezing of gait (FOG) and difficulty with balance, drug-induced paranoia and hallucinations, and drug-induced dyskinesias. Droxidopa, a drug that increases norepinephrine, treats orthostatic hypotension, cholinomimetic drugs sometimes help with FOG and difficulty with balance, pimavanserin, a drug that blocks serotonin receptors, treats paranoia and hallucinations, and anti-glutaminergic drugs treat dyskinesias. Thus, there are ample opportunities for non-dopaminergic drugs in PD.

Overcoming obstacles in Parkinson's disease

Improved symptomatic and disease-modifying treatments are needed for Parkinson's disease (PD). Although significant advances have been made in the understanding of PD etiology, the translation of these discoveries into novel transformative therapies has been limited as a result of systemic challenges in PD drug development. Preclinical testing lacks clear standards and prioritization criteria for advancing therapies to the clinic. Clinical testing is marked by expensive, long, and uninformative studies. In parallel to these scientific challenges, funding of late-stage drug development has become increasingly scarce and risk averse. In this context, novel models of collaboration and funding are opening up new avenues for pursuing treatments. This review will discuss the most critical challenges in PD drug development and the innovative approaches being developed to overcome these hurdles.

PND18 Impact of Co-Morbidities on the Economic Burden of Parkinson'S Disease in Germany Post-2000

To collate the published evidence evaluating economic burden of co-morbidities in patients with Parkinson's disease (PD) in Germany. A systematic search of electronic literature databases (Embase® and MEDLINE®) was conducted from January 2001 to June 2012 to identify economic studies in English evaluating co-morbidities in patients with PD in Germany. Four studies of the 267 citations retrieved met the pre-defined inclusion criteria. During 2000-2002, direct costs were higher in patients with dyskinesias and/or motor fluctuations (€3300 [€4630]) or dementia (€3110 [€5610]) than patients without motor complications (€1450 [€3760]) or dementia (€1530 [3460]). However, indirect costs were higher for patients without dementia (€3780 [€6870]) than patients with dementia (€1080 [€4110]). In 2006, daily total costs and PD drug treatment costs decreased significantly in patients with dementia (€7.3 [7.3]; p<0.05) and depression (€6.6 [5.8]; p<0.05) than patients without dementia (€9.3 [13.9]) and depression (€7.6 [6.8]), respectively. The decrease in the costs observed across patients presenting with these co-morbidities may be attributed to the inadequate treatment of depression or dementia among patients with PD. In 2009, direct costs demonstrated a significant increase in patients with dyskinesia (€16,544 vs. €11,322; p=0.003), dementia (€21,142 vs. €10,619; p<0.001), depression (€15,904 vs. €8826; p<0.001), or psychosis (€15,398 vs. €8614; p=0.016) than patients without these co-morbidities. Indirect costs were also higher in PD patients with these co-morbidities than patients with PD alone; the difference being significant only for dementia (€8201 vs. €2964; p=0.037). Co-morbid dyskinesia, dementia, or depression were observed to be the major contributors to the fiscal burden of PD in Germany, post-2000. An overall increase in the (estimated) costs associated with these co-morbidities was evident during the time-period evaluated. Further studies to understand the cause of increased (estimated) costs associated with these co-morbidities in PD are warranted.

Therapeutic potential of natural products in Parkinson's disease.

The central objective in treating patients with Parkinson's disease (PD) is two-fold (i) to increase the striatal dopamine content and (ii) to prevent further degeneration of the surviving dopaminergic neurons in the substantia nigra region of the ventral midbrain. Most of the current PD drugs contribute to the former and provide symptomatic relief. Although compounds such as Levodopa (L-DOPA) improve the striatal dopamine content, their long-term usage is associated with progressive decrease in drug response, motor fluctuations, dyskinesias and drug-induced toxicity. In addition, these drugs fail to prevent the progression of the degenerative process. This has shifted the focus onto alternative therapeutic approaches involving natural products that could provide independent therapy or offer neuroprotective support to the existing drugs. The current review describes the neuroprotective and therapeutic utility of such natural products including herbal extracts, phytochemicals and bioactive ingredients from other natural sources either in isolation or in combination, with potential application in PD, highlighting the relevant patents.

