DOPA brain barrier

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

Attention has been given to the possibility that some of the above motor effects may arise from a metabolite of levodopa. The prime suspect is OMD which has a half-life of some 20 hours and reaches plasma concentrations three- to fourfold those of dopa. Suggestions that it may compete with dopa for entry across the blood-brain barrier or act as a partial agonist (effective antagonist) have not been substantiated experimentally although it does reduce DA release from rat striatal slices. Also if free radical production through deamination of DA is neurotoxic (see below) then this would be increased by levodopa. 

FIGURE 29-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase, and catechol-O-methyltransferase. Carbidopa does not cross the blood-brain barrier. Large, neutral amino acids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain (plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals. 

Carbidopa, a dopa-decarboxylase inhibitor, is added to the levodopa in order to decrease the peripheral conversion of levodopa to dopamine. It does not cross the blood-brain barrier and does not interfere with levodopa conversion in the brain. Concomitant administration of carbidopa and levodopa allows for lower levodopa doses and minimizes levodopa peripheral side effects such as nausea, vomiting, anorexia, and hypotension. For most patients, at least 75 to 100 mg daily of carbidopa is required to adequately block dopamine decarboxylase in the peripheral metabolism of levodopa in most patients. Taking extra carbidopa may reduce nausea related to initiating levodopa.8,16... 

L-dopa is effective in the treatment of Parkinson s disease, a disorder characterised by low levels of dopamine, since L-dopa is metabolised into dopamine. However, this biosynthesis normally occurs in both the peripheral nervous system (PNS) and the central nervous system CNS. The related drug carbidopa inhibits aromatic L-amino acid decarboxylase only in the periphery, since it does not cross the blood-brain barrier. So, when carbidopa is given with L-dopa, it reduces the biosynthesis of L-dopa to dopamine in the periphery and, thus, increases the bioavailability of L-dopa for the dopaminergic neurons in the brain. Hence, carbidopa increases the clinical efficacy of L-dopa for Parkinsonian patients. 

Levodopa is converted to dopamine in the peripheral tissues by dopa decarboxylase, which has pyridoxine as a cofactor. Excess of this vitamin will increase this reaction, which is an undesirable effect because dopamine does not cross the blood-brain barrier where the therapeutic effect is desired. 

L-dopa, the most effective drug available, is the immediate precursor of dopamine. It crosses the blood-brain barrier, whereas dopamine does not. Ultimately, all PD patients will require L-dopa. 

An interesting example of the above difference is l-DOPA 4, which is used in the treatment of Parkinson s disease. The active drug is the achiral compound dopamine formed from 4 via in vivo decarboxylation. As dopamine cannot cross the blood-brain barrier to reach the required site of action, the prodrug 4 is administered. Enzyme-catalyzed in vivo decarboxylation releases the drug in its active form (dopamine). The enzyme l-DOPA decarboxylase, however, discriminates the stereoisomers of DOPA specifically and only decarboxylates the L-enantiomer of 4. It is therefore essential to administer DOPA in its pure L-form. Otherwise, the accumulation of d-DOPA, which cannot be metabolized by enzymes in the human body, may be dangerous. Currently l-DOPA is prepared on an industrial scale via asymmetric catalytic hydrogenation. 

Involvement of several proteolytic enzymes, secretases, is probably crucial for this process but other hypotheses, including, for example, cholinergic transmission or accumulation of metal ions, have also been considered. Future perspectives in this area concern the search for novel pharmaceuticals that cross the blood-brain barrier, without side effects (e.g., the dyskinesias of L-Dopa), or potent and selective inhibitors of improper cleavage of amyloid protein, or even stem cell therapy to restore neuronal cells. 

The fact that the modes of action of clonidine and a-methylnoradrenaline are similar to the mode of action of the physiological transmitter noradrenaline indicates the importance of the role of the latter in the central control of blood pressure. It may be mentioned that 1-dopa too, the precursor of noradrenaline, penetrates the blood-brain barrier and causes hypotension and bradycardia after systemic administration, when do-... 

T. Kageyama, M. Nakamura, A. Matsuo, Y. Yamasaki, Y. Takakura, M. Hashida, Y. Kanai, M. Naito, T. Tsuruo, N. Minato, and S. Shimohama. The 4F2hc/LATl complex transports L-DOPA across the blood-brain barrier. Brain Res. 879 115— 121 (2000). 

Six patients with Parkinson s disease were withdrawn from their antiparkinsonian medications (L-DOPA/carbidopa, bromocriptine, or lisuride) (Rabey et al. 1992, 1993). After 12 hours off medication, the subjects ate 250 g of cooked fava beans. Significant improvements in motor symptoms were noted, comparable to those seen with 125 mg of L-DOPA and 12.5 mg of carbidopa. In fact, three subjects developed severe dyskinesias after fava ingestion, akin to those seen after larger doses of pharmaceutical L-DOPA. Plasma levels of L-DOPA increased after fava ingestion in a manner comparable to that seen with administration of oral L-DOPA. These results suggest that the L-DOPA contained in fava beans was transported into the CNS and converted to dopamine. In five nonparkinsonian, healthy volunteers, a similar increase in plasma L-DOPA was observed after fava ingestion, although much lower. The difference in plasma L-DOPA between normal volunteers and parkinsonian patients is apparently due to a residual effect of carbidopa in the subjects with Parkinson s disease. Without carbidopa, the L-DOPA from fava is rapidly converted to dopamine in the blood stream and never crosses the blood-brain barrier. 

