Levodopa-induced dyskinesia | |
---|---|
Specialty | Neurology |
Levodopa-induced dyskinesia (LID) is a form of dyskinesia associated with levodopa (l-DOPA), used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis. [1]
In the context of Parkinson's disease (PD), dyskinesia is often the result of long-term dopamine therapy. These motor fluctuations occur in up to 80% of PD patients after 5–10 years of l-DOPA treatment, [2] with the percentage of affected patients increasing over time. [3] Based on the relationship with levodopa dosing, dyskinesia most commonly occurs at the time of peak l-DOPA plasma concentrations and is thus referred to as peak-dose dyskinesia (PDD). As patients advance, they may present with symptoms of diphasic dyskinesia (DD), which occurs when the drug concentration rises or falls. If dyskinesia becomes too severe or impairs the patient's quality of life, a reduction in l-Dopa might be necessary, however this may be accompanied by a worsening of motor performance. Therefore, once established, LID is difficult to treat. [4] Amongst pharmacological treatments, N-methyl-D-aspartate (NMDA) antagonist, (a glutamate receptor), amantadine, has been proven to be clinically effective in a small number of placebo controlled randomized controlled trials, while many others have only shown promise in animal models. [5] [6] Attempts to moderate dyskinesia by the use of other treatments such as bromocriptine (Parlodel), a dopamine agonist, appears to be ineffective. [7] In order to avoid dyskinesia, patients with the young-onset form of the disease or young-onset Parkinson's disease (YOPD) are often hesitant to commence l-DOPA therapy until absolutely necessary for fear of suffering severe dyskinesia later on.[ citation needed ] Alternatives include the use of DA agonists (i.e. ropinirole or pramipexole) in lieu of early l-DOPA treatment which delays the use of l-DOPA. Additionally, a review [8] shows that highly soluble l-DOPA prodrugs may be effective in avoiding the in vivo blood concentration swings that potentially lead to motor fluctuations and dyskinesia.
Levodopa-induced dyskinesia has long been thought to arise through pathological alterations in pre-synaptic and post-synaptic signal transduction in the nigrostriatal pathway (dorsal striatum). [9] It is thought that the stage of illness, dosage of l-DOPA, frequency of l-DOPA treatment and the youth of the patient at the onset of symptoms contribute to the severity of the involuntary movements associated with LID. [4]
In experiments employing real-time electrophysiological recordings in awake and active animals, LIDs have been shown to be strongly associated with cortical gamma-oscillations with accompanying Δc-fos overexpression, proposedly due to a dysregulation of dopamine signaling in the cortico-basal ganglia circuitry. This was concluded partially from reduced tyrosine hydroxylase (TH) staining in the cortex - and the fact that a dopamine receptor 1 antagonist, delivered exclusively to the cortex, relieved the dyskinesia at its peak-time. [10]
ΔFosB overexpression in the dorsal striatum (nigrostriatal dopamine pathway) via viral vectors generates levodopa-induced dyskinesia in animal models of Parkinson's disease. [11] [12] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias; [12] moreover, postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression. [12]
Levetiracetam, an antiepileptic drug which has been demonstrated to reduce the severity of levodopa-induced dyskinesias, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa. Although the signal transduction mechanism involved in this effect is unknown. [12]
Nicotine (administered by dermal adhesive patches) has also been shown to improve Levodopa-induced dyskinesia and other PD symptoms. [13] [14]
Patients with prominent dyskinesia resulting from high doses of antiparkinsonian medications may benefit from deep brain stimulation (DBS), which may benefit the patient in two ways: 1) DBS theoretically allows a reduction in l-DOPA dosage of 50–60% (tackling the underlying cause); 2) DBS treatment itself (in the subthalamic nucleus or globus pallidus) has been shown to reduce dyskinesia. [15]
In 2017, the FDA approved the first treatment for levodopa-induced dyskinesia for Parkinson's patients: Gocovri, amantadine manufactured by Adamas Pharmaceuticals. [16] Mavoglurant and ketamine are also currently studied for the treatment of this disease. [17]
Mesdopetam is under development for the treatment of levodopa-induced dyskinesia. [18] [19] [20]
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle.
