Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson’s Disease? The Potential Role of Zolpidem in the Treatment of Parkinson’s Disease

At present, patients with advanced Parkinson’s disease (PD) are unsatisfactorily controlled by currently used anti-Parkinsonian dopaminergic drugs. Various studies suggest that therapeutic strategies based on nondopaminergic drugs might be helpful in PD. Zolpidem, an imidazopyridine widely used as sleep inducer, shows high affinity only forGABAAreceptors containing theα-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation ofGABAAreceptors. Various observations, although preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable) effects on motor symptoms even after single doses and may also improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr), it was hypothesized that in PD patients zolpidem may induce throughGABAAreceptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus also), resulting in an increased activity of motor cortical areas (such as supplementary motor area), which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD.

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Potential Role of Caffeine in the Treatment of Parkinson’s Disease

The Open Neurology Journal ◽

10.2174/1874205x01610010042 ◽

2016 ◽

Vol 10 (1) ◽

pp. 42-58 ◽

Cited By ~ 8

Author(s):

Mohsin H.K. Roshan ◽

Amos Tambo ◽

Nikolai P. Pace

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Randomized Clinical Trials ◽

Neurodegenerative Disorder ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Muscle Rigidity ◽

Therapeutic Effects ◽

Motor Symptoms ◽

Wide Range

Parkinson’s disease [PD] is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1% of the population over the age of 55. The underlying neuropathology seen in PD is characterised by progressive loss of dopaminergic neurons in the substantia nigra pars compacta with the presence of Lewy bodies. The Lewy bodies are composed of aggregates of α-synuclein. The motor manifestations of PD include a resting tremor, bradykinesia, and muscle rigidity. Currently there is no cure for PD and motor symptoms are treated with a number of drugs including levodopa [L-dopa]. These drugs do not delay progression of the disease and often provide only temporary relief. Their use is often accompanied by severe adverse effects. Emerging evidence from bothin vivoandin vitrostudies suggests that caffeine may reduce parkinsonian motor symptoms by antagonising the adenosine A2Areceptor, which is predominately expressed in the basal ganglia. It is hypothesised that caffeine may increase the excitatory activity in local areas by inhibiting the astrocytic inflammatory processes but evidence remains inconclusive. In addition, the co-administration of caffeine with currently available PD drugs helps to reduce drug tolerance, suggesting that caffeine may be used as an adjuvant in treating PD. In conclusion, caffeine may have a wide range of therapeutic effects which are yet to be explored, and therefore warrants further investigation in randomized clinical trials.

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Adaptive deep brain stimulation as advanced Parkinson’s disease treatment (ADAPT study): protocol for a pseudo-randomised clinical study

BMJ Open ◽

10.1136/bmjopen-2019-029652 ◽

2019 ◽

Vol 9 (6) ◽

pp. e029652 ◽

Cited By ~ 7

Author(s):

Dan Piña-Fuentes ◽

Martijn Beudel ◽

Simon Little ◽

Peter Brown ◽

D L Marinus Oterdoom ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Deep Brain Stimulation ◽

