scholarly journals Targeting β-arrestin2 in the treatment of l-DOPA–induced dyskinesia in Parkinson’s disease

2015 ◽  
Vol 112 (19) ◽  
pp. E2517-E2526 ◽  
Author(s):  
Nikhil M. Urs ◽  
Simone Bido ◽  
Sean M. Peterson ◽  
Tanya L. Daigle ◽  
Caroline E. Bass ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
G Protein ◽  
Pharmacological Intervention ◽  
Protein Signaling ◽  
Da Receptors ◽  
Conventional Animal ◽  
Locomotor Deficits ◽  
6 Hydroxydopamine

Parkinson’s disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursorl-3,4-dihydroxyphenylalanine (l-DOPA), but its prolonged use causes dyskinesias referred to asl-DOPA–induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G protein-mediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PDl-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson’s symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronicl-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine–treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect ofl-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.

scholarly journals Therapeutic Effects of Hydrogen in Animal Models of Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Kyota Fujita ◽  
Yusaku Nakabeppu ◽  
Mami Noda
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Animal Studies ◽  
Clinical Symptoms ◽  
Therapeutic Effects ◽  
Therapeutic Approaches ◽  
Cellular Apoptosis ◽  
6 Hydroxydopamine

Since the first description of Parkinson's disease (PD) nearly two centuries ago, a number of studies have revealed the clinical symptoms, pathology, and therapeutic approaches to overcome this intractable neurodegenerative disease. 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are neurotoxins which produce Parkinsonian pathology. From the animal studies using these neurotoxins, it has become well established that oxidative stress is a primary cause of, and essential for, cellular apoptosis in dopaminergic neurons. Here, we describe the mechanism whereby oxidative stress evokes irreversible cell death, and propose a novel therapeutic strategy for PD using molecular hydrogen. Hydrogen has an ability to reduce oxidative damage and ameliorate the loss of nigrostriatal dopaminergic neuronal pathway in two experimental animal models. Thus, it is strongly suggested that hydrogen might provide a great advantage to prevent or minimize the onset and progression of PD.

scholarly journals Classic and New Animal Models of Parkinson's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Javier Blesa ◽  
Sudarshan Phani ◽  
Vernice Jackson-Lewis ◽  
Serge Przedborski
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Molecular Mechanisms ◽  
Behavioral Outcomes ◽  
Disease Process ◽  
Alpha Synuclein ◽  
Cellular Models ◽  
6 Hydroxydopamine ◽  
Almost All

Neurological disorders can be modeled in animals so as to recreate specific pathogenic events and behavioral outcomes. Parkinson’s Disease (PD) is the second most common neurodegenerative disease of an aging population, and although there have been several significant findings about the PD disease process, much of this process still remains a mystery. Breakthroughs in the last two decades using animal models have offered insights into the understanding of the PD disease process, its etiology, pathology, and molecular mechanisms. Furthermore, while cellular models have helped to identify specific events, animal models, both toxic and genetic, have replicated almost all of the hallmarks of PD and are useful for testing new neuroprotective or neurorestorative strategies. Moreover, significant advances in the modeling of additional PD features have come to light in both classic and newer models. In this review, we try to provide an updated summary of the main characteristics of these models as well as the strengths and weaknesses of what we believe to be the most popular PD animal models. These models include those produced by 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydropiridine (MPTP), rotenone, and paraquat, as well as several genetic models like those related to alpha-synuclein, PINK1, Parkin and LRRK2 alterations.

scholarly journals Peripheral Inflammation Increases the Damage in Animal Models of Nigrostriatal Dopaminergic Neurodegeneration: Possible Implication in Parkinson's Disease Incidence

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
A. Machado ◽  
A. J. Herrera ◽  
J. L. Venero ◽  
M. Santiago ◽  
R. M. De Pablos ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Substantia Nigra ◽  
Dopaminergic System ◽  
Disease Incidence ◽  
Epidemiological Studies ◽  
Peripheral Inflammation ◽  
Dopaminergic Neurodegeneration ◽  
6 Hydroxydopamine

Inflammatory processes described in Parkinson’s disease (PD) and its animal models appear to be important in the progression of the pathogenesis, or even a triggering factor. Here we review that peripheral inflammation enhances the degeneration of the nigrostriatal dopaminergic system induced by different insults; different peripheral inflammations have been used, such as IL-1β and the ulcerative colitis model, as well as insults to the dopaminergic system such as 6-hydroxydopamine or lipopolysaccharide. In all cases, an increased loss of dopaminergic neurons was described; inflammation in the substantia nigra increased, displaying a great activation of microglia along with an increase in the production of cytokines such as IL-1β and TNF-α. Increased permeability or disruption of the BBB, with overexpression of the ICAM-1 adhesion molecule and infiltration of circulating monocytes into the substantia nigra, is also involved, since the depletion of circulating monocytes prevents the effects of peripheral inflammation. Data are reviewed in relation to epidemiological studies of PD.

