-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal
biology
Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary i ...
of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA, make it via
biosynthesis
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
from the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
-tyrosine. -DOPA is the
precursor
Precursor or Precursors may refer to:
*Precursor (religion), a forerunner, predecessor
** The Precursor, John the Baptist
Science and technology
* Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of unr ...
to the
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
,
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
(noradrenaline), and
epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
(adrenaline), which are collectively known as
catecholamine
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a subst ...
s. Furthermore, -DOPA itself mediates
neurotrophic factor
Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and cell differentiation, differentiation of both developing and mature neurons. Most ...
release by the brain and CNS. -DOPA can be manufactured and in its pure form is sold as a
psychoactive drug
A psychoactive drug, psychopharmaceutical, psychoactive agent or psychotropic drug is a chemical substance, that changes functions of the nervous system, and results in alterations in perception, mood, consciousness, cognition or behavior. ...
with the
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical
treatment of
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
and
dopamine-responsive dystonia.
-DOPA has a counterpart with opposite
chirality
Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object.
An object or a system is ''chiral'' if it is distinguishable from ...
,
-DOPA. As is true for many molecules, the human body produces only one of these
isomer
In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
Iso ...
s (the -DOPA form). The
enantiomeric purity of -DOPA may be analyzed by determination of the optical rotation or by chiral
thin-layer chromatography
Thin-layer chromatography (TLC) is a chromatography technique used to separate non-volatile mixtures.
Thin-layer chromatography is performed on a sheet of an inert substrate such as glass, plastic, or aluminium foil, which is coated with a t ...
.
Medical use
-DOPA crosses the protective
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
, whereas
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
itself cannot. Thus, -DOPA is used to increase dopamine concentrations in the treatment of
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
,
Parkinsonism
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...
,
dopamine-responsive dystonia and
Parkinson-plus syndrome
Parkinson-plus syndromes (PPS) are a group of neurodegenerative diseases featuring the classical features of Parkinson's disease ( tremor, rigidity, akinesia/bradykinesia, and postural instability) with additional features that distinguish them f ...
. The therapeutic efficacy is different for different kinds of symptoms.
Bradykinesia
Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sym ...
and
rigidity are the most responsive symptoms while
tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...
s are less responsive to levodopa therapy. Speech,
swallowing disorders, postural instability and freezing gait are the least responsive symptoms.
Once -DOPA has entered the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
, it is converted into dopamine by the
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
aromatic -amino acid decarboxylase, also known as
DOPA decarboxylase
Aromatic L-amino acid decarboxylase (AADC or AAAD), also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme (), located in region 7p12.2-p12.1.
Mechanism
The enzyme uses pyrid ...
.
Pyridoxal phosphate
Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent ac ...
(
vitamin B6) is a required
cofactor in this
reaction
Reaction may refer to a process or to a response to an action, event, or exposure:
Physics and chemistry
*Chemical reaction
*Nuclear reaction
*Reaction (physics), as defined by Newton's third law
*Chain reaction (disambiguation).
Biology and me ...
, and may occasionally be administered along with -DOPA, usually in the
form
Form is the shape, visual appearance, or configuration of an object. In a wider sense, the form is the way something happens.
Form also refers to:
*Form (document), a document (printed or electronic) with spaces in which to write or enter data
...
of
pyridoxine
Pyridoxine, is a form of vitamin B6 found commonly in food and used as a dietary supplement. As a supplement it is used to treat and prevent pyridoxine deficiency, sideroblastic anaemia, pyridoxine-dependent epilepsy, certain metabolic disorde ...
. Because levodopa bypasses the enzyme
tyrosine hydroxylase
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and t ...
, the rate-limiting step in dopamine synthesis, it is much more readily converted to dopamine than tyrosine, which is normally the natural precursor for dopamine production.
In humans, conversion of -DOPA to dopamine does not only occur within the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
. Cells in the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
perform the same task. Thus administering -DOPA alone will lead to increased dopamine signaling in the periphery as well. Excessive peripheral dopamine signaling is undesirable as it causes many of the adverse
side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s seen with sole
L-DOPA administration. To bypass these effects, it is standard clinical practice to coadminister (with -DOPA) a peripheral
DOPA decarboxylase inhibitor
An aromatic L-amino acid decarboxylase inhibitor (synonyms: DOPA decarboxylase inhibitor, Extracerebral decarboxylase inhibitor, DDCI and AAADI) is a medication of type enzyme inhibitor which inhibits the synthesis of dopamine by the enzyme ar ...
(DDCI) such as
carbidopa
Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–bra ...
