Levodopa-Induced Dyskinesia in Parkinson’s Disease: Pathogenesis and Emerging Treatment Strategies
Abstract
:1. Introduction
2. Epidemiology and Risk Factors
3. Overview of LID in PD
4. Causes and Mechanisms
5. Dopaminergic Management and Treatment
6. Non-Dopaminergic Management and Treatment
Targeted System | Mechanism of Action | Side Effects | Name of Drug | Route of Administration | References |
---|---|---|---|---|---|
Adenosine | Adenosine A2A receptor antagonist | Falls in systolic and diastolic blood pressure, nausea, dizziness, insomnia, stiffness, vomiting, headache, hallucinations | ST1535 | Oral | [121,122] |
Istradefylline (KW-6002) | Oral | [123] | |||
Preladenant (SCH-420814) | Oral | [121,124] | |||
Tozadenant (SYN115) | Oral | [121,124] | |||
Vipadenant (V2006) | Oral | [121,124] | |||
Ciforadenant (CPI-444, V81444) | Oral | [121,124] | |||
PBF-509 | Oral | [121,124] | |||
ST4206 | Oral | [121,124] | |||
Nonspecific adenosine receptor antagonist | N/A | Caffeine | Oral | [125] | |
Adrenergic | Alpha-2 adrenergic receptor antagonist | Nausea, vomiting, dysgeusia, headache, oral hypoesthesia, flushing, and increases in systolic and diastolic blood pressure; potentially severe adverse effects affecting the cardiovascular system | Idazoxan | Oral | [20] |
Yohimbine | Oral | [126] | |||
Fipamezole (JP-1730) | Oral | [127] | |||
Beta-2 adrenergic receptor antagonist | Risk of bronchospasm, masked symptoms of hypoglycemia, bradycardia, hypotension, dizziness, lowered heart rate and blood pressure | Propranolol | Oral | [128] | |
Salbutamol | Oral | [129] | |||
Glutamatergic | NMDA receptor antagonist | confusion, worsening of hallucinations, peripheral oedema, skin rash, re-emergence of palpitations, nausea, dry mouth, swelling of feet and constipation | Amantadine & Amantadine extended-release capsules (Gocovri®) | Oral | [113,130,131] |
Amnesia, dissociation | Traxoprodil | Oral | [132] | ||
tiredness, vertigo, increased off time | Memantine | Oral | [133] | ||
Neurotoxicity, hyperactivity | Dizocilpine (MK-801) | Oral | [134] | ||
Perceptual distortions, detachment, anxiety, nausea, dissociation, confusion | Ketamine (FDA Approves IND for Ketamine in Parkinson Disease Dyskinesia, 2021) | Intravenous infusion, oral | [135,136] | ||
GluN2B antagonist | Amnesia, dissociation | Ifenprodil | Oral | [132] | |
Traxoprodil (CP-101606) | Oral, intravenous infusion | [132] | |||
AMPA receptor antagonist | Dry eyes and mouth, hallucinations, worsening dyskinesia, anxiety/depression, breathing problems | Topiramate | Oral | [137] | |
Somnolence, dizziness, worsening of dyskinesia | Perampanel | Oral | [138] | ||
N/A (ongoing clinical trial) | Talampanel (LY-300164) | N/A (ongoing clinical trial) | [132] | ||
Tezampanel (LY-293558) | N/A (ongoing clinical trial) | [132] | |||
mGlu4R positive allosteric modulator | N/A (preclinical) | ADX88178 | N/A (preclinical) | [132] | |
Lu AF21934 | N/A (preclinical) | [132] | |||
on and off phenomenon, dyskinesia, headache | Foliglurax | Oral | [139] | ||
mGluR5 receptor antagonist | Dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, insomnia | Mavoglurant | Oral | [140] | |
mGlu5R negative allosteric modulator | N/A (preclinical) | MPEP [2-Methyl-6-(phenylethynyl)-pyridine] | N/A (preclinical) | [141] | |
MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine) | N/A (preclinical) | [141] | |||
memory loss, dizziness, hallucinations | Fenobam | Oral | [142] | ||
Dizziness, nausea | Dipraglurant (ADX48621) | Oral | [141] | ||
mGlu7R allosteric agonist | N/A (preclinical) | AMN082 (N,N′-dibenzhydrylethane-1,2-diamine) | N/A (preclinical) | [143] | |
Serotonergic | 5-HT1AR agonist | Dizziness, increase in “off” time | Buspirone | Oral | [144] |
N/A (ongoing clinical trial) | Befiradol (F-13,640; NLX-112) | N/A (ongoing clinical trial) | [145] | ||
N/A (preclinical) | F13714 | N/A (preclinical) | [146] | ||
5-HT1BR agonist | N/A (preclinical) | CP-94253 | N/A (preclinical) | [147] | |
5-HT1AR/5-HT1BR agonist, 5-HT2CR antagonist | Fatigue, nausea, dizziness, mild somnolence/sedation | Eltoprazine | Oral | [88] | |
5-HT1AR agonist, partial D2 agonist | Worsening of parkinsonism, falls, aggravated tremor, somnolence, fatigue, headache, and arthralgia | Sarizotan | Oral | [148] | |
Partial 5-HT1AR agonist | Sedation, muscle relaxation | Tandospirone | Oral | [149] | |
5-HT2AR inverse agonist and antagonist | Urinary tract infections, falls | Pimavanserin (ACP-103) | Oral | [150] | |
5-HT2AR, 5-HT2CR antagonist, D1R agonist, D2R, D4R antagonist | Diurnal drowsiness, somnolence, excessive sweating, hypereosinophilia, worsening of parkinsonism | Clozapine | Oral | [151] | |
5-HT2AR agonist and adrenergic, muscarinic, histaminergic, dopaminergic receptor action | Sedation, dizziness | Quetiapine | Oral | [152] | |
5-HT2AR antagonist, partial 5-HT1AR agonist, partial D2 agonist | headache, insomnia, agitation, anxiety, dyspepsia, nausea, lightheadedness, somnolence, akathisia | Aripiprazole | Intramuscular injection, oral | [153] | |
5-HT2R agonist/5-HT3R antagonist | Hallucinations, confusion | Mirtazapine | Oral | [154] | |
Worsening of parkinsonism | Mianserin | Oral | [132] | ||
Histamine | H3 antagonist | N/A (preclinical) | Thioperamide | N/A (preclinical) | [155] |
H3 receptor agonist | N/A (preclinical) | Immepip | N/A (preclinical) | [156,157] | |
N/A (preclinical) | Imetit | N/A (preclinical) | [157] | ||
Cholinergic | M1 receptor antagonist | dry mouth, blurred vision, constipation, confusion, hallucination, memory disturbance, urinary retention | Trihexyphenidyl | Oral | [158] |
Benzatropine | Oral | [159] | |||
M4 positive allosteric moderator | N/A (preclinical) | VU0467154 | N/A (preclinical) | [132] | |
M4 positive allosteric moderator | N/A (preclinical) | VU0476406 | N/A (preclinical) | [132] | |
Nicotinic agonist | nausea, vomiting, lung damage, dizziness, | Nicotine | Oral, inhaled | [160,161] | |
Non-selective nicotinic receptor antagonist | constipation, blurred vision, dry mouth, orthostatic hypotension | Mecamylamine | Oral | [162] | |
ɑ7 nicotinic receptor agonist | N/A (preclinical) | ABT-107 | N/A (preclinical) | [163] | |
agitation, constipation, diarrhea, fall, and headache | ABT-126 | Oral | [163,164] | ||
ꞵ2 nicotinic receptor agonist | Worsening of parkinsonism | ABT-089 | Oral | [163] | |
ABT-894 | Oral | [163] | |||
Opioid | к agonist, μ antagonist | Sedation (Non-human primate models) | Nalbuphine | Injection (Non-human primate models) | [165] |