The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum in the forebrain. It is one of the four major dopamine pathways in the brain, and is critical in the production of movement as part of a system called the basal ganglia motor loop. Dopaminergic neurons of this pathway release dopamine from axon terminals that synapse onto GABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), located in the striatum.
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of the hands to an uncontrollable movement of the upper body or lower extremities. Discoordination can also occur internally especially with the respiratory muscles and it often goes unrecognized. Dyskinesia is a symptom of several medical disorders that are distinguished by their underlying cause.
Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespread drug resistance. It is also used for a variety of other uses. The drug is taken by mouth.
Neuropharmacology is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.
Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.
Progabide is an analogue and prodrug of γ-aminobutyric acid (GABA) used in the treatment of epilepsy. Via conversion into GABA, progabide behaves as an agonist of the GABAA, GABAB, and GABAA-ρ receptors.
Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.
The medial forebrain bundle (MFB) is a neural pathway containing fibers from the basal olfactory regions, the periamygdaloid region and the septal nuclei, as well as fibers from brainstem regions, including the ventral tegmental area and nigrostriatal pathway.
In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.
A catechol-O-methyltransferase inhibitor is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor. The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-O-methyldopa, thus increasing the bioavailability of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.
Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.
Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like carbidopa or benserazide. Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat.
Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system observed in some individuals taking dopaminergic medications for an extended length of time. It is characterized by severely disinhibited patterns of behavior, leading to problems such as addiction to the offending medication, gambling addiction, or compulsive sexual behavior, along with a general orientation towards immediate gratification. It typically occurs in people with Parkinson's disease or restless legs syndrome (RLS) who have taken dopamine agonist medications for an extended period of time.
Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease of mainly the central nervous system that affects both the motor and non-motor systems of the body. The symptoms usually emerge slowly, and, as the disease progresses, non-motor symptoms become more common. Usual symptoms include tremors, slowness of movement, rigidity, and difficulty with balance, collectively known as parkinsonism. Parkinson's disease dementia, falls and neuropsychiatric problems such as sleep abnormalities, psychosis, mood swings, or behavioral changes may also arise in advanced stages.
Befiradol is an experimental drug being studied for the treatment of levodopa-induced dyskinesia. It is a potent and selective 5-HT1A receptor full agonist.
Gene therapy in Parkinson's disease consists of the creation of new cells that produce a specific neurotransmitter (dopamine), protect the neural system, or the modification of genes that are related to the disease. Then these cells are transplanted to a patient with the disease. There are different kinds of treatments that focus on reducing the symptoms of the disease but currently there is no cure.
3-O-Methyldopa (3-OMD) is one of the most important metabolites of L-DOPA, a drug used in the treatment of the Parkinson's disease.
Mesdopetam (INNTooltip International Nonproprietary Name; developmental code names IRL-790, IPN60170) is a dopamine D2 and D3 receptor antagonist with preference for the D3 receptor which is under development for the treatment of Parkinson's disease, drug-induced dyskinesia, and psychotic disorders. It has been described by its developers as having "psychomotor stabilizing" properties.
The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson's disease (PD) for over 40 years. The response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission.
Furthermore, the transgenic overexpression of ΔFosB reproduces AIMs in hemiparkinsonian rats without chronic exposure to L-DOPA [13]. ... FosB/ΔFosB immunoreactive neurons increased in the dorsolateral part of the striatum on the lesion side with the used antibody that recognizes all members of the FosB family. All doses of levetiracetam decreased the number of FosB/ΔFosB positive cells (from 88.7 ± 1.7/section in the control group to 65.7 ± 0.87, 42.3 ± 1.88, and 25.7 ± 1.2/section in the 15, 30, and 60 mg groups, resp.; Figure 2). These results indicate dose-dependent effects of levetiracetam on FosB/ΔFosB expression. ... In addition, transcription factors expressed with chronic events such as ΔFosB (a truncated splice variant of FosB) are overexpressed in the striatum of rodents and primates with dyskinesias [9, 10]. ... Furthermore, ΔFosB overexpression has been observed in postmortem striatal studies of Parkinsonian patients chronically treated with l-DOPA [26]. ... Of note, the most prominent effect of levetiracetam was the reduction of ΔFosB expression, which cannot be explained by any of its known actions on vesicular protein or ion channels. Therefore, the exact mechanism(s) underlying the antiepileptic effects of levetiracetam remains uncertain.