The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models
Abstract
:1. Introduction
2. Essential Tremor (ET)
2.1. Epidemiology
2.2. ET Etiology
2.2.1. Genetic Background
2.2.2. Environmental Factors
2.3. The Pathophysiology of ET
2.3.1. The Neurodegenerative Hypothesis
2.3.2. The Central Oscillatory Network Hypothesis
2.3.3. The GABAergic Hypothesis
2.4. The Current Treatment of ET
2.4.1. Pharmacological Therapy
2.4.2. Neurosurgical Methods
2.5. Animal Models of ET
2.5.1. Harmaline-Induced Tremor
2.5.2. Genetic Models
3. The Dopaminergic System and Dopamine Receptors—The Role in ET
3.1. The Participation of Dopamine and Its Receptors in the Modulation of ET and Harmaline-Induced Tremor
3.2. Involvement of Dopamine D3 Receptors in the Harmaline-Induced Tremor
4. Adenosine and Its Receptors—The Role in ET
4.1. Adenosine Metabolism
4.2. Adenosine Receptors, Their Localization, and Homomeric and Heteromeric Complexes
4.3. The Involvement of Adenosine and Its Receptors in Tremor Modulation
4.4. Adenosine A1 Receptors and Their Role in Harmaline-Induced Tremor
5. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drugs | Main Mechanism of Action | Therapeutic Effect | Main Side-Effects |
---|---|---|---|
First-line therapies Approved by the FDA, or supported by double-blinded, placebo controlled studies that meet the criteria for class I evidence (defined by USPSTF) | |||
Propranolol | Non-selective β-adrenergic receptor antagonist Anti-tremor mechanism: probably acting on peripheral non-cardiac β2 receptors (for more information see Section 2.4.1). | Tremor reduction by 50–70% (>50% ET patients respond), mainly for tremor affecting upper extremities, and head tremor response islimited | Frequent, rather mild, occurs in >60% ET patients: hypotension, bradycardia, slow heartbeat, fatigue, dizziness, exertional dyspnea, erectile dysfunction, headaches, somnolence |
Primidone | Derivative of barbituric acid, antiepileptic drug Anti-tremor mechanism: still unknown; interacts with voltage-gated sodium channels or opening/potentiating GABA receptors | Tremor reduction by 50–70% (30–50% ET patients respond) | In 22–72% ET patients: sedation, fatigue, drowsiness, dizziness, ataxia, confusion, nausea, loss of coordination, anorexia, nausea, vomiting, flu-like symptoms |
Second-line therapies Supported by double-blinded, placebo-controlled trials that do not meet the requirements for class I evidence studies | |||
Topiramate Most effective second-line treatment | Blockade of voltage-gated sodium channels, inhibition of high voltage-activated calcium channels Anti-tremor mechanism: not clear | Tremor improvement by 20–37% (30–40% response rate) | Paresthesias, difficulties with concentration, nausea, somnolence, fatigue, malaise, dyspepsia, weight loss, confusion, psychomotor slowing, abnormal taste perception, visual disturbances, nephrolithiasis Discontinuation of therapy because of adverse side-effects in approximately 30% of ET patients |
Gabapentin Pregabalin | Structural analogs of GABA Inhibit α2δ subunits of voltage-gated calcium N-type channels; do not bind directly to GABA-A, GABA-B receptors Anti-tremor mechanism: not clear | Tremor improvement by 30–40% (approximately 30–50% response rate) | Sleepiness, dizziness, ataxia, nausea, weight gain in 30–40% of patients (mild) Discontinuation in cases of increased anxiety, insomnia, nausea, increased risk of depression and suicidal behavior |
Alprazolam Clonazepam | Benzodiazepines Bind to GABA-A receptor complex, Cl- influx | Tremor improvement by 30–50% (>50% response rate) | Sedation, cognitive impairment, tolerance, dependency, abuse, withdrawal symptoms, side-effects in approximately 50% of ET patients |
Atenolol | Competitive β1-adenergic antagonist | Only in patients responding to propranolol (37% tremor reduction); response rate similar to other β-blockers | Similar to propranolol (see above), without possible bronchospasm |
Metoprolol | Competitive β1-adenergic antagonist | Equal efficacy to propranolol (single dose), but no effect on tremor after chronic use | Similar to propranolol (see above) |