Mu-delta opioid receptor agonist | N/A (preclinical) | Lactomorphin (MMP-2200) | N/A (preclinical) | [166] | |
δ antagonist | N/A (preclinical) | Naltrindole | N/A (preclinical) | [167] | |
Kappa (к) opioid receptor agonist | Worsening of parkinsonism | U50,488 | N/A (preclinical) | [168] | |
Sigma-1 | σ1 receptor antagonist | N/A (preclinical) | BMY-14802 | N/A (preclinical) | [169] |
σ1 receptor agonist | Fatigue, somnolence, dizziness, constipation | Dextromethorphan | Oral | [170] | |
Nitric Oxide | NO Donor | Worsening of parkinsonism | Molsidomine | Oral | [171] |
7. Surgical Options
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Dyskinesia Types | Movement | Body Part | Occurrence |
---|---|---|---|
Peak dose (IDI) | Primarily choreiform movement; may also be characterized by dystonia, myoclonus, or ballism | Primarily neck, axial, and proximal limbs | High plasma levels, coincidence with antiparkinsonian benefit |
Diphasic (DID) | Repetitive dystonia, ballism | Lower limbs | Plasma levels rise or fall at the start of the levodopa effect and as levodopa wears off |
Off-period Dystonia (Early Morning Dystonia) | Dystonia | Usually, one foot | Low plasma levels, “off” period |
Mechanism of Action | Name of Drug | Route of Administration | Side Effects | References |
---|---|---|---|---|
Dopamine receptor agonists | Cabergoline (ergot D2 agonist) | Oral | Nausea, postural hypotension, somnolence, sleep disorder, hallucination | [71] |
Dihydroergocryptine (ergot D2 agonist, partial D1 agonist) | Oral | Nausea, vomiting, dry mouth, diarrhea, abdominal pain | [72] | |
Bromocriptine (ergot partial D2 agonist) | Oral | Nausea, postural hypotension, hallucination, vomiting, dizziness, | [73] | |
Pergolide (ergot D2/D3 agonist) | Oral | Nausea, hallucination | [74] | |
Pramipexole (non-ergot) | Oral | nausea, vomiting, postural hypotension, oedema, hallucinations, somnolence, sudden-onset sleep disorder | [75] | |
Ropinirole (non-ergot D2 agonist) | Oral | Nausea, hallucination, postural hypotension | [73] | |
Rotigotine (non-ergot D3/D2/D1 agonist) | Transdermal patch | nausea, vomiting, somnolence, dizziness and application-site reactions | [76] | |
Piribedil (non-ergot D2/D3 agonist) | Oral | nausea, postural hypotension, vomiting, confusion, hallucinations, agitation, dizziness, drowsiness | [77] | |
Apomorphine (non-ergot D2 agonist) | Intermittent subcutaneous injection or continuous subcutaneous infusion | Administration site reactions, nausea, vomiting, transient sedation, somnolence, dizziness, confusion, hallucinations | [78,79,80] | |
Tavapdon (D1/D5 agonist) | Oral | headache, nausea, and vomiting | [81] | |
DETQ (D1 agonist) | N/A (preclinical) | N/A (preclinical) | [82] | |
SK609 (D3 agonist) | N/A (preclinical) | N/A (preclinical) | [83] | |
D-512 (D2/D3 agonist) | N/A (preclinical) | N/A (preclinical) | [84] | |
D-636 (D2/D3 agonist) | N/A (preclinical) | N/A (preclinical) | [85] | |
D-536 (D2/D3 agonist) | N/A (preclinical) | N/A (preclinical) | [85] | |
D-656 (D2/D3 agonist) | N/A (preclinical) | N/A (preclinical) | [85] | |
Pardoprunox (D2/D3 partial agonist, 5-HT1A receptor agonist) | Oral | Nausea, vomiting, dizziness, somnolence, headache, insomnia, hallucination | [86] | |
D4 antagonist | VU6004461 | N/A (preclinical | N/A (preclinical) | [87] |
