Parkinson Drug Research Articles

An expert opinion on safinamide in Parkinson's disease

Background: Dopamine replacement therapies (levodopa, dopamine receptor agonists, anticholinergics, monoamine oxidase B inhibitors, and catechol-O-methyltransferase inhibitors) remain the cornerstones of therapeutic interventions for Parkinson's disease (PD). Despite the treatment options for PD symptoms, a cure remains elusive. An optimal treatment would be one that combined relief in both motor and nonmotor symptoms with neuroprotective properties. Safinamide is an investigational drug for PD currently in development as add-on therapy to both dopamine agonists and levodopa. Safinamide is a unique molecule with a novel mode of action, targeting both dopaminergic and glutaminergic systems, and potentially provides motor symptom control. Preliminary results from experimental models suggest potential neuroprotective effects. Studies on the potential effects on nonmotor symptoms are ongoing. Objective: To review the mechanism of action and pharmacokinetics, and to evaluate the available clinical safety and efficacy results of safinamide. Methods: A search of the electronic database MEDLINE (PubMed, no time limits) was performed on 14 December 2007. The full text of all citations was obtained for review. Furthermore, two abstracts on safinamide published as proceedings of a European conference were reviewed. Results/conclusion: Safinamide is a promising investigational drug for PD with a novel mode of action. Early reports confirm the potential efficacy of safinamide in PD. Further studies on potential effects on cognition and neuroprotection are needed.

Differences in reserpine-induced striatal dopamine output and content between female and male mice: Implications for sex differences in vesicular monoamine transporter 2 function

In this report a series of six in vitro experiments in which reserpine-evoked dopamine output and two in vivo experiments in which the effects of reserpine injections upon dopamine content from striatal tissue of female and male mice were performed as a means to assess possible sex differences in vesicular monoamine transporter 2 (VMAT2) function. Significantly greater amounts of dopamine were obtained from striatal tissue of female mice in response to either a brief (experiment 1) or continuous (experiment 2) infusion of reserpine. Similarly, reserpine-evoked dopamine output from striatal tissue of gonadectomized females was significantly greater that that of gonadectomized males (experiment 3). When reserpine-evoked dopamine responses were compared directly between intact versus gonadectomized females (experiment 4) or males (experiment 5) no statistically significant differences were obtained. Finally, comparisons of gonadectomized females treated or not with estrogen revealed no statistically significant differences in reserpine-evoked dopamine output (experiment 6). Injections of reserpine produced significantly greater depletions of striatal dopamine content within intact female versus male mice (experiment 7). Dopamine contents of gonadectomized females treated or not with estrogen did not differ following treatment with reserpine, but were significantly greater than that of gonadectomized males (experiment 8). Taken together, these results show that female striatal tissue is more responsive to reserpine-evoked dopamine output, and this sex difference appears to be estrogen independent. Similarly, the dopamine depleting effects of reserpine are greater in intact female mice, however, gonadectomy reverses this effect in an estrogen independent manner. The data suggest that female mice may have a greater amount/activity of VMAT2 function as revealed by the increased responsiveness to the VMAT2 blocking drug, reserpine. Such differences in VMAT2 function may be related to the gender differences observed in conditions like Parkinson's disease and drug addiction.

Noninvasive Measurement of Protein Aggregation by Mutant Huntingtin Fragments or α-Synuclein in the Lens

Many diverse human diseases are associated with protein aggregation in ordered fibrillar structures called amyloid. Amyloid formation may mediate aberrant protein interactions that culminate in neurodegeneration in Alzheimer, Huntington, and Parkinson diseases and in prion encephalopathies. Studies of protein aggregation in the brain are hampered by limitations in imaging techniques and often require invasive methods that can only be performed postmortem. Here we describe transgenic mice in which aggregation-prone proteins that cause Huntington and Parkinson disease are expressed in the ocular lens. Expression of a mutant huntingtin fragment or alpha-synuclein in the lens leads to protein aggregation and cataract formation, which can be monitored in real time by noninvasive, highly sensitive optical techniques. Expression of a mutant huntingtin fragment in mice lacking the major lens chaperone, alphaB-crystallin, markedly accelerated the onset and severity of aggregation, demonstrating that the endogenous chaperone activity of alphaB-crystallin suppresses aggregation in vivo. These novel mouse models will facilitate the characterization of protein aggregation in vivo and are being used in efficient and economical screens for chemical and genetic modifiers of disease-relevant protein aggregation.

Modulation of of l‐Aromatic Amino Acid Decarboxylase by 3, 4‐dihydroxyphenylalanine in the MPTP mouse model.

