Dopamine in Parkinson s disease

Levodopa is the amino precursor of dopamine. It is used to replenish depleted dopamine in Parkinson s disease. Levodopa may cause insomnia, reddish discoloration of urine and headache. 

Txvo balanced systems are important in the extrapyramidal control of motor activity at the level of the corpus striatum and substantia nigra in one the neurotransmitter is acetylcholine in the other it is a dopamine. In Parkinson s disease there is degenerative loss of nigrostriatal dopaminergic neurons and the sjunptoms and signs of the disease are due to dopamine depletion. 

Adult dopamin-containing neurons in the substantia nigra rely on Cavl. 3 channels as pacemaker channels. It appears that