scholarly journals G-protein coupled receptor 88knock-down in the associative striatum reduces the psychiatric symptoms in a translational model of Parkinson’s disease

2019 ◽  
Author(s):  
Benjamin Galet ◽  
Manuela Ingallinesi ◽  
Jonathan Pegon ◽  
Anh Do Thi ◽  
Philippe Ravassard ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
G Protein ◽  
Rat Model ◽  
Psychiatric Symptoms ◽  
Symptomatic Relief ◽  
Protein Signaling ◽  
G Protein Coupled Receptor ◽  
Motor Disability ◽  
G Protein Coupled

ABSTRACTBeyond the motor disability, Parkinson’s disease (PD) is also characterized by an early appearance of psychiatric symptoms such as apathy, depression, anxiety and cognitive deficits, which can entail dementia and psychosis in later stages. While current treatments may provide some level of symptomatic relief, their use is limited by the development of adverse effects such as impulse-control disorders. There is thus a medical need for targets with novel modes of action to treat these aspects of PD. In this context, we investigated GPR88, an orphan G-protein coupled receptor that is associated with psychiatric disorders and highly enriched in the striatum, where it exerts an inhibitory control over neurotransmitter systems that are compromised in PD. To evaluate the potential of GPR88 as a target for the treatment of the psychiatric symptoms of PD, we knocked-down (KD) its expression in sensorimotor (dorsolateral, DLS) or associative (dorsomedial, DMS) striatal areas in a translational rat model of early PD. Our findings indicate thatGpr88-KD in the DMS, but not DLS, reduced the alterations in mood, motivation and cognition that characterized the model, through modulation of the expression ofregulator of G-protein signaling 4(Rgs4) and of transcription factor ΔFosB. Furthermore, the rat model of PD exhibited allostatic changes in striatal activity markers that may be related to patterns observed in patients, and which were reduced byGpr88-KD. Taken together, these results thus highlight the relevance of GPR88 as a therapeutic target for the psychiatric symptoms of PD.

Progressive Dopamine Neuron Loss in Parkinson's Disease: The Multiple Hit Hypothesis

2006 ◽  
Vol 15 (3) ◽  
pp. 239-250 ◽  
Author(s):  
Paul M. Carvey ◽  
Ashok Punati ◽  
Mary B. Newman
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Animal Models ◽  
Postnatal Exposure ◽  
New Era ◽  
Progressive Loss ◽  
History Of ◽  
6 Hydroxydopamine ◽  
Multiple Hit

Animal models have been an essential tool for researchers and clinicians in their efforts to study and treat Parkinson's disease (PD). Thus, the various ways 6-hydroxydopamine is employed, the use of MPTP in rodents and nonhuman primates, the prenatal exposure to bacterial endotoxin, the postnatal exposure to environmental toxins such as paraquat and rotenone, the assessment of dopamine (DA) neurons in genetic knockout mouse, and even the behavioral analysis of fruit flies and worms have added significantly to our knowledge base of PD—or have they? Are these animal models manifesting a true model of PD? Have the 7786 published studies (to date) on PD with animal models led to a clearer understanding of its etiology, treatment, or progression? In this review we critically assess this question. We begin with a succinct history of the major contributions, which have led to the current animal models of PD. We then evaluate the primary issue of the progressive loss of DA neurons, which, except for a few studies, has not been addressed in animal models of PD, even though this is the major pathological characteristic of the disease. Lastly, we discuss the possibility that more than one risk factor for PD may be necessary to develop an animal model that shows synergy—the progressive loss of DA neurons. Thus, the multiple hit hypothesis of PD—that is, the effect of more then one risk factor—may be the start of new era in animal models of PD that is one step closer to mimicking the pathology of PD in humans.

scholarly journals KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease

2020 ◽  
Author(s):  
Min-Ho Nam ◽  
Jong-Hyun Park ◽  
Hyo Jung Song ◽  
Ji Won Choi ◽  
Siwon Kim ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Therapeutic Effect ◽  
Therapeutic Potential ◽  
Alpha Synuclein ◽  
Post Treatment ◽  
Motor Deficit ◽  
Mao B ◽  
6 Hydroxydopamine