(medicines containing carbidopa, either alone or in combination with -DOPA, are branded as
Lodosyn (
Aton Pharma)
Sinemet (
Merck Sharp & Dohme Limited), Pharmacopa (
Jazz Pharmaceuticals
Jazz Pharmaceuticals plc (a merger of Jazz Pharmaceuticals, Inc. and Azur Pharma plc) is a biopharmaceutical company based in Ireland. It was founded in 2003. One of the company's considerable products is the United States Food and Drug Adminis ...
),
Atamet (
UCB), Syndopa and
Stalevo
Carbidopa/levodopa/entacapone, sold under the brand name Stalevo among others, is a dopaminergic fixed-dose combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease. It is marketed by Swis ...
(
Orion Corporation
Orion Corporation ( fi, Orion Oyj), founded in 1917 and headquartered at Espoo, Finland, is a globally operating Finnish company which develops, manufactures and markets human and veterinary Pharmaceutical company, pharmaceuticals and Active ing ...
) or with a
benserazide
Benserazide (also called Serazide or Ro 4-4602) is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier.
It is on the World Health Organization's List of E ...
(combination medicines are branded Madopar or Prolopa), to prevent the peripheral synthesis of dopamine from -DOPA).
Inbrija (previously known as CVT-301) is an inhaled powder formulation of levodopa indicated for the intermittent treatment of "off episodes" in patients with Parkinson's disease currently taking
carbidopa/levodopa
Carbidopa/levodopa, also known as levocarb and co-careldopa, is the combination of the two medications carbidopa and levodopa. It is primarily used to manage the symptoms of Parkinson's disease, but it does not slow down the disease or stop it ...
. It was approved by the United States
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
on December 21, 2018, and is marketed by
Acorda Therapeutics
Acorda Therapeutics, Inc. is an American biotechnology company based in Pearl River, New York. The company develops therapies that improve neurological function in people with Parkinson's disease, multiple sclerosis and other neurological disorder ...
.
Coadministration of
pyridoxine
Pyridoxine, is a form of vitamin B6 found commonly in food and used as a dietary supplement. As a supplement it is used to treat and prevent pyridoxine deficiency, sideroblastic anaemia, pyridoxine-dependent epilepsy, certain metabolic disorde ...
without a DDCI accelerates the peripheral
decarboxylation
Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
of -DOPA to such an extent that it negates the effects of -DOPA administration, a phenomenon that historically caused great confusion.
In addition, -DOPA, co-administered with a peripheral DDCI, is efficacious for the short-term treatment of
restless leg syndrome
Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...
.
The two types of response seen with administration of -DOPA are:
* The short-duration response is related to the half-life of the drug.
* The longer-duration response depends on the accumulation of effects over at least two weeks, during which
ΔFosB
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.
The FOS gene family consists of four members: FOS, F ...
accumulates in
nigrostriatal neurons. In the treatment of Parkinson's disease, this response is evident only in early therapy, as the inability of the brain to store dopamine is not yet a concern.
Biological role
-DOPA is produced from the amino acid -
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
by the enzyme
tyrosine hydroxylase
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and t ...
. -DOPA can act as an -tyrosine mimetic and be incorporated into proteins by mammalian cells in place of L-tyrosine, generating
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
-resistant and
aggregate-prone proteins ''in vitro'' and may contribute to neurotoxicity with chronic -DOPA administration.
It is also the precursor for the
monoamine
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.
All monoamines are ...
or
catecholamine
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a subst ...
neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Dopamine is formed by the decarboxylation of -DOPA by
aromatic -amino acid decarboxylase (AADC).
-DOPA can be directly metabolized by
catechol-''O''-methyl transferase to
3-''O''-methyldopa, and then further to
vanillactic acid. This metabolic pathway is nonexistent in the healthy body, but becomes important after peripheral -DOPA administration in patients with Parkinson's disease or in the rare cases of patients with AADC enzyme deficiency.
-Phenylalanine, -tyrosine, and -DOPA are all precursors to the biological
pigment
A pigment is a colored material that is completely or nearly insoluble in water. In contrast, dyes are typically soluble, at least at some stage in their use. Generally dyes are often organic compounds whereas pigments are often inorganic compo ...
melanin
Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...
. The enzyme
tyrosinase
Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis otherwise known as the Raper Mason pathway. Firstly, the hydroxylat ...
catalyzes
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the
oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
of -DOPA to the reactive intermediate
dopaquinone
-Dopaquinone also known as ''o''-dopaquinone is a metabolite of L-DOPA (L-dihydroxyphenylalanine) and a precursor of melanin.
Biosynthesis of melanin occurs in melanocytes, where tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxy ...