D3 antagonist | IRL790 | Oral | Asthenia, dissociation, headache, worsening of parkinsonism | [88] |
COMT inhibitor | Entacapone | Oral | Diarrhea, nausea, constipation, abdominal pain | [89,90] |
COMT inhibitor | Tolcapone | Oral | dyskinesia, nausea, sleep disorders, dystonia, orthostatic hypotension, diarrhea, dizziness, hallucinations, potential elevated liver transaminase concentrations, possible fulminant hepatic failure | [91] |
COMT inhibitor | Opicapone | Oral | Dry mouth, dizziness, nausea, constipation, insomnia, hallucination, fall | [92] |
MAO-B inhibitor | Safinamide | Oral | Headache, hypertension, cataract, back pain | [93,94] |
MAO-B inhibitor | Selegiline | Oral | insomnia, nausea, benign cardiac arrhythmias, dizziness and headache | [95] |
MAO-B inhibitor | Rasagiline | Oral | Infection, headache, musculoskeletal pain | [96,97] |
Name of Drug | Mechanism of Action | Route of Administration | Side Effects | References |
---|---|---|---|---|
XP21279 | L-DOPA prodrug, activated by carboxylesterase, creates more stable plasma concentration | Oral | Headache, dizziness, anorexia, insomnia, gastroesophageal reflux disease, and somnolence | [101,102] |
CVT-301 | L-DOPA powder | Inhaled | Dizziness, cough, and nausea | [101,103] |
L-DOPA/benserazide microspheres | Inactivity of D1R/Shp-2/ERK1/2 pathway, inhibition of tau protein phosphorylation and PKA signaling | N/A (preclinical) | N/A (preclinical) | [104,105] |
Chitosan-coated nanoliposomes | Reduced expression of ERK ½, DARPP-32, and FosB/ΔFosB | N/A (preclinical) | N/A (preclinical) | [106] |
ODM-101 | LD/CD/ENT formulation | Oral | nausea, dizziness, headache, diarrhea, and insomnia | [107,108] |
ND0612 | Liquid formulation of LD/CD, continuous administration | Transcutaneous, patch-pump device | Small transient papules at infusion sites, infusion site bruising, and erythema | [101,109] |
LCIG | Gel formulation of LD/CD, finer and more continuous titrations of levodopa | Intestinal, injected through PEG-J tube | peristomal complications, problems flushing the tube, accidental removal of the tube, tube occlusion, weight loss, nausea, and hallucinations | [66,110] |
Accordion Pill | Immediate-release CD and both immediate and extended-release LD | Oral | Nausea, vomiting, mild somnolence, and fatigue | [111,112] |
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Kwon, D.K.; Kwatra, M.; Wang, J.; Ko, H.S. Levodopa-Induced Dyskinesia in Parkinson’s Disease: Pathogenesis and Emerging Treatment Strategies. Cells 2022, 11, 3736. https://doi.org/10.3390/cells11233736
Kwon DK, Kwatra M, Wang J, Ko HS. Levodopa-Induced Dyskinesia in Parkinson’s Disease: Pathogenesis and Emerging Treatment Strategies. Cells. 2022; 11(23):3736. https://doi.org/10.3390/cells11233736
Chicago/Turabian StyleKwon, Destany K., Mohit Kwatra, Jing Wang, and Han Seok Ko. 2022. "Levodopa-Induced Dyskinesia in Parkinson’s Disease: Pathogenesis and Emerging Treatment Strategies" Cells 11, no. 23: 3736. https://doi.org/10.3390/cells11233736
APA StyleKwon, D. K., Kwatra, M., Wang, J., & Ko, H. S. (2022). Levodopa-Induced Dyskinesia in Parkinson’s Disease: Pathogenesis and Emerging Treatment Strategies. Cells, 11(23), 3736. https://doi.org/10.3390/cells11233736