AbstractBackground and PurposeMonoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinson’s disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD.Experimental ApproachWe designed and synthesized α-aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates.Key ResultsKDS2010 showed the highest potency, specificity, and reversibility among the α-aminoamide derivatives, with high bioavailability (>100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates.Conclusion and ImplicationsKDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD.Representative SchematicWhat is already knownKDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor.MAO-B is critical for PD pathology through astrocytic GABA and H2O2 synthesis.What this study addsKDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD.KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates.What is the clinical significance?KDS2010 is a safe and promising therapeutic candidate for Parkinson’s disease.Reversible MAO-B inhibitors could be more effective for treatment of Parkinson’s disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.

scholarly journals Cardiac and Autonomic Dysfunctions Assessed Through Recurrence Quantitative Analysis of Electrocardiogram Signals and an Application to the 6-Hydroxydopamine Parkinson’s Disease Animal Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Lucas Shinoda ◽  
Laís Damasceno ◽  
Leandro Freitas ◽  
Ruy Campos ◽  
Sergio Cravo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Heart Rate ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Animal Models ◽  
Ecg Signals ◽  
Electrocardiogram Signals ◽  
Long Time ◽  
Quantification Analysis ◽  
6 Hydroxydopamine

A classic method to evaluate autonomic dysfunction is through the evaluation of heart rate variability (HRV). HRV provides a series of coefficients, such as Standard Deviation of n-n intervals (SDNN) and Root Mean Square of Successive Differences (RMSSD), which have well-established physiological associations. However, using only electrocardiogram (ECG) signals, it is difficult to identify proper autonomic activity, and the standard techniques are not sensitive and robust enough to distinguish pure autonomic modulation in heart dynamics from cardiac dysfunctions. In this proof-of-concept study we propose the use of Poincaré mapping and Recurrence Quantification Analysis (RQA) to identify and characterize stochasticity and chaoticity dynamics in ECG recordings. By applying these non-linear techniques in the ECG signals recorded from a set of Parkinson’s disease (PD) animal model 6-hydroxydopamine (6-OHDA), we showed that they present less variability in long time epochs and more stochasticity in short-time epochs, in their autonomic dynamics, when compared with those of the sham group. These results suggest that PD animal models present more “rigid heart rate” associated with “trembling ECG” and bradycardia, which are direct expressions of Parkinsonian symptoms. We also compared the RQA factors calculated from the ECG of animal models using four computational ECG signals under different noise and autonomic modulatory conditions, emulating the main ECG features of atrial fibrillation and QT-long syndrome.

scholarly journals Potential of animal models for advancing the understanding and treatment of pain in Parkinson’s disease

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Yazead Buhidma ◽  
Katarina Rukavina ◽  
Kallol Ray Chaudhuri ◽  
Susan Duty
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Predictive Validity ◽  
Molecular Mechanisms ◽  
Face Validity ◽  
Motor Symptom ◽  
Preclinical Models ◽  
Underlying Mechanisms ◽  
6 Hydroxydopamine

AbstractPain is a commonly occurring non-motor symptom of Parkinson’s disease (PD). Treatment of pain in PD remains less than optimal and a better understanding of the underlying mechanisms would facilitate discovery of improved analgesics. Animal models of PD have already proven helpful for furthering the understanding and treatment of motor symptoms of PD, but could these models offer insight into pain in PD? This review addresses the current position regarding pain in preclinical models of PD, covering the face and predictive validity of existing models and their use so far in advancing understanding of the mechanisms contributing to pain in PD. While pain itself is not usually measured in animals, nociception in the form of thermal, mechanical or chemical nociceptive thresholds offers a useful readout, given reduced nociceptive thresholds are commonly seen in PD patients. Animal models of PD including the reserpine-treated rat and neurodegenerative models such as the MPTP-treated mouse and 6-hydroxydopamine (6-OHDA)-treated rat each exhibit reduced nociceptive thresholds, supporting face validity of these models. Furthermore, some interventions known clinically to relieve pain in PD, such as dopaminergic therapies and deep brain stimulation of the subthalamic nucleus, restore nociceptive thresholds in one or more models, supporting their predictive validity. Mechanistic insight gained already includes involvement of central and spinal dopamine and opioid systems. Moving forward, these preclinical models should advance understanding of the cellular and molecular mechanisms underlying pain in PD and provide test beds for examining the efficacy of novel analgesics to better treat this debilitating non-motor symptom.

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