-DOPA crosses the protective blood-brain barrier, whereas dopamine itself cannot. Thus, -DOPA is used to increase dopamine concentrations in the treatment of Parkinson's disease and dopamine-responsive dystonia. Once -DOPA has entered the central nervous system, it is converted into dopamine by the enzymearomatic -amino acid decarboxylase, also known as DOPA decarboxylase. Pyridoxal phosphate is a required cofactor in this reaction, and may occasionally be administered along with -DOPA, usually in the form of pyridoxine. In humans, conversion of -DOPA to dopamine does not only occur within the central nervous system. Cells in the peripheral nervous system 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 effects seen with sole L-DOPA administration. To bypass these effects, it is standard clinical practice to coadminister a peripheral DOPA decarboxylase inhibitor such as carbidopa Sinemet, Pharmacopa, Atamet, Syndopa and Stalevo or with a benserazide, to prevent the peripheral synthesis of dopamine from -DOPA. Inbrija 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. It was approved by the United Statee Food and Drug Administration on December 21, 2018 and is marketed by Acorda Therapeutics. Coadministration of pyridoxine without a DDCI accelerates the peripheral decarboxylation 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. 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 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 by the enzyme tyrosine hydroxylase. It is also the precursor for the monoamine or catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine. Dopamine is formed by the decarboxylation of -DOPA by aromatic -amino acid decarboxylase. -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 pigmentmelanin. The enzyme tyrosinasecatalyzes the oxidation of -DOPA to the reactive intermediate dopaquinone, which reacts further, eventually leading to melanin oligomers. In addition, tyrosinase can convert tyrosine directly to -DOPA in the presence of a reducing agent such as ascorbic acid.
Nausea, which is often reduced by taking the drug with food, although protein reduces drug absorption. -DOPA is an amino acid, so protein competitively inhibits -DOPA absorption.
Although many adverse effects are associated with -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 -DOPA administration in the treatment of Parkinson's disease, which include:
Possible dopamine dysregulation: The long-term use of -DOPA in Parkinson's disease has been linked to the so-called dopamine dysregulation syndrome.
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 led enzymatic degradation of synthesized dopamine causing neuronal damage and cytotoxicity. The oxidative stress is caused by the formation of reactive oxygen species during the monoamine oxidase led metabolism of dopamine. It is further perpetuated by the richness of Fe2+ ions in striatum via the Fenton reaction and the intracellular auto-oxidation. The increased oxidation can potentially cause mutations in the DNA due to the formation of 8-oxoguanine which is capable of pairing with adenosine.
History
In work that earned him a Nobel Prize in 2000, Swedish scientist Arvid Carlsson first showed in the 1950s that administering -DOPA to animals with drug-induced Parkinsonian symptoms caused a reduction in the intensity of the animals' symptoms. In 1960/61 Oleh Hornykiewicz, after discovering greatly reduced levels of dopamine in autopsied brains of patients with Parkinson's disease, published together with the neurologistWalther 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, for which they won the 1969 Lasker Prize., who used greatly increased oral doses. The neurologist Oliver Sacks describes this treatment in human patients with encephalitis lethargica in his book Awakenings, upon which the 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 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 reactions, the most noted example of which was used for the synthesis of -DOPA.
Dietary supplements
containing -DOPA are available; high-yielding sources include Mucuna pruriens, and Vicia faba, while other sources include the genera Phanera, Piliostigma, Cassia, Canavalia, and Dalbergia.
Marine adhesion
-DOPA is a key compound in the formation of marine adhesive proteins, such as those found in mussels. 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.
Research
Age-related macular degeneration
In 2015, a retrospective analysis comparing the incidence of age-related macular degeneration 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.
