L-Dopa in Parkinson’s disease

An alternative delivery strategy for small molecules is based on the presence of the nutrient transporters. Drugs that are structurally similar to substrates of a carrier system can undergo facilitated brain uptake as pseudoneutrients. The best example of this is the therapeutic use of L-DOPA in Parkinson s disease. Unlike the neurotransmitter dopamine itself, which cannot cross the BBB in significant amounts, its precursor L-DOPA is a substrate for LAT, the transporter of large neutral amino acids [56]. Its uptake by the brain is saturable, and subject to competition by the other substrates of the carrier present in plasma. 

Hussain G, Manyam BV, Mucunapruriens more effective than L-DOPA in Parkinson s disease animal model. Phytotherapy Res 11 419—423, 1997. 

Phenothiazine-type antipsychotics will potentiate the CNS depressant action of many drugs including opiates and will potentiate the effects of general anaesthetic agents. All antipsychotics will antagonise the effect of L-dopa in Parkinson s disease, making management of this difficult where it co-occurs with psychosis. 

Fig. 7. Depiction of the hypothetical relationship between the locus of DA depletion in cortico-striatal loops , cognitive and motor performance and the effects of L-Dopa (see Swainson et al., 2000 Cools et al., 2001). Whereas some forms of cognitive performance are improved by L-Dopa in Parkinson s disease, reversal learning is impaired- possibly as a consequence of the ventral cortico-striatal loops being less severely depleted than the more dorsal loops , thus leading to effective over-dosing of this circuitry by L-Dopa. Adapted from Swainson et ah (2000).

Q5 Present the rationale for prescribing carbidopa in combination with L-dopa in Parkinson s disease. 

Camicioli R, Lea E, Nutt JG, Sexton G, Oken BS. Methylphenidate increases the motor effects of L-dopa in Parkinson s disease a pilot study. Clin Neuropharmacol 2001 24(4) 208-13. 

Wodak J, Gilligan BS, Veale JL, Dowty BJ, Review of 12 months treatment with L-dopa in Parkinson s disease, with remarks on unusual side effects, MedJAust (1972) 2,1277-82. 

Heikkinen H, Nutt JG, LeWitt PA, Roller WC, Gordin A. The effects of different repeated doses of entacapone on the pharmacokinetics of L-dopa and on the clinical response to L-dopa in Parkinson s disease. Clin Neuropharmacol (2001) 24,150-7. 

DOPA-responsive dystonia (DRD) is a disorder characterized by childhood or adolescent onset dystonia and by the dramatic response to low-dose l-DOPA, a precursor of dopamine. DRD is a hereditary disorder in an autosomal dominant trait with reduced penetrance, and constitutes approximately 5 to 10% of primary dystonia in childhood and adolescence. DRD is caused by the dysfunction of nigro-striatal dopaminergic neurons, as indicated by the dramatic effect of l-DOPA. Although Parkinson s disease is also caused by the dysfunction of nigro-striatal dopaminergic neurons due to the degeneration of the dopaminergic neurons, the differences in symptoms, i.e. dystonia in DRD and parkinsonism in Parkinson s disease, has not yet been clarified. 

Antipsychotic medications are indicated in the treatment of acute and chronic psychotic disorders. These include schizophrenia, schizoaffective disorder, and manic states occurring as part of a bipolar disorder or schizoaffective disorder. The co-adminstration of antipsychotic medication with antidepressants has also been shown to increase the remission rate of severe depressive episodes that are accompanied by psychotic symptoms. Antipsychotic medications are frequently used in the management of agitation associated with delirium, dementia, and toxic effects of both prescribed medications (e.g. L-dopa used in Parkinson s disease) and illicit dtugs (e.g. cocaine, amphetamines, andPCP). They are also indicated in the management of tics that result from Gilles de la Tourette s syndrome, and widely used to control the motor and behavioural manifestations of Huntington s disease. 

The nigrostriatal system is predominantly involved in motor control, which is particularly evident in Parkinson s disease (PD), where a progressive loss of these neurons results in loss of motor function. In the early stages of the disorder, the motor impairment can be reversed by the administration of the dopamine precursor l-DOPA (L-3,4-dihydroxyphenylalanine), which bypasses the need for TH in dopamine... 