Parkinson's disease (PD) is a neurological disorder resulting from a deficiency of dopamine (DA) in the neostriatum due to degeneration of dopaminergic neurons in the substantia nigra. The major therapeutic drug for PD is L‐3,4‐dihydroxyphenylalanine (L‐DOPA), which is the precursor of DA. However, long‐term treatment of L‐DOPA induces side effects including dyskinesias, wearing‐off and on‐off phenomenon. Previous studies in our lab led to investigation of the metabolic events of L‐DOPA treatment, including the role of L‐dopa on L‐aromatic amino acid decarboxylase (LAAD), the enzyme that catalyzes the formation of DA from L‐DOPA. In this project we prepare 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) PD disease mouse model and treat them with L‐dopa at 100 mg/kg. We studied the locomotor activity of the mice and performed Western blot assay for LAAD. The results showed that the sub‐chronic administration of L‐DOPA decreased LAAD expression in the striatum of the MPTP‐PD mouse model, but increased it in the cortex. L‐DOPA generates high amounts of DA, therefore, the data suggest that DA causes a feedback or allosteric downregulation of striatal LAAD. This down‐regulation of LAAD may contribute to the wearing‐off phenomenon and may show that the key side effects of L‐dopa may be due to the disturbance of the homeostasis of the catecholamine enzymes by the overload of L‐DOPA.

Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP

The development of selective type 5 metabotropic glutamate receptor (mGlu5) antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), has revealed an important role for these receptors in various disorders of the nervous system including depression, anxiety, epilepsy, Parkinson's disease, drug addiction, and alcoholism. In this study, we used microarray technology to examine changes in gene expression induced by repeated administration of the mGlu5 antagonists MPEP and MTEP. Male Wistar rats (n=5 per treatment group) were administered MPEP (10 mg/kg), MTEP (10 mg/kg) or vehicle intraperitoneally twice daily for 5 days. Approximately 30 min following the final drug administration, rats were sacrificed and frontal cortices were then dissected and examined for changes in gene expression by cDNA microarray analysis. Changes in gene expression with p-values less than 0.01 were considered to be statistically significant. The expression of 63 genes was changed by both MPEP and MTEP, with 58 genes down-regulated and 5 genes up-regulated. Quantitative PCR verified the magnitude and direction of change in expression of 9 of these genes (r2=0.556, p=0.017). Pathway analysis revealed that many of the biological processes altered by repeated MPEP and MTEP treatment were related to ATP synthesis, hydrolase activity, and signaling pathways associated with mitogen-activated protein kinase (MAPK). Our results demonstrate diverse effects of MPEP and MTEP gene expression in the frontal cortex, and these results may help elucidate the mechanisms by which these compounds produce beneficial effects in animal models of various disorders of the central nervous system.

Novel computational models for predicting dopamine interactions

Dopamine is a crucial neurotransmitter responsible for functioning and maintenance of the nervous system. Dopamine has also been implicated in a number of diseases including schizophrenia, Parkinson's disease and drug addiction. Dopamine agonists are used in early Parkinson's disease treatment. Dopamine antagonists suppress schizophrenia. Therefore, molecules modulating dopamine receptors activity are vastly important for understanding the nervous system functioning and for the treatment of neurological diseases. In this study we describe novel computational models that efficiently predict binding affinity of the existing small molecule dopamine analogs to dopamine receptor. The model provides the set of molecular descriptors that can be used for the development of new small molecule dopamine agonists.

Neuroprotective effects of atypical D1 receptor agonist SKF83959 are mediated via D1 receptor‐dependent inhibition of glycogen synthase kinase‐3β and a receptor‐independent anti‐oxidative action

3-methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959), a selective agonist for the putative phosphatidylinositol (PI)-linked dopamine receptor (DAR), has been shown to possess potent anti-Parkinson disease effects but produces less dyskinesia and motor fluctuation that are frequently observed in Parkinson disease drug therapies. The present study was designed to detect the neuroprotection of SKF83959 and its potential mechanism for the effect in cultured rat cortical cells. The presence of SKF83959 with a dose range of 0.1-30 micromol/L improved H2O2-reduced cell viability in a dose-dependent manner. The anti-apoptotic action of SKF83959 was partially abolished by pre-application of the D1 antagonist SCH23390 (30 micromol/L) and the PI 3-kinase (PI 3-K) inhibitor LY294002 but not by the MEK1/2 inhibitor PD98059 (30 micromol/L). Moreover, SKF83959 treatment significantly inhibited H2O2-activated glycogen synthase kinase-3beta (GSK-3beta) which was associated with the drug's neuroprotective effect, but this inhibition was attenuated by SCH23390 and a selective PI 3-K inhibitor. Moreover, the application of either SKF83959 or a pharmacological inhibitor of GSK-3beta attenuated the inhibition by H2O2 on the expression of inducible NO synthase and production of NO. This indicates that D1-like receptor, presumably PI-linked D1 receptor, -mediated alteration of PI 3-K/Akt/GSK-3beta pathway is involved in the neuroprotection by SKF83959. In addition, SKF83959 also effectively decreased the level of the lipid peroxidation and increased the activity of GSH-peroxidase altered by H2O2. These results suggest that SKF83959 exerts its neuroprotective effect through both receptor-dependent and independent mechanisms: Inhibition of GSK-3beta and consequently increasing the expression of inducible NO synthase via putative PI-linked DAR; and its anti-oxidative activity which is independent of DAR.

