scholarly journals Vector-mediated l-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease

Brain ◽  
2019 ◽  
Vol 142 (8) ◽  
pp. 2402-2416 ◽  
Author(s):  
Carl Rosenblad ◽  
Qin Li ◽  
Elsa Y. Pioli ◽  
Sandra Dovero ◽  
André SLM Antunes ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Tyrosine Hydroxylase ◽  
Oral Delivery ◽  
Viral Vector ◽  
Optimal Dose ◽  
Motor Fluctuations ◽  
Motor Impairments ◽  
Primate Model

Abstract Ever since its introduction 40 years ago l-3,4-dihydroxyphenylalanine (l-DOPA) therapy has retained its role as the leading standard medication for patients with Parkinson’s disease. With time, however, the shortcomings of oral l-DOPA treatment have become apparent, particularly the motor fluctuations and troublesome dyskinetic side effects. These side effects, which are caused by the excessive swings in striatal dopamine caused by intermittent oral delivery, can be avoided by delivering l-DOPA in a more continuous manner. Local gene delivery of the l-DOPA synthesizing enzymes, tyrosine hydroxylase and guanosine-tri-phosphate-cyclohydrolase-1, offers a new approach to a more refined dopaminergic therapy where l-DOPA is delivered continuously at the site where it is needed i.e. the striatum. In this study we have explored the therapeutic efficacy of adeno-associated viral vector-mediated l-DOPA delivery to the putamen in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys, the standard non-human primate model of Parkinson’s disease. Viral vector delivery of the two enzymes, tyrosine hydroxylase and guanosine-5’-tri-phosphate-cyclohydrolase-1, bilaterally into the dopamine-depleted putamen, induced a significant, dose-dependent improvement of motor behaviour up to a level identical to that obtained with the optimal dose of peripheral l-DOPA. Importantly, this improvement in motor function was obtained without any adverse dyskinetic effects. These results provide proof-of-principle for continuous vector-mediated l-DOPA synthesis as a novel therapeutic strategy for Parkinson’s disease. The constant, local supply of l-DOPA obtained with this approach holds promise as an efficient one-time treatment that can provide long-lasting clinical improvement and at the same time prevent the appearance of motor fluctuations and dyskinetic side effects associated with standard oral dopaminergic medication.

Dissociation of hemi-spatial and hemi-motor impairments in a unilateral primate model of Parkinson’s disease

2004 ◽  
Vol 150 (1-2) ◽  
pp. 55-63 ◽  
Author(s):  
A.L. Milton ◽  
J.W.B. Marshall ◽  
R.M. Cummings ◽  
H.F. Baker ◽  
R.M. Ridley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Motor Impairments ◽  
Primate Model

A Potential Compensatory Role for Endogenous Striatal Tyrosine Hydroxylase-Positive Neurons in a Nonhuman Primate Model of Parkinson's Disease

2015 ◽  
Vol 24 (4) ◽  
pp. 673-680 ◽  
Author(s):  
Andrew N. Bubak ◽  
D. Eugene Redmond ◽  
John D. Elsworth ◽  
Robert H. Roth ◽  
Timothy J. Collier ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Tyrosine Hydroxylase ◽  
Nonhuman Primate ◽  
Nonhuman Primate Model ◽  
Primate Model

scholarly journals Implication of the Subthalamic Nucleus in the Pathophysiology and Pathogenesis of Parkinson's Disease

2000 ◽  
Vol 9 (2) ◽  
pp. 215-221 ◽  
Author(s):  
A. Benazzouz ◽  
B. Piallat ◽  
Z. G. Ni ◽  
A. Koudsie ◽  
P. Pollak ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Subthalamic Nucleus ◽  
Functional Organization ◽  
Critical Role ◽  
High Frequency Stimulation ◽  
Motor Symptoms ◽  
Primate Model ◽  
Abnormal Movements

The subthalamic nucleus (STN) has been shown to play an important role in the control of movement and has been considered as a key structure in the functional organization of the basal ganglia. Several studies postulated that the STN plays a critical role in the pathophysiology of Parkinson's disease and that its inhibition or its lesioning can reverse the cardinal motor symptoms. Nevertheless, the beneficial effect was accompanied by dyskinetic abnormal movements. In order to avoid unpleasant and irreversible side effects we used high-frequency stimulation (HFS) of the STN instead of lesions. We have shown that parkinsonian motor symptoms, akinesia, rigidity, and tremor can be alleviated by HFS of the STN in the nonhuman primate model. Side effects were controllable and appeared only at intensities higher than that inducing the improvement of motor symptoms. In severe parkinsonian patients, bilateral STN-HFS greatly improved parkinsonian motor symptoms. Motor fluctuations were attenuated and patients became independent in most activities of daily living. It appears that STN-HFS mimics the effects of lesions by inhibiting its neuronal activity. In a rat model of parkinsonism, we studied the implication of the STN in the excitotoxicity of nigral dopamine cells. We showed that kainic acid lesioning of the STN can protect nigral dopaminergic cells against 6-hydroxydopamine-induced toxicity. The evidence reviewed in the present article clearly demonstrates that the STN is implicated in the pathophysiology and pathogenesis of Parkinson's disease.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Neural Cells ◽  
Blood Brain ◽  
The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

scholarly journals Limb and trunk accelerometer data collected with wearable sensors from subjects with Parkinson’s disease

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Gloria Vergara-Diaz ◽  
Jean-Francois Daneault ◽  
Federico Parisi ◽  
Chen Admati ◽  
Christina Alfonso ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Symptom Severity ◽  
Wearable Sensors ◽  
Motor Fluctuations ◽  
Sensor Data ◽  
Accelerometer Data ◽  
Motor Tasks ◽  
Specific Symptom ◽  
At Home

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Dyskinesia and motor fluctuations are complications of PD medications. An objective measure of on/off time with/without dyskinesia has been sought for some time because it would facilitate the titration of medications. The objective of the dataset herein presented is to assess if wearable sensor data can be used to generate accurate estimates of limb-specific symptom severity. Nineteen subjects with PD experiencing motor fluctuations were asked to wear a total of five wearable sensors on both forearms and shanks, as well as on the lower back. Accelerometer data was collected for four days, including two laboratory visits lasting 3 to 4 hours each while the remainder of the time was spent at home and in the community. During the laboratory visits, subjects performed a battery of motor tasks while clinicians rated limb-specific symptom severity. At home, subjects were instructed to use a smartphone app that guided the periodic performance of a set of motor tasks.

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