D1 Dopamine Receptor Signaling Is Modulated by the R7 RGS Protein EAT-16 and the R7 Binding Protein RSBP-1 in Caenoerhabditis elegans Motor Neurons

Dopamine signaling modulates voluntary movement and reward-driven behaviors by acting through G protein-coupled receptors in striatal neurons, and defects in dopamine signaling underlie Parkinson's disease and drug addiction. Despite the importance of understanding how dopamine modifies the activity of striatal neurons to control basal ganglia output, the molecular mechanisms that control dopamine signaling remain largely unclear. Dopamine signaling also controls locomotion behavior in Caenorhabditis elegans. To better understand how dopamine acts in the brain we performed a large-scale dsRNA interference screen in C. elegans for genes required for endogenous dopamine signaling and identified six genes (eat-16, rsbp-1, unc-43, flp-1, grk-1, and cat-1) required for dopamine-mediated behavior. We then used a combination of mutant analysis and cell-specific transgenic rescue experiments to investigate the functional interaction between the proteins encoded by two of these genes, eat-16 and rsbp-1, within single cell types and to examine their role in the modulation of dopamine receptor signaling. We found that EAT-16 and RSBP-1 act together to modulate dopamine signaling and that while they are coexpressed with both D1-like and D2-like dopamine receptors, they do not modulate D2 receptor signaling. Instead, EAT-16 and RSBP-1 act together to selectively inhibit D1 dopamine receptor signaling in cholinergic motor neurons to modulate locomotion behavior.

The emerging role of norepinephrine in cognitive dysfunctions of Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1% of the population over age 60. In those patients cognitive dysfunction is a persistent issue that impairs quality of life and productivity. Neuropathological studies demonstrate significant damage in brain regions outside the nigral dopamine (DA) system, including early degeneration of locus coeruleus norepinephrine (LC-NE) neurons, yet discussion of PD and treatment focus has remained dopaminergic-based. Motor symptoms benefit from DA replacement for many years, but other symptoms including several cognitive deficits continue unabated. Recent interest in non-DA substrates of PD highlights early involvement of LC-NE neurons and provides evidence for a prodromal phase, with cognitive disturbance, even in sporadic PD. We outline insights from basic research in LC-NE function to clinical and pathological evidence highlighting a role for NE in PD cognitive dysfunction. We propose that loss of LC-NE regulation, particularly in higher cortical regions, critically underlies certain cognitive dysfunctions in early PD. As a major unmet need for patients, research and use of NE drugs in PD may provide significant benefits for cognitive processing.

Neuronal signaling and behavior

Neuronal signaling and behavior

Genetic mouse models for understanding LRRK2 biology, pathology and pre-clinical application

Missense mutations in Leucine-Rich Repeat kinase 2 (LRRK2) are the most common cause of inherited Parkinson's disease (PD). Elucidation of LRRK2 biology and pathophysiology is central to the development of therapeutic intervention. Our group and others have developed a number of genetic mouse models of LRRK2 utilizing different genetic approaches. These models exhibit certain PD-related pathologies (e.g. impaired dopamine transmission and tauopathies) and abnormal motor functions, providing valuable insight into potential LRRK2-mediated pathogenesis of PD. However, not surprisingly they lack of substantial neuropathology and clinical syndromes of PD. Ongoing investigation of these models has begun to shed light on LRRK2 cellular functions and pathogenic pathways and is expected to assist the identification and validation of PD drug targets. This report summarizes the recent findings in our genetic LRRK2 models and discusses their utility in understanding much needed knowledge regarding early stage (pre-symptomatic) disease progression, drug target identification, and potential application in chemical screening focused on inhibitors of kinase activity of LRRK2.

Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse, and Parkinson’s Disease

The neurotransmitter dopamine plays important roles in modulating cognitive, affective, and motor functions. Dysregulation of dopaminergic neurotransmission is thought to be involved in the pathophysiology of several psychiatric and neurological disorders, including schizophrenia, Parkinson's disease and drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input. Not surprisingly, increasing evidence implicates muscarinic acetylcholine receptor-mediated pathways as potential targets for the treatment of these disorders classically viewed as "dopamine based". There are five known muscarinic receptor subtypes (M(1) to M(5)). Due to their overlapping expression patterns and the lack of receptor subtype-specific ligands, the roles of the individual muscarinic receptors have long remained elusive. During the past decade, studies with knock-out mice lacking specific muscarinic receptor subtypes have greatly advanced our knowledge of the physiological roles of the M(1)-M(5) receptors. Recently, new ligands have been developed that can interact with allosteric sites on different muscarinic receptor subtypes, rather than the conventional (orthosteric) acetylcholine binding site. Such agents may lead to the development of novel classes of drugs useful for the treatment of psychosis, drug abuse and Parkinson's disease. The present review highlights recent studies carried out using muscarinic receptor knock-out mice and new subtype-selective allosteric ligands to assess the roles of M(1), M(4), and M(5) receptors in various central processes that are under strong dopaminergic control. The outcome of these studies opens new perspectives for the use of novel muscarinic drugs for several severe disorders of the CNS.