Clinical Study ◽

Side Effects ◽

Brain Stimulation ◽

Rating Scale ◽

Motor Symptoms ◽

Internal Globus Pallidus ◽

Deep Brain

IntroductionAdaptive deep brain stimulation (aDBS), based on the detection of increased beta oscillations in the subthalamic nucleus (STN), has been assessed in patients with Parkinson’s disease (PD) during the immediate postoperative setting. In these studies, aDBS was shown to be at least as effective as conventional DBS (cDBS), while stimulation time and side effects were reduced. However, the effect of aDBS on motor symptoms and stimulation-induced side effects during the chronically implanted phase (after the stun effect of DBS placement has disappeared) has not yet been determined.Methods and analysisThis protocol describes a single-centre clinical study in which aDBS will be tested in 12 patients with PD undergoing battery replacement, with electrodes implanted in the STN, and as a proof of concept in the internal globus pallidus. Patients included will be allocated in a pseudo-randomised fashion to a three-condition (no stimulation/cDBS/ aDBS), cross-over design. A battery of tests will be conducted and recorded during each condition, which aim to measure the severity of motor symptoms and side effects. These tests include a tablet-based tapping test, a subscale of the Movement Disorder Society-unified Parkinson’s disease rating scale (subMDS-UPDRS), the Speech Intelligibility Test (SIT) and a tablet-based version of the Stroop test. SubMDS-UPDRS and SIT recordings will be blindly assessed by independent raters. Data will be analysed using a linear mixed-effects model.Ethics and disseminationThis protocol was approved by the Ethical Committee of the University Medical Centre Groningen, where the study will be carried out. Data management and compliance to research policies and standards of our centre, including data privacy, storage and veracity, will be controlled by an independent monitor. All the scientific findings derived from this protocol are aimed to be made public through publication of articles in international journals.Trial registration numberNTR 5456; Pre-results.

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The role of nurse specialists in the evaluation of non-motor symptoms within the overall care of patients with Parkinson's disease

Revista Científica de la Sociedad de Enfermería Neurológica (English ed ) ◽

10.1016/j.sedeng.2018.11.001 ◽

2019 ◽

Vol 50 ◽

pp. 2-11

Author(s):

Teresa de Deus Fonticoba ◽

Diego Santos García

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Motor Symptoms ◽

Non Motor Symptoms

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Could Small Heat Shock Protein HSP27 Be a First-Line Target for Preventing Protein Aggregation in Parkinson’s Disease?

International Journal of Molecular Sciences ◽

10.3390/ijms22063038 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3038

Author(s):

Javier Navarro-Zaragoza ◽

Lorena Cuenca-Bermejo ◽

Pilar Almela ◽

María-Luisa Laorden ◽

María-Trinidad Herrero

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nervous System ◽

Heat Shock ◽

Stress Proteins ◽

Small Heat Shock Protein ◽

Substantia Nigra Pars Compacta ◽

Motor Symptoms ◽

Dopaminergic Drugs ◽

Non Motor Symptoms

Small heat shock proteins (HSPs), such as HSP27, are ubiquitously expressed molecular chaperones and are essential for cellular homeostasis. The major functions of HSP27 include chaperoning misfolded or unfolded polypeptides and protecting cells from toxic stress. Dysregulation of stress proteins is associated with many human diseases including neurodegenerative diseases, such as Parkinson’s disease (PD). PD is characterized by the presence of aggregates of α-synuclein in the central and peripheral nervous system, which induces the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and in the autonomic nervous system. Autonomic dysfunction is an important non-motor phenotype of PD, which includes cardiovascular dysregulation, among others. Nowadays, the therapies for PD focus on dopamine (DA) replacement. However, certain non-motor symptoms with a great impact on quality of life do not respond to dopaminergic drugs; therefore, the development and testing of new treatments for non-motor symptoms of PD remain a priority. Since small HSP27 was shown to prevent α-synuclein aggregation and cytotoxicity, this protein might constitute a suitable target to prevent or delay the motor and non-motor symptoms of PD. In the first part of our review, we focus on the cardiovascular dysregulation observed in PD patients. In the second part, we present data on the possible role of HSP27 in preventing the accumulation of amyloid fibrils and aggregated forms of α-synuclein. We also include our own studies, highlighting the possible protective cardiac effects induced by L-DOPA treatment through the enhancement of HSP27 levels and activity.

