Revisiting the Medical Management of Parkinson's Disease: Levodopa versus Dopamine Agonist

Zhang, Jinglin; Tan, Louis C.S.

doi:10.2174/1570159x14666151208114634

Cited by 28 publications

(20 citation statements)

References 88 publications

(118 reference statements)

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“…Antioxidant effects, 4) Antiapoptotic effects and 5) Amelioration of STN-mediated excitotoxicity (Grandas 2000;Olanow, Jenner, and Brooks 1998;Schapira 2003;Zhang and Tan 2016). In the present study, we focus on amelioration of STN-mediated excitotoxicity.…”

Section: Dopamine Restoration Therapymentioning

confidence: 95%

A computational model of loss of dopaminergic cells in Parkinson’s disease due to glutamate-induced excitotoxicity

Muddapu

Mandali

Chakravarthy

et al. 2018

Preprint

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Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). A full understanding of the underlying pathogenesis of this cell loss is unavailable, though a number of mechanisms have been indicated in the literature. A couple of these mechanisms, however, show potential for the development of radical and promising PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells by virtue of their excessive energy demands; the other is the excitotoxicity caused by excessive glutamate release onto SNc by an overactive Subthalamic Nucleus (STN). To investigate the latter hypothesis computationally, we developed a spiking neuron network model of the SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in a 'stress' variable; when the stress in a SNc neuron exceeds a stress threshold the neuron dies. The model shows that the interaction between SNc and STN involves a positive feedback due to which, an initial loss of SNc cells that crosses a threshold causes a runaway effect that leads to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned PD mechanisms: metabolic vulnerability and glutamate excitotoxicity. Our simulation results show that the excitotoxic cause of SNc cell loss in PD might be initiated by weak excitotoxicity mediated by energy deficit, followed by strong excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies are simulated in the model to test their efficacy in slowing down or arresting SNc cell loss. Among the current therapeutics,

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Section: Dopamine Restoration Therapymentioning

confidence: 95%

A computational model of loss of dopaminergic cells in Parkinson’s disease due to glutamate-induced excitotoxicity

Muddapu

Mandali

Chakravarthy

et al. 2018

Preprint

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“…Currently, there are only symptomatic treatments for Parkinson's, and no disease-modifying therapies have been described. The most commonly used approaches to treat motor deficiencies are based on pharmacological stimulation of the dopaminergic pathway—e.g., levodopa (L-DOPA, dopamine precursor), dopamine agonists [ 558 ], and nonpharmacological treatments such as deep brain stimulation (DBS) [ 559 ]. However, none of these are capable of delaying or stopping the progression of the disease.…”

Section: Overview and Conclusionmentioning

confidence: 99%

Autophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act

Jiménez-Moreno

Lane

2020

Oxidative Medicine and Cellular Longevity

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated primarily from endogenous biochemical reactions in mitochondria, endoplasmic reticulum (ER), and peroxisomes. Typically, ROS/RNS correlate with oxidative damage and cell death; however, free radicals are also crucial for normal cellular functions, including supporting neuronal homeostasis. ROS/RNS levels influence and are influenced by antioxidant systems, including the catabolic autophagy pathways. Autophagy is an intracellular lysosomal degradation process by which invasive, damaged, or redundant cytoplasmic components, including microorganisms and defunct organelles, are removed to maintain cellular homeostasis. This process is particularly important in neurons that are required to cope with prolonged and sustained operational stress. Consequently, autophagy is a primary line of protection against neurodegenerative diseases. Parkinson’s is caused by the loss of midbrain dopaminergic neurons (mDANs), resulting in progressive disruption of the nigrostriatal pathway, leading to motor, behavioural, and cognitive impairments. Mitochondrial dysfunction, with associated increases in oxidative stress, and declining proteostasis control, are key contributors during mDAN demise in Parkinson’s. In this review, we analyse the crosstalk between autophagy and redoxtasis, including the molecular mechanisms involved and the detrimental effect of an imbalance in the pathogenesis of Parkinson’s.

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“…The vast majority of patients experience motor complications by 15 years of treatment, although they can occur within a year of commencement, impacting quality of life and influencing treatment decisions. Levodopa treatment is often delayed and replaced by less effective, poorly tolerated alternatives, such as dopamine agonists (DA) . It is therefore important to identify those at greater risk of motor complications.…”

mentioning

confidence: 99%

Predictors of motor complications in early Parkinson's disease: A prospective cohort study

et al. 2019

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Objective The objective of this study was to identify clinical predictors of motor complications (dyskinesia and motor fluctuations) of levodopa in a prospectively recruited PD cohort using longitudinal analysis. Methods An inception cohort (Oxford Discovery) of 734 patients was followed to a maximum of 10 years from diagnosis using a discrete‐time survival analysis. A subset analysis was used to validate an online dyskinesia‐risk calculator developed from the results of the Stalevo Reduction in Dyskinesia Evaluation PD trial. Results A total of 186 cases of dyskinesia and 254 cases of motor fluctuations were observed. Dyskinesia incidence increased with time (risk per 100 participants [95% confidence interval] 13 [11–16] <3.5 years, 16 [13–21] 3.5–5.0 years, 19 [14–26] 5–6.5 years, and 23 [16–33] >6.5 years from diagnosis). Motor complication predictors were grouped as medication predictors, disease predictors and patient predictors. Baseline nonmotor feature severity, low mood, anxiety, and age at symptom onset were associated with motor complications among a number of previously identified predictors. Replication of the Stalevo Reduction in Dyskinesia Evaluation PD calculator was reasonable with the area under the curve for dyskinesia risk score as a predictor of dyskinesia being 0.68 (95% confidence interval, 0.55–0.81). Conclusions This study quantifies risk of motor complications, finds consistent predictors, and demonstrates the novel finding that nonmotor features of PD, particularly low mood and anxiety, are significant risk factors for motor complications. Further validation of dyskinesia risk scores are required as well as evidence to determine if the routine use of such scores can be clinically valuable in enhancing patient care and quality of life. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Revisiting the Medical Management of Parkinson's Disease: Levodopa versus Dopamine Agonist

Cited by 28 publications

References 88 publications

A computational model of loss of dopaminergic cells in Parkinson’s disease due to glutamate-induced excitotoxicity

A computational model of loss of dopaminergic cells in Parkinson’s disease due to glutamate-induced excitotoxicity

Autophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act

Predictors of motor complications in early Parkinson's disease: A prospective cohort study

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