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Potts L.F.,Emory University | Uthayathas S.,Emory University | Greven A.C.M.,Emory University | Dyavarshetty B.,Emory University | And 2 more authors.
Behavioural Pharmacology | Year: 2015

The aim of this study was to develop a quantitative scale to assess levodopa-induced dyskinesias (LIDs) in nonhuman primates using a video-based scoring system [Quantitative Dyskinesia Scale (QDS)]. Six macaques with stable Parkinsonism and LID were used for tests of the new QDS, in comparison with our current standardized scale (Drug-Related Side effects), which provides a classic subjective measurement of dyskinesia. QDS scoring is based on systematic movement counts in time frames, using videotape recordings. For both scales, body segments scored included each extremity, the trunk, the neck, and the face, and raters were blinded to L-dopa treatments. Comparison of the two scales revealed that their scores are highly correlated with and are parallel to the L-dopa pharmacokinetic profile, although the QDS provided significantly more quantifiable measurements. This remained the case after separating animals into groups of mild and severe dyskinesias. Inter-rater reliability for application of the QDS was confirmed from scores obtained by three examiners. We conclude that the QDS is a quantitative tool for reliably scoring LID in parkinsonian monkeys at all levels of severity of dyskinesia. The application of this new standard for scoring LID in primates will allow for more precise measurements of the effects of experimental treatments and will improve the quality of results obtained in translational studies. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Braithwaite S.P.,Signum Biosciences | Voronkov M.,Signum Biosciences | Stock J.B.,Signum Biosciences | Stock J.B.,Princeton University | Mouradian M.M.,Center for Neurodegenerative and Neuroimmunologic Diseases
Neurochemistry International | Year: 2012

Phosphorylation is a key post-translational modification for cellular signaling, and abnormalities in this process are observed in several neurodegenerative disorders. Among these disorders, Parkinson's disease (PD) is particularly intriguing as there are both genetic causes of disease that involve phosphorylation, and pathological hallmarks of disease composed of a hyperphosphorylated protein. Two of the major genes linked to PD are themselves kinases - leucine rich repeat kinase 2 (LRRK2) and phosphatase and tensin induced homolog kinase 1 (PINK1). Mutations in LRRK2 lead to its increased kinase activity and dominantly inherited PD, while mutations in PINK1 lead to loss of function and recessive PD. A third genetic linkage to disease is α-synuclein, a protein that is heavily phosphorylated in Lewy bodies and Lewy neurites, the pathological hallmarks of PD. The phosphorylation of α-synuclein at various residues influences its aggregation, either positively or negatively, thereby impacting its central role in disease pathogenesis. Given these associations of phosphorylation with PD, modulation of this modification is an attractive therapeutic strategy. The kinases that act in these disease relevant pathways have been the primary target for such approaches. But, the development of kinase inhibitors has been complicated by the necessary specificity to retain safety, the redundancy of kinases leading to lack of efficacy, and the difficulties in overcoming the blood-brain barrier. The field of modulating phosphatases has the potential to overcome some of these issues and provide the next generation of therapeutic targets for PD. In this review, we address the phosphorylation pathways involved in PD, the kinases and issues related to their inhibition, and the evolving field of the phosphatases relevant in PD and how they may be targeted pharmacologically. © 2011 Elsevier Ltd. All rights reserved. Source

Wider C.,University of Lausanne | Mouradian M.M.,Center for Neurodegenerative and Neuroimmunologic Diseases
Neurology | Year: 2015

Parkinson disease (PD) and other Lewy body disorders are common neurodegenerative conditions manifesting with progressive motor and nonmotor symptoms. Although their pathogenesis remains to be fully elucidated, a number of genetic findings have helped better understand the molecular mechanisms involved.1 Mutations in genes causing PD that are inherited in a Mendelian fashion as well as genetic variants that modify disease risk have been identified, some overlapping with those involved in other Lewy body disorders. Recently, mutations in a gene named coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) were found in Japanese patients from families with autosomal dominantly inherited PD.2 Moreover, a patient-control analysis suggested that variants in CHCHD2 associate with increased risk for sporadic, late-onset PD.2 These findings have raised strong interest given that (1) the CHCHD2 protein is localized in mitochondria and (2) mitochondrial dysfunction plays an important role in PD, particularly early-onset PD due to mutations in PINK1 and PARKIN.3 © 2015 American Academy of Neurology. Source

Potts L.F.,Emory University | Potts L.F.,University of Kentucky | Park E.S.,Center for Neurodegenerative and Neuroimmunologic Diseases | Woo J.-M.,Center for Neurodegenerative and Neuroimmunologic Diseases | And 8 more authors.
Annals of Neurology | Year: 2015

Objective Effective medical management of levodopa-induced dyskinesia (LID) remains an unmet need for patients with Parkinson disease (PD). Changes in opioid transmission in the basal ganglia associated with LID suggest a therapeutic opportunity. Here we determined the impact of modulating both mu and kappa opioid receptor signaling using the mixed agonist/antagonist analgesic nalbuphine in reducing LID and its molecular markers in the nonhuman primate model. Methods 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques with advanced parkinsonism and reproducible LID received a range of nalbuphine doses or saline subcutaneously as: (1) monotherapy, (2) acute coadministration with levodopa, and (3) chronic coadministration for 1 month. Animals were assessed by blinded examiners for motor disability and LID severity using standardized rating scales. Plasma levodopa levels were determined with and without nalbuphine, and postmortem brain samples were subjected to Western blot analyses. Results Nalbuphine reduced LID in a dose-dependent manner by 48% (p < 0.001) without compromising the anti-PD effect of levodopa or changing plasma levodopa levels. There was no tolerance to the anti-LID effect of nalbuphine given chronically. Nalbuphine coadministered with levodopa was well tolerated and did not cause sedation. Nalbuphine monotherapy had no effect on motor disability. Striatal tissue analyses showed that nalbuphine cotherapy blocks several molecular correlates of LID, including overexpression of ΔFosB, prodynorphin, dynorphin A, cyclin-dependent kinase 5, and increased phosphorylation of DARPP-32 at threonine-34. Interpretation Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti-LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID. Ann Neurol 2015;77:930-941 © 2015 American Neurological Association. Source

Grosso H.,Center for Neurodegenerative and Neuroimmunologic Diseases | Mouradian M.M.,Center for Neurodegenerative and Neuroimmunologic Diseases
Pharmacology and Therapeutics | Year: 2012

Neurodegenerative disorders are characterized by progressive neuronal loss and the aggregation of disease-specific pathogenic proteins in hallmark neuropathologic lesions. Many of these proteins, including amyloid Αβ, tau, α-synuclein and huntingtin, are cross-linked by the enzymatic activity of transglutaminase 2 (TG2). Additionally, the expression and activity of TG2 is increased in affected brain regions in these disorders. These observations along with experimental evidence in cellular and mouse models suggest that TG2 can contribute to the abnormal aggregation of disease causing proteins and consequently to neuronal damage. This accumulating evidence has provided the impetus to develop inhibitors of TG2 as possible neuroprotective agents. However, TG2 has other enzymatic activities in addition to its cross-linking function and can modulate multiple cellular processes including apoptosis, autophagy, energy production, synaptic function, signal transduction and transcription regulation. These diverse properties must be taken into consideration in designing TG2 inhibitors. In this review, we discuss the biochemistry of TG2, its various physiologic functions and our current understanding about its role in degenerative diseases of the brain. We also describe the different approaches to designing TG2 inhibitors that could be developed as potential disease-modifying therapies. © 2012 Elsevier Inc. All rights reserved. Source

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