, which reacts further, eventually leading to melanin
oligomer
In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
s. In addition,
tyrosinase
Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis otherwise known as the Raper Mason pathway. Firstly, the hydroxylat ...
can convert tyrosine directly to -DOPA in the presence of a reducing agent such as
ascorbic acid
Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) an ...
.
Marine adhesion
-DOPA is a key
compound
Compound may refer to:
Architecture and built environments
* Compound (enclosure), a cluster of buildings having a shared purpose, usually inside a fence or wall
** Compound (fortification), a version of the above fortified with defensive struct ...
in the formation of
marine adhesive proteins, such as those found in
mussel
Mussel () is the common name used for members of several families of bivalve molluscs, from saltwater and Freshwater bivalve, freshwater habitats. These groups have in common a shell whose outline is elongated and asymmetrical compared with other ...
s. It is believed to be responsible for the water-resistance and rapid curing abilities of these proteins. -DOPA may also be used to prevent surfaces from fouling by bonding antifouling polymers to a susceptible
substrate. The versatile chemistry of L-DOPA can be exploited in nanotechnology. For example, DOPA-containing self-assembling peptides were found to form functional nanostructures, adhesives and gels.
Side effects and adverse reactions
The side effects of -DOPA may include:
*
Hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
, especially if the dosage is too high
*
Arrhythmia
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
s, although these are uncommon
*
Nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, which is often reduced by taking the drug with food, although
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
reduces drug absorption. -DOPA is an amino acid, so protein competitively inhibits -DOPA absorption.
* Gastrointestinal bleeding
* Disturbed
respiration
Respiration may refer to:
Biology
* Cellular respiration, the process in which nutrients are converted into useful energy in a cell
** Anaerobic respiration, cellular respiration without oxygen
** Maintenance respiration, the amount of cellula ...
, which is not always harmful, and can actually benefit patients with upper airway obstruction
*
Hair loss
Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarri ...
*
Disorientation
Orientation is a function of the mind involving awareness of three dimensions: time, Location (geography), place and person. Problems with orientation lead to ''dis''orientation, and can be due to various conditions, from delirium to Substance int ...
and
confusion
In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion"
* Extreme
emotion
Emotions are mental states brought on by neurophysiological changes, variously associated with thoughts, feelings, behavioral responses, and a degree of pleasure or displeasure. There is currently no scientific consensus on a definition. ...
al states, particularly
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
, but also excessive
libido
Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act up ...
* Vivid
dream
A dream is a succession of images, ideas, emotions, and sensations that usually occur involuntarily in the mind during certain stages of sleep. Humans spend about two hours dreaming per night, and each dream lasts around 5 to 20 minutes, althou ...
s or
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
*
Auditory or
visual hallucinations
A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...
* Effects on learning; some evidence indicates it improves
working memory
Working memory is a cognitive system with a limited capacity that can hold information temporarily. It is important for reasoning and the guidance of decision-making and behavior. Working memory is often used synonymously with short-term memory, ...
, while impairing other complex functions
*
Somnolence
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
and
narcolepsy
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...
* A condition similar to
stimulant psychosis
Stimulant psychosis is a mental disorder characterized by psychotic symptoms (such as hallucinations, paranoid ideation, delusions, disorganized thinking, grossly disorganized behaviour) which involves and typically occurs following an overdose or ...
Although many adverse effects are associated with -DOPA, in particular psychiatric ones, it has fewer than other
antiparkinsonian agents, such as
anticholinergic
Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system.
These agents inhibit the parasympathetic nervous system ...
s and
dopamine receptor agonist
A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...
s.
More serious are the effects of chronic -DOPA administration in the treatment of Parkinson's disease, which include:
* End-of-dose deterioration of function
* "On/off" oscillations
* Freezing during movement
* Dose failure (
drug resistance
Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, ...
)
*
Dyskinesia
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 t ...
at peak dose (
levodopa-induced dyskinesia
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.
In the context of Parkinson's dis ...
)
* Possible dopamine dysregulation: The long-term use of -DOPA in Parkinson's disease has been linked to the so-called
dopamine dysregulation syndrome
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 typically occurs in people with Parkinson's disease (PD) who have taken dop ...
.
Clinicians try to avoid these side effects and adverse reactions by limiting -DOPA doses as much as possible until absolutely necessary.
The long term use of L-Dopa increases oxidative stress through
monoamine oxidase
Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first ...
led enzymatic degradation of synthesized dopamine causing neuronal damage and cytotoxicity. The oxidative stress is caused by the formation of
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(H
2O
2) during the monoamine oxidase led metabolism of dopamine. It is further perpetuated by the richness of Fe
2+ ions in striatum via the Fenton reaction and intracellular
autooxidation
Autoxidation (sometimes auto-oxidation) refers to oxidations brought about by reactions with oxygen at normal temperatures, without the intervention of flame or electric spark. The term is usually used to describe the gradual degradation of organic ...