Intracellular Fe is usually tightly regulated, being bound by ferritin in an insoluble ferrihydrite core, and impaired Fe homeostasis has been linked to Parkinson s disease and Alzheimer s disease. A consistent neurochemical abnormality in Parkinson s disease is degeneration of dopaminergic neurons relating to a reduction of striatal dopamine levels. As tyrosine hydroxylase (Fig. 24) (494), an Fe enzyme, catalyzes the formation of l-DOPA, the rate-limiting step in the biosynthesis of dopamine, the disease can be considered as a tyrosine... 

Figure 11.17 Supplementation of diet with y-linolenic acid to overcome a deficiency of A desaturase Supplementation of a diet with DOPA to overcome a deficiency of monooxygenase in Parkinson s disease. A desaturase is a rate-limiting enzyme in the synthesis of arachidonic acid. Supplementation of diet with y-linolenic acid bypasses this enzyme. Damage to neurones in the brain that use dopamine as a neurotransmitter causes a deficiency of rate-limiting a supplement - enzyme, tyrosine monooxygenase, which is bypassed by a supplement, DOPA (dihydroxyphenylalanine). DOPA (usually, described as L-DOPA) is considered by the medical profession as a drug but, in reality, it is a dietary supplement.

Luginger E, Wenning GK, BOsch S, Poewe W (2000) Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson s disease. Mov Disord 15 873-878 Ly CD, Roche KW, Lee HK, Wenthold RJ (2002) Identification of rat EMAP, a delta-glutamate receptor binding protein. Biochem Biophys Res Commun 291 85-90 Madden DR (2002) The structure and function of glutamate receptor ion channels. Nat Rev Neurosci 3 91-101... 

This approach is also applied successfully in Parkinson s disease. Drugs such as entacapone inhibit the activity of the enzyme catechol-omethyltransferase (COMT), which is involved in degradation of the neurotransmitter dopamine, and thus increase and prolong the availability of dopamine in the synaptic cleft. Inhibition of COMT and substitution of L-Dopa are often combined in the therapy of Parkinson patients. 

The etiology of progressive death of dopaminergic neurons in substantia nigra of Parkinson s disease brains remains unclear. Dopamine deficiency in Parkinson s disease is commonly treated with L-dopa and carbidopa, a periphera dopa decarboxylase inhibitor (Sinemet). Since its introduction, L-dopa has been shown to be effective in treating Parkinson s disease. However, high concentrations of L-dopa produce side effects such as psychosis, on-off effects, abnormal involuntary movements, and akinetic crisis. 

Dopamine biosynthesis is diminished in Parkinson s disease. L-Dopa, a precursor of dopamine, is given in large doses as a therapeutic agent. 

Cools R, Lewis SJ, Clark L, Barker RA, Robbins TW. 2007. L-DOPA disrupts activity in the nucleus accumbens during reversal learning in Parkinson s disease. Neuropsychophar-... 

Lange KW, Robbins TW, Marsden CD, James M, Owen AM, Paul GM (1992) L-dopa withdrawal selectively impairs performance in tests of frontal lobe function in Parkinson s disease. Psychopharmacology 707 394-404. 

Pyridoxine (vitamin Bb, in the form of pyridoxal phosphate) is a cofactor in the formation of dopamine from L-DOPA. It used to be thought that pyridoxine supplements would be helpful to treat Parkinson s disease. The opposite was found vitamin B6 apparently also enhances L-DOPA conversion to dopamine in other areas of the body. This means that less of the administered L-DOPA is available for entry into tlie brain. Therefore, Be treatment presently is contraindicated in Parkinson s disease. 

Kaasinen V, Maguire RP, Hundemer HP, Leenders KL (2006) Corticos-triatal covariance patterns of 6-[(18)F]fluoro-L-dopa and [(18)F]fluor odeoxyglucose PET in Parkinson s disease. J Neurol 253 340-348. 

De Keyser J, Vincken W. L-dopa-induced respiratory disturbance in Parkinson s disease suppressed by tiapride. Neurology 1985 35(2) 235-7. 

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