Now the great thing about L-dopa is that it does get across the blood-brain barrier. Once in the brain, an enzyme known as dopa decarboxylase converts it to dopamine. The results for patients can be dramatic have a look at stories in Oliver Sacks book... 

There is one further elaboration on this therapeutic scheme well worth knowing about. Dopa decarboxylase occurs in peripheral tissues and blood as well as in the brain. Close to 90% of administered L-dopa can be converted to dopamine by this enzyme before it gets into the brain. That is not good since a huge fraction of the L-dopa is lost. This problem was overcome in a very neat way. Carbidopa is an inhibitor of dopa decarboxylase that does not penetrate the blood-brain barrier ... 

In the central nervous system (brain and spinal cord), capillary endo-theUa lack pores and there is little transcytotic activity. In order to cross the blood-brain barrier, drugs must diffuse transcellularly, i.e., penetrate the luminal and basal membrane of endothelial cells. Drug movement along this path requires specific physicochemical properties (p. 26) or the presence of a transport mechanism (e.g., L-dopa, p. 188). Thus, the blood-brain barrier is permeable only to certain types of drugs. 

Methyldopa (dopa = dihydroxy-phenylalanine), as an amino acid, is transported across the blood-brain barrier, decarboxylated in the brain to a-methyldopamine, and then hydroxylat-ed to a-methyl-NE The decarboxylation of methyldopa competes for a portion of the available enzymatic activity, so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter a-methyl-NE can be stored however, unlike the endogenous mediator, it has a higher affinity for a2- than for ai-receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral adrenergic neurons. 

L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier however, its natural precursor, L-dihydroxy-phenylalanine (levodopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy-lated by DOPA-decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed, likely causing undesirable effects (tachycardia, arrhythmias resulting from activation of Pi-adrenoceptors [p. 114], hypotension, and vomiting). Extracerebral production of dopamine can be prevented by inhibitors of DOPA-decarboxylase (car-bidopa, benserazide) that do not penetrate the blood-brain barrier, leaving intracerebral decarboxylation unaffected. Excessive elevation of brain dopamine levels may lead to undesirable reactions, such as involuntary movements (dyskinesias) and mental disturbances. 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

Entacapone is a reversible inhibitor of peripheral catechol-O-methyltransferase (COMT). It is given at the dose of 200 mg with each dose of levodopa. It prolongs the action of levodopa and reduces synthesis of 3-O-methyldopa which is presumed to antagonize dopa passage through the blood-brain barrier. 

Medicinal chemistry has many examples of the development of successful therapeutics based on an exploration of endogenous compounds. The treatment of diabetes mellitus, for example, is based upon the administration of insulin, the hormone that is functionally deficient in this disease. The current treatment of Parkinson s disease is based upon the observation that the symptoms of Parkinson s disease arise from a deficiency of dopamine, an endogenous molecule within the human brain. Since dopamine cannot be given as a drug since it fails to cross the blood-brain barrier and enter the brain, its biosynthetic precursor, L-DOPA, has been successfully developed as an anti-Parkinson s drug. Analogously, the symptoms of Alzheimer s disease arise from a relative deficiency of acetylcholine within the brain. Current therapies for Alzheimer s-type dementia are based upon the administration of cholinesterase... 

Carbidopa (4.75), a hydrazine analog of a-methyldopa, is an important DOPA decarboxylase inhibitor. It is used to protect the DOPA that is administered in large doses in Parkinson s disease (section 4.4.4) from peripheral decarboxylation. DOPA concentrations in the CNS will therefore increase without requiring the administration of extremely high, toxic doses of DOPA. The exclusive peripheral mode of action of carbidopa is due to its ionic character and inability to cross the blood-brain barrier. Because of this effect, carbidopa is co-administered with DOPA in a single tablet formulation as a first-line therapy for Parkinson s disease. Benserazide (4.76) has similar activity. 

Since Parkinson s disease arises from a deficiency of DA in the brain, the logical treatment is to replace the DA. Unfortunately, dopamine replacement therapy cannot be done with DA because it does not cross the blood-brain barrier. However, high doses (3-8 g/day, orally) of L(-)-DOPA (levodopa), a prodrug of DA, have a remarkable effect on the akinesia and rigidity. The side effects of such enormous doses are numerous and unpleasant, consisting initially of nausea and vomiting and later of uncontrolled movements (limb dyskinesias). The simultaneous administration of carbidopa (4.75) or benserazide (4.76)—peripheral DOPA decarboxylase inhibitors—allows the administration of smaller doses, and also prevents the metabolic formation of peripheral DA, which can act as an emetic at the vomiting center in the brainstem where the blood-brain barrier is not very effective and can be penetrated by peripheral DA. 

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