. The increased oxidation can potentially cause mutations in DNA due to the formation of
8-oxoguanine
8-Oxoguanine (8-hydroxyguanine, 8-oxo-Gua, or OH8Gua) is one of the most common DNA lesions resulting from reactive oxygen species modifying guanine, and can result in a mismatched pairing with adenine resulting in G to T and C to A substitutions ...
, which is capable of pairing with adenosine during
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
.
History
In work that earned him a
Nobel Prize
The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
in 2000,
Swedish
Swedish or ' may refer to:
Anything from or related to Sweden, a country in Northern Europe. Or, specifically:
* Swedish language, a North Germanic language spoken primarily in Sweden and Finland
** Swedish alphabet, the official alphabet used by ...
scientist
Arvid Carlsson
Arvid Carlsson (25 January 1923 – 29 June 2018) was a Swedish neuropharmacologist who is best known for his work with the neurotransmitter dopamine and its effects in Parkinson's disease. For his work on dopamine, Carlsson was awarded the No ...
first showed in the 1950s that administering -DOPA to animals with drug-induced (
reserpine
Reserpine is a drug that is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic reduces m ...
) Parkinsonian
symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
s caused a reduction in the intensity of the animals' symptoms. In 1960/61
Oleh Hornykiewicz
Oleh Hornykiewicz (17 November 1926 - 26 May 2020) was an Austrian biochemist.
Life
Oleh Hornykiewicz was born in 1926 in Sykhiw (a district of Lviv), then in Poland (now Ukraine). In 1951, he received his M.D. degree from the University of Vie ...
, after discovering greatly reduced levels of dopamine in autopsied brains of patients with Parkinson's disease,
published together with the neurologist
Walther Birkmayer dramatic therapeutic antiparkinson effects of intravenously administered -DOPA in patients.
This treatment was later extended to manganese poisoning and later Parkinsonism by
George Cotzias and his coworkers, who used greatly increased oral doses, for which they won the 1969
Lasker Prize
The Lasker Awards have been awarded annually since 1945 to living persons who have made major contributions to medical science or who have performed public service on behalf of medicine. They are administered by the Lasker Foundation, which was f ...
. The
neurologist
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
Oliver Sacks
Oliver Wolf Sacks, (9 July 1933 – 30 August 2015) was a British neurologist, naturalist, historian of science, and writer. Born in Britain, Sacks received his medical degree in 1958 from The Queen's College, Oxford, before moving to the Uni ...
describes this treatment in human patients with
encephalitis lethargica
Encephalitis lethargica is an atypical form of encephalitis. Also known as "sleeping sickness" or "sleepy sickness" (distinct from tsetse fly-transmitted sleeping sickness), it was first described in 1917 by neurologist Constantin von Economo a ...
in his 1973 book ''
Awakenings
''Awakenings'' is a 1990 American drama film directed by Penny Marshall. It is written by Steven Zaillian, who based his screenplay on Oliver Sacks's 1973 memoir ''Awakenings''. It tells the story of neurologist Dr. Malcolm Sayer (Robin Williams ...
'', upon which
the 1990 movie of the same name is based. The first study reporting improvements in patients with Parkinson's disease resulting from treatment with L-dopa was published in 1968.
The 2001
Nobel Prize in Chemistry
)
, image = Nobel Prize.png
, alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
was also related to -DOPA: the Nobel Committee awarded one-quarter of the prize to
William S. Knowles for his work on chirally catalysed
hydrogenation
Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a Catalysis, catalyst such as nickel, palladium or platinum. The process is commonly employed to redox, reduce or S ...
reactions, the most noted example of which was used for the synthesis of -DOPA.
:
Research
Age-related macular degeneration
In 2015, a retrospective analysis comparing the incidence of
age-related macular degeneration
Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...
(AMD) between patients taking versus not taking -DOPA found that the drug delayed onset of AMD by around 8 years. The authors state that significant effects were obtained for both dry and wet AMD.
See also
*
-DOPA (Dextrodopa)
*
-DOPS (Droxidopa)
*
Methyldopa
Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blood pressure including hypertensive e ...
(Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc.)
*
Dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
(Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.)
*
Ciladopa
*
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to neuroleptic or antipsychotic medication. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fas ...
*
Melanin
Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...
(a metabolite)
References
External links
*
{{DEFAULTSORT:DOPA, L-
Aromatic amino acids
Antiparkinsonian agents
Carbonic anhydrase activators
Catecholamines
Dopamine agonists
Prodrugs
Monoamine precursors