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L-DOPA ( or ) (alt., L-3,4-dihydroxyphenylalanine) is a chemical that is made and used as part of the normal biology of humans, some animals and plants. Some animals and humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. L-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Parcopa, Atamet, Stalevo, Madopar, and Prolopa. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.
L-DOPA has a counterpart with opposite chirality, D-DOPA. As is true for many molecules, the human body produces only one of these isomers (the L-DOPA form).
L-DOPA crosses the protective Lasker Prize.[1][2] Once L-DOPA has entered the central nervous system, it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase. Pyridoxal phosphate (vitamin B6) is a required cofactor in this reaction, and may occasionally be administered along with L-DOPA, usually in the form of pyridoxine.
Besides the central nervous system, L-DOPA is also converted into dopamine from within the peripheral nervous system. Excessive peripheral dopamine signaling causes many of the adverse side effects seen with sole L-DOPA administration. To bypass these effects, it is standard clinical practice to coadminister (with L-DOPA) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines containing carbidopa, either alone or in combination with L-DOPA, are branded as Lodosyn, Sinemet, Parcopa, Atamet, and Stalevo) or with a benserazide (combination medicines are branded Madopar or Prolopa), to prevent the peripheral synthesis of dopamine from L-DOPA. Coadministration of pyridoxine without a DDCI accelerates the peripheral decarboxylation of L-DOPA to such an extent that it negates the effects of L-DOPA administration, a phenomenon that historically caused great confusion.
In addition, L-DOPA, co-administered with a peripheral DDCI, has been investigated as a potential treatment for restless leg syndrome. However, studies have demonstrated "no clear picture of reduced symptoms".[3]
The two types of response seen with administration of L-DOPA are:
Herbal extracts containing L-DOPA are available; high-yielding sources include Mucuna pruriens (velvet bean),[4] and Vicia faba (broad bean),[5] while other sources include the genera Phanera, Pileostigma, Cassia, Canavalia, and Dalbergia.[6]
L-DOPA is produced from the amino acid L-tyrosine by the enzyme tyrosine hydroxylase. It is also the precursor for the monoamine or catecholamine neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Dopamine is formed by the decarboxylation of L-DOPA.
L-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 L-DOPA administration in patients with Parkinson's disease or in the rare cases of patients with aromatic L-amino acid decarboxylase enzyme deficiency.[9]
L-Phenylalanine, L-tyrosine, and L-DOPA are all precursors to the biological pigment melanin. The enzyme tyrosinase catalyzes the oxidation of L-DOPA to the reactive intermediate dopaquinone, which reacts further, eventually leading to melanin oligomers.
The side effects of L-DOPA may include:
Although many adverse effects are associated with L-DOPA, in particular psychiatric ones, it has fewer than other antiparkinsonian agents, such as anticholinergics and dopamine receptor agonists.
More serious are the effects of chronic L-DOPA administration in the treatment of Parkinson's disease, which include:
Clinicians try to avoid these side effects by limiting L-DOPA doses as much as possible until absolutely necessary.
Some in vitro studies suggest a cytotoxic role in the promotion and occurrence of adverse effects associated with L-DOPA treatment.[11] Though the drug is generally safe in humans, some researchers have reported an increase in cytotoxicity markers in rat pheochromocytoma PC12 cell lines treated with L-DOPA.[12][13] Other authors have attributed the observed toxic effects of L-DOPA in neural dopamine cell lines to enhanced formation of quinones through increased auto-oxidation and subsequent cell death in mesencephalic cell cultures.[14][15] There is no evidence of neurotoxicity in patients with Parkinson's disease and it is generally considered safe, but some controversy surrounds its use in the treatment of Parkinson's disease, given some test tube data indicate a deleterious effect on intracellular and neuronal tissue involved in the pathogenesis of the disease.[16]
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One double-blind, placebo controlled study (n=40) found that L-DOPA enhances learning of pseudowords. The drug group showed better learning in all comparisons. Furthermore, a dose-response relationship was tested and found to be the case: lighter people from the drug group did better than the heavier people.[25]
L-DOPA is a key compound in the formation of marine adhesive proteins, such as those found in mussels.[22][23] It is believed to be responsible for the water-resistance and rapid curing abilities of these proteins. L-DOPA may also be used to prevent surfaces from fouling by bonding antifouling polymers to a susceptible substrate.[24]
The 2001 Nobel Prize in Chemistry was also related to L-DOPA: the Nobel Committee awarded one-quarter of the prize to William S. Knowles for his work on chirally catalysed hydrogenation reactions, the most noted example of which was used for the synthesis of L-DOPA:[20][21]
is based. the movie of the same name, upon which Awakenings in his book encephalitis lethargica describes this treatment in human patients with Oliver Sacks neurologist who used greatly increased oral doses. The [19]
L-dopa, Norepinephrine, Amphetamine, Parkinson's disease, Schizophrenia
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