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Role of neuron specific enolase as a biomarker in Parkinson’s disease

Journal of Neuroscience and Neurological Disorders ◽

10.29328/journal.jnnd.1001052 ◽

2021 ◽

Vol 5 (2) ◽

pp. 061-068

Author(s):

Dutta Rajib

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Neuron Specific Enolase ◽

Alpha Synuclein ◽

Substantia Nigra Pars Compacta ◽

Diagnostic Tools ◽

Clinical Image ◽

Motor Symptoms

Parkinson’s disease (PD) is thought to be the most common neurodegenerative disease with movement disorder. The key motor symptoms are rigidity, tremor, akinesis/hypokinesia/bradykinesia, and postural instability. However, in our day-to-day clinical practice we tend to see several other symptoms which may be motor or non-motor. Non-motor symptoms (NMS) are quite common and debilitating. The pathological hallmarks of PD are loss of dopaminergic neurons in the substantia nigra pars compacta (SNPc) and accumulation of unfolded or misfolded alpha-synuclein. Diagnosis of PD is difficult in the pre-motor stage. Late diagnosis renders a substantial loss of dopaminergic neurons in SNPc and spread of disease in other parts of the brain. This may manifest as either full blown symptoms requiring multiple medications or may even lead to life threatening condition due to lack of early diagnostic tools and techniques. Biomarkers are required to diagnose PD at a very early stage when prevention is possible. Hence, we see a lot of interest among researchers involved in finding a biomarker specific to the disease. Biomarkers may be clinical, image based, genetic, and biochemical. Cerebrospinal fluid (CSF) and serum markers which may correlate with disease pathophysiology are of great significance. One such molecule which recently gained a lot of attention is neuron-specific enolase (NSE). The main aim of this paper is to highlight the role of NSE in predicting neurodegeneration and neuroinflammation ultimately reflecting damage of brain cells in PD.

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The role of continuous dopaminergic stimulation in the management of non-motor symptoms in Parkinson’s disease

Non-motor Symptoms of Parkinson's Disease ◽

10.1093/med/9780199684243.003.0031 ◽

2014 ◽

pp. 468-482

Author(s):

P. Reddy ◽

A. Antonini ◽

P. Odin

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Motor Symptoms ◽

Continuous Dopaminergic Stimulation ◽

Non Motor Symptoms ◽

Dopaminergic Stimulation

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The effect of deep brain stimulation on motor and cognitive symptoms of Parkinson's disease: A literature review

Dementia & Neuropsychologia ◽

10.1590/s1980-57642015dn91000005 ◽

2015 ◽

Vol 9 (1) ◽

pp. 24-31 ◽

Cited By ~ 6

Author(s):

Flavia Amaral Machado ◽

Caroline Tozzi Reppold

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drug Treatment ◽

Randomized Clinical Trials ◽

Assessment Tools ◽

Cochrane Library ◽

Motor Symptoms ◽

Cognitive Symptoms ◽

Conventional Drug ◽

Deep Brain

Deep brain stimulator (DBS) implant surgery is considered a breakthrough in the treatment of Parkinson's disease, especially in cases where motor symptoms cannot be controlled through conventional drug treatment. Its benefits have been studied extensively in the literature, particularly in relation to motor symptoms. However, the disease's cognitive aspects have been studied to a lesser extent. OBJECTIVE: This systematic review aims to assess the effects of DBS surgery on motor and cognitive symptoms in patients with Parkinson's disease. METHODS: The search strategy included MEDLINE, LILACs, SCIELO and the Cochrane Library. Randomized clinical trials with DBS surgical intervention and Parkinson's disease were included. Of the 178 studies identified, 19 met the eligibility criteria. These studies were descriptively analyzed as regards to their results. RESULTS: Control of motor symptoms, as assessed by the UPDRS Part III scale, was found in all of the studies, pointing to great interest in this outcome and demonstrating an advantage of DBS over conventional drug treatment. Regarding cognitive aspects, heterogeneity in the choice of subjects studied and the use of different assessment tools for each was evident, hampering comparisons and leading to inconclusive results. CONCLUSION: This review provides a broad overview of the effects of DBS on Parkinson's disease symptoms. However, it is suggested that future studies be conducted to establish a gold-standard protocol for neuropsychological assessment, thereby enabling data comparison and more consistent conclusions.

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