Parkinson disease drug screening based on the interaction between D2 dopamine receptor and beta-arrestin 2 detected by capillary zone electrophoresis

Parkinson’s disease is the second most common neurodegenerative disease in the world. Beta-arrestin-2 has been reported to be an important protein involved in D2 dopamine receptor desensitization, which is essential to Parkinson’s disease. Moreover, the potential value of pharmacological inactivation of G protein-coupled receptor kinase or arrestin in the treatment of patients with Parkinson’s disease has recently been shown. We studied the interaction between D2 dopamine receptor and beta-arrestin-2 and the pharmacological regulation of chemical compounds on such interaction using capillary zone electrophoresis. The results from screening more than 40 compounds revealed three compounds that remarkably inhibit the beta-arrestin-2/D2 dopamine receptor interaction among them. These compounds are promising therapies for Parkinson’s disease, and the method used in this study has great potential for application in large-scale drug screening and evaluation.

ChemInform Abstract: Recent Advances in the Development of Dopamine D3 Receptor Antagonists: A Medicinal Chemistry Perspective

AbstractReview: ca. 150 refs.

Disease Modification in Parkinsonʼs Disease

Parkinson's disease (PD) is an age-related, progressive, multisystem neurodegenerative disorder resulting in significant morbidity and mortality, as well as a growing social and financial burden in an aging population. The hallmark of PD is loss of dopaminergic neurons of the substantia nigra pars compacta, leading to bradykinesia, rigidity and tremor. Current pharmacological treatment is therefore centred upon dopamine replacement to alleviate symptoms. However, two major problems complicate this approach: (i) motor symptoms continue to progress, requiring increasing doses of medication, which result in both short-term adverse effects and intermediate- to long-term motor complications; (ii) dopamine replacement does little to treat non-dopaminergic motor and non-motor symptoms, which are an important source of morbidity, including dementia, sleep disturbances, depression, orthostatic hypotension, and postural instability leading to falls. It is critical, therefore, to develop a broader and more fundamental therapeutic approach to PD, and major research efforts have focused upon developing neuroprotective interventions. Despite many encouraging preclinical data suggesting the possibility of addressing the underlying pathophysiology by slowing cell loss, efforts to translate this into the clinical realm have largely proved disappointing in the past. Barriers to finding neuroprotective or disease-modifying drugs in PD include a lack of validated biomarkers of progression, which hampers clinical trial design and interpretation; difficulties separating symptomatic and neuroprotective effects of candidate neuroprotective therapies; and possibly fundamental flaws in some of the basic preclinical models and testing. However, three recent clinical trials have used a novel delayed-start design in an attempt to overcome some of these roadblocks. While not examining markers of cell loss and function, which would determine neuroprotective effects, this trial design pragmatically tests whether earlier versus later intervention is beneficial. If positive (i.e. if an earlier intervention proves more effective), this demonstrates disease modification, which could result from neuroprotection or from other mechanisms. This strategy therefore provides a first step towards supporting neuroprotection in PD. Of the three delayed-start design clinical trials, two have investigated early versus later start of rasagiline, a specific irreversible monoamine oxidase B inhibitor. Each trial has supported, although not proven, disease-modifying effects. A third delayed-start-design clinical trial examining potential disease-modifying effects of pramipexole has unfortunately reportedly been negative according to preliminary presentations. The suggestion that rasagiline is disease modifying is made all the more compelling by in vitro and PD animal-model studies in which rasagiline was shown to have neuroprotective effects. In this review, we examine efforts to demonstrate neuroprotection in PD to date, describe ongoing neuroprotection trials, and critically discuss the results of the most recent delayed-start clinical trials that test possible disease-modifying activities of rasagiline and pramipexole in PD.

Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry.

Vesicular monoamine transporters (VMAT) are responsible for the uptake of cytosolic monoamines into synaptic vesicles in monoaminergic neurons. Two closely related VMATs with distinct pharmacological properties and tissue distributions have been characterized. VMAT1 is preferentially expressed in neuroendocrine cells and VMAT2 is primarily expressed in the CNS. The neurotoxicity and addictive properties of various psychostimulants have been attributed, at least partly, to their interference with VMAT2 functions. The quantitative assessment of the VMAT2 density by PET scanning has been clinically useful for early diagnosis and monitoring of the progression of Parkinson's and Alzheimer's diseases and drug addiction. The classical VMAT2 inhibitor, tetrabenazine, has long been used for the treatment of chorea associated with Huntington's disease in the United Kingdom, Canada, and Australia, and recently approved in the United States. The VMAT2 imaging may also be useful for exploiting the onset of diabetes mellitus, as VMAT2 is also expressed in the β-cells of the pancreas. VMAT1 gene SLC18A1 is a locus with strong evidence of linkage with schizophrenia and, thus, the polymorphic forms of the VMAT1 gene may confer susceptibility to schizophrenia. This review summarizes the current understanding of the structure-function relationships of VMAT2, and the role of VMAT2 on addiction and psychostimulant-induced neurotoxicity, and the therapeutic and diagnostic applications of specific VMAT2 ligands. The evidence for the linkage of VMAT1 gene with schizophrenia and bipolar disorder I is also discussed.