Where do we stand in the treatment of Parkinson's disease?

This article reviews the current situation regarding the treatment of Parkinson's disease (PD). How to apply the various therapeutic options to treat PD appears to be internationally agreed, but the currently available treatment methods are said to be all symptomatic ones. However, some of these may have marginal disease modifying effects. In addition, there are many investigational interventions aiming at modification of the disease processes; some of these interesting strategies are reviewed here. Regarding the currently available drugs, dopamine agonists may delay the loss of dopamine transporters in the striatum and even L-dopa may have some neuroprotective effects. Monoamine oxidase B inhibitors and coenzyme Q 10 may also be disease modifying. Recently, a more systemic approach to finding disease modifying drugs has been initiated in the United States which has revealed that creatine and minocycline might have a small disease modifying effect. Although the disease modifying effect of each drug is small, eventually it may be possible to find more potent drugs for PD using this approach. Another important issue is to exchange specialists'"know-how" on the management of various problems arising from long-term L-dopa treatment such as disabling dyskinesia. Although it has not been proven by controlled clinical trials, giving small amounts of liquid L-dopa in frequent doses may be helpful in reducing the severity of dyskinesia and wearing off phenomenon.

Realistic synaptic inputs applied to coupled oscillator model of the dopamine neuron

Midbrain dopamine neurons are involved in motivation and the control of movement, and have been implicated in various pathologies such as Parkinson's disease, schizophrenia and drug abuse. Dopamine neurons in the presence of their afferent inputs in vivo can exhibit one of several firing modes: silence, regular single-spike firing, irregular single-spike firing, and bursting. Bursts in dopamine neurons are thought to convey the reward prediction and salience signals. Dopamine neurons in a slice preparation fire spontaneously in a regular, pacemaker-like manner at a low frequency (~2–3 Hz). This regular firing appears to be driven by a subthreshold oscillation caused by interaction of a low voltage threshold, noninactivating Ca2+ current and a Ca2+-activated small conductance K+ current. Somatic injection of depolarizing bias current can increase the frequency of sustained firing only up to 10 Hz before the neurons go into depolarization block. Bursts observed in vivo have higher instantaneous frequencies. Two theories have been advanced for how higher frequencies are achieved in vivo. One is that during pacemaking, the natural frequencies of the soma and proximal dendrites drive the subthreshold oscillation, whereas during bursting the NMDA input to the dendrites amplifies the current associated with the distal dendritic oscillation, and drives the soma, resulting in high-frequency spiking. The other hypothesis is that the rapidly varying synaptic input (particularly the AMPA component) is not equivalent to a constant depolarizing pulse but this rapid variation can drive faster spiking that can be observed in response to a constant pulse. We have constructed a realistic multicompartmental model to test the contribution of intrinsic and synaptic currents in the dendrites to the firing pattern. The oscillatory dendrites regularize the firing pattern, decrease the frequency compared to a model in which the subthreshold oscillation is confined to the soma, and contribute to grouping of spikes into bursts.

Parkinson's Drug Permax Removed From Market

Parkinson's Drug Permax Removed From Market

Parkinson's Drug Permax Withdrawn From Market

Parkinson's Drug Permax Withdrawn From Market

Inflammation as a causative factor in the aetiology of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting mainly the elderly, although a small proportion of PD patients develop the illness at a much younger age. In the former group, idiopathic PD patients, the causes of the illness have been the subject of longstanding debate with environmental toxins, mitochondrial dysfunction, abnormal protein handling and oxidative stress being suggested. One problem has been that the epidemiology of PD has offered few clues to provide evidence for a single major causative factor. Comparatively recently it has been found that in both patients and experimental models of PD in animals neuroinflammation appears to be a ubiquitous finding. These cases present with all of the classical features of inflammation including phagocyte activation, increased synthesis and release of proinflammatory cytokines and complement activation. Although this process is vital for normal function and protection in both the CNS, as in the periphery, it is postulated that in the aetiology of PD this process may spiral out of control with over activation of microglia, over production of cytokines and other proinflammatory mediators as well as the release of destructive molecules such as reactive oxygen species. Given that dopaminergic neurons in the substantia nigra are relatively vulnerable to 'stress' and the region has a large population of microglia in comparison to other CNS structures, these events may easily trigger neurodegeneration. These factors are examined in this review along with a consideration of the possible use of anti-inflammatory drugs in PD.

Valvulopathy From Parkinson's Drug Drives It Off the U.S. Market

Valvulopathy From Parkinson's Drug Drives It Off the U.S. Market

Parkinson's Drug Permax Withdrawn From Market

Parkinson's Drug Permax Withdrawn From Market

Accuracy of medicare claims data in identifying Parkinsonism cases: Comparison with the medicare current beneficiary survey

Administrative databases are commonly used to examine use of healthcare service, with researchers relying on diagnostic codes to identify medical conditions. This study evaluates the accuracy of administrative claims in identifying Parkinsonism cases compared to the self-reported Parkinson's disease (PD). The reference cases were identified based on the self-reported PD status and the use of PD drugs collected by the 1992-2000 Medicare Current Beneficiary Survey that contained 72,922 observations from 30,469 individuals. Using ICD-9 CM, cases with PD were extracted from the corresponding Medicare claims. We compared prevalence of PD obtained using different types of claims. The sensitivities were the highest when all claims were used (66%). All the specificities were greater than 99%. When drug use information was included in the gold standard, the sensitivities became lower, while the specificities and positive predictive values (PPVs) increased. Using more diagnostic codes improved the sensitivity of the identification process but reduced PPVs. Administrative claims can provide fairly accurate and practical approach to "rule in" patients with PD. Depending on the purpose of evaluation, researchers may consider using more categories of claims to improve the sensitivity of the identification algorithm or use fewer diagnoses to minimize number of false positive cases.

Fluorescence imaging of amyloid formation in living cells by a functional, tetracysteine-tagged α-synuclein

Alpha-synuclein is a major component of intraneuronal protein aggregates constituting a distinctive feature of Parkinson disease. To date, fluorescence imaging of dynamic processes leading to such amyloid deposits in living cells has not been feasible. To address this need, we generated a recombinant alpha-synuclein (alpha-synuclein-C4) bearing a tetracysteine target for fluorogenic biarsenical compounds. The biophysical, biochemical and aggregation properties of alpha-synuclein-C4 matched those of the wild-type protein in vitro and in living cells. We observed aggregation of alpha-synuclein-C4 transfected or microinjected into cells, particularly under oxidative stress conditions. Fluorescence resonance energy transfer (FRET) between FlAsH and ReAsH confirmed the close association of fibrillized alpha-synuclein-C4 molecules. Alpha-synuclein-C4 offers the means for directly probing amyloid formation and interactions of alpha-synuclein with other proteins in living cells, the response to cellular stress and screening drugs for Parkinson disease.

Two Parkinson's Drugs Linked With Valve Damage

Two Parkinson's Drugs Linked With Valve Damage

Recognition of category-related visual stimuli in Parkinson's disease: Before and after pharmacological treatment

Visual-sensory dysfunctions and semantic processing impairments are widely reported in Parkinson's disease (PD) research. The present study investigated the category-specific deficit in object recognition as a function of both the semantic category and spatial frequency content of stimuli. In the first experiment, the role of dopamine in object-recognition processing was assessed by comparing PD drug naïve (PD-DN), PD receiving levodopa treatment (PD-LD), and control subjects. Experiment 2 consisted of a retest session for PD drug naïve subjects after a period of pharmacological treatment. All participants completed an identification task which displayed animals and tools at nine levels of filtering. Each object was revealed in a sequence of frames whereby the object was presented at increasingly less-filtered images up to a complete version of the image.Results indicate an impaired identification pattern for PD-DN subjects solely for animal category stimuli. This differential pharmacological therapy effect was also confirmed at retest (experiment 2). Thus, our data suggest that dopaminergic loss has a specific role in category-specific impairment. Two possible hypotheses are discussed that may account for the defective recognition of semantically different objects in PD.

Parkinson's Drugs Associated With Valvular Disease

Parkinson's Drugs Associated With Valvular Disease

Gene and protein signatures in sporadic Parkinson's disease and a novel genetic model of PD

High-throughput gene-based platform studies in human post-mortem substantia nigra from sporadic Parkinson's disease (PD) cases have revealed significant dysregulation of genes involved in biological processes linked to previously established neurodegenerative mechanisms both in sporadic and hereditary PD. These include protein aggregation, mitochondrial dysfunction, oxidative stress, cell cycle, vesicle trafficking, synaptic transmission, dopamine metabolism and cell adhesion/cytoskeleton maintenance. These observations have extended our current view on the molecular pathways underlying the etio-pathology of the disease and provided a basis for the development of a novel genetic model of sporadic PD, centered on gradual silencing/over-expression of the candidate genes. The uncovered signatures may serve as future predictive biomarkers for early PD diagnosis, disease progression and drug development.