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 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 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.

scholarly journals The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses

2021 ◽  
Vol 22 (15) ◽  
pp. 8338
Author(s):  
Asad Jan ◽  
Nádia Pereira Gonçalves ◽  
Christian Bjerggaard Vaegter ◽  
Poul Henning Jensen ◽  
Nelson Ferreira
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Cellular Factors ◽  
Recent Developments ◽  
Novel Targets ◽  
Presynaptic Protein

The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.

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 The Role of NOX4 in Parkinson’s Disease with Dementia

2019 ◽  
Vol 20 (3) ◽  
pp. 696 ◽  
Author(s):  
Dong-Hee Choi ◽  
In-Ae Choi ◽  
Cheol Lee ◽  
Ji Yun ◽  
Jongmin Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Alpha Synuclein ◽  
Cognitive Status ◽  
Dopamine Neurons ◽  
Parkinson’S Disease With Dementia ◽  
6 Hydroxydopamine ◽  
Nigrostriatal Dopamine Neurons

The neuropathology of Parkinson’s disease with dementia (PDD) has been reported to involve heterogeneous and various disease mechanisms. Alpha-synuclein (α-syn) and amyloid beta (Aβ) pathology are associated with the cognitive status of PDD, and NADPH oxidase (NOX) is known to affect a variety of cognitive functions. We investigated the effects of NOX on cognitive impairment and on α-syn and Aβ expression and aggregation in PDD. In the 6-hydroxydopamine (6-OHDA)-injected mouse model, cognitive and motor function, and the levels of α-syn, Aβ, and oligomer A11 after inhibition of NOX4 expression in the hippocampal dentate gyrus (DG) were measured by the Morris water maze, novel object recognition, rotation, and rotarod tests, as well as immunoblotting and immunohistochemistry. After 6-OHDA administration, the death of nigrostriatal dopamine neurons and the expression of α-syn and NOX1 in the substantia nigra were increased, and phosphorylated α-syn, Aβ, oligomer A11, and NOX4 were upregulated in the hippocampus. 6-OHDA dose-dependent cognitive impairment was observed, and the increased cognitive impairment, Aβ expression, and oligomer A11 production in 6-OHDA-treated mice were suppressed by NOX4 knockdown in the hippocampal DG. Our results suggest that increased expression of NOX4 in the hippocampal DG in the 6-OHDA-treated mouse induces Aβ expression and oligomer A11 production, thereby reducing cognitive function.

scholarly journals Cytotoxicity and Mitochondrial Dysregulation Caused by α-Synuclein in Dictyostelium discoideum

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2289 ◽  
Author(s):  
Sanjanie Fernando ◽  
Claire Y. Allan ◽  
Katelyn Mroczek ◽  
Xavier Pearce ◽  
Oana Sanislav ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dictyostelium Discoideum ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Cell Cortex ◽  
Mutant Proteins ◽  
C Terminus

Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum.

scholarly journals Alpha-Synuclein and LRRK2 in Synaptic Autophagy: Linking Early Dysfunction to Late-Stage Pathology in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1115 ◽  
Author(s):  
Giulia Lamonaca ◽  
Mattia Volta
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Late Stage ◽  
Disease Onset ◽  
Disease Process ◽  
Alpha Synuclein ◽  
Synaptic Activity ◽  
Early Event ◽  
Cellular Targets ◽  
Disease Modifying

The lack of effective disease-modifying strategies is the major unmet clinical need in Parkinson’s disease. Several experimental approaches have attempted to validate cellular targets and processes. Of these, autophagy has received considerable attention in the last 20 years due to its involvement in the clearance of pathologic protein aggregates and maintenance of neuronal homeostasis. However, this strategy mainly addresses a very late stage of the disease, when neuropathology and neurodegeneration have likely “tipped over the edge” and disease modification is extremely difficult. Very recently, autophagy has been demonstrated to modulate synaptic activity, a process distinct from its catabolic function. Abnormalities in synaptic transmission are an early event in neurodegeneration with Leucine-Rich Repeat Kinase 2 (LRRK2) and alpha-synuclein strongly implicated. In this review, we analyzed these processes separately and then discussed the unification of these biomolecular fields with the aim of reconstructing a potential “molecular timeline” of disease onset and progression. We postulate that the elucidation of these pathogenic mechanisms will form a critical basis for the design of novel, effective disease-modifying therapies that could be applied early in the disease process.

scholarly journals Progress in the pathogenesis and genetics of Parkinson's disease

2008 ◽  
Vol 363 (1500) ◽  
pp. 2215-2227 ◽  
Author(s):  
Yoshikuni Mizuno ◽  
Nobutaka Hattori ◽  
Shin-ichiro Kubo ◽  
Shigeto Sato ◽  
Kenya Nishioka ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Disease Process ◽  
Ubiquitin Proteasome System ◽  
Neurodegenerative Process ◽  
Molecular Events ◽  
Ubiquitin Proteasome ◽  
Sporadic Parkinson’S Disease ◽  
Synuclein Proteins

Recent progresses in the pathogenesis of sporadic Parkinson's disease (PD) and genetics of familial PD are reviewed. There are common molecular events between sporadic and familial PD, particularly between sporadic PD and PARK1 -linked PD due to α - synuclein ( SNCA ) mutations. In sporadic form, interaction of genetic predisposition and environmental factors is probably a primary event inducing mitochondrial dysfunction and oxidative damage resulting in oligomer and aggregate formations of α-synuclein. In PARK1 -linked PD, mutant α-synuclein proteins initiate the disease process as they have increased tendency for self-aggregation. As highly phosphorylated aggregated proteins are deposited in nigral neurons in PD, dysfunctions of proteolytic systems, i.e. the ubiquitin–proteasome system and autophagy–lysosomal pathway, seem to be contributing to the final neurodegenerative process. Studies on the molecular mechanisms of nigral neuronal death in familial forms of PD will contribute further on the understanding of the pathogenesis of sporadic PD.

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