Nadolol Sotalol Indenolol Arotinolol Timolol | Non-selective β-blockers | Effective, but only in ET patients who responded previously to propranolol | Most common side-effect isreduced alertness, otherwise similar to propranolol (see above) Adverse effects in approximately 25% patients |
Third-line therapies Based on open-label studies or case series | |||
Nimodipine Flunarizine Nicardipine | Calcium channel blockers Binds to L-type voltage-gated Ca2+ channel | Tremor improvement by 50% (>50% response rate), based on studies on small numbers of ET patients | Most common: hypotension, oedema, headaches in 10–20% patients, dizziness, nausea, constipation, fatigue, palpitations and others (rather well-tolerated) |
Clozapine | Atypical antipsychotic High affinity to D1, D4, 5HT2A, 5HT2C, 5HT6, 5HT7, α1- and α 2-adrenergic receptors, H1 and M1-M5 muscarinic receptors, weak affinity for D2 receptors | Tremor improvement by 50% (75% response rate), based on small clinical trials | Main: sedation, orthostatic hypotension, tachycardia, syncope, weight gain, metabolic syndrome (adverse effects in approximately 50% of ET patients) Possible: agranulocytosis, cardiomyopathy, tachycardia, risk of seizure, risk of neutropenia (not observed) |
Olanzapine Quetiapine | Atypical antipsychotics High/moderate affinity to 5HT2A/C, 5HT6, 5HT7, D1-D4, H1, α1-adrenergic receptors, and M1-M5 muscarinic receptors | Tremor improvement by <50% | Insomnia, anxiety, headache, sedation, somnolence, dizziness, weight gain, orthostatic hypotension In long-term treatment there is an increased risk of parkinsonism |
Imaging Study | Clinical Diagnosis, Subjects | Key Findings | References |
---|---|---|---|
Markers of DAT | |||
[123I]β-CIT SPECT | ET (n = 32), controls (n = 30) | No difference in the striatum between ET and controls | Asenbaum et al. (1998) [161] |
[123I]FP-CIT SPECT | ET (n = 27), controls (n = 35) | No alterations in ET patients vs. controls | Benamer et al. (2000) [162] |
ET (n = 20), controls (n = 23) | No alterations in ET patients vs. controls | Isaias et al. (2010) [163] | |
[11C]FE-CIT PET | ET (n = 5), controls (n = 8) | No difference between ET patients and controls | Antonini et al. (2001) [164] |
[123I]ioflupane SPECT | ET (n = 15), controls (n = 17) | No alterations in ET patients vs. controls | Di Giuda et al. (2012) [165] |
ET (n = 22), controls (n = 13) | No alterations in ET patients vs. controls | Waln et al. (2015) [166] | |
ET (n = 12), controls (n = 10) | No alterations in ET with rest tremor vs. controls | Barbagallo et al. (2017) [167] | |
ET (n = 28), controls (n = 28) | Mild striatal deficit in ET patients vs. control (less marked than in PD) | Gerasimou et al. (2012) [168] | |
ET (n = 32, including 16 familial), controls (n = 31) | Mild striatal deficit in ET patients vs. control (less marked than in PD) | Isaias et al. (2008) [169] | |
[99mTc]TRODAT-1 SPECT | ET (n = 12), control (n = 10) | No alterations in ET patients vs. controls | Wang et al. (2005) [170] |
[11C]dMP PET | ET (n = 6), controls (n = 10) | No alterations in ET patients vs. controls | Breit et al. (2006) [171] |
Presynaptic radioligand (measures DA synthesis) | |||
[18F]DOPA PET | ET (n = 20, including 8 familial), controls (n = 30) | ↓ 13% uptake in putamen (familial ET) and ↓ 10% (sporadic ET) vs. control | Brooks et al. (1992) [172] |
Postsynaptic (D2 R) | |||
[123I]IBZM SPECT | ET (n = 11), no controls | No alterations in ET patients | Plotkin et al. (2005) [173] |
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Kosmowska, B.; Wardas, J. The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models. Biomolecules 2021, 11, 1813. https://doi.org/10.3390/biom11121813
Kosmowska B, Wardas J. The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models. Biomolecules. 2021; 11(12):1813. https://doi.org/10.3390/biom11121813
Chicago/Turabian StyleKosmowska, Barbara, and Jadwiga Wardas. 2021. "The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models" Biomolecules 11, no. 12: 1813. https://doi.org/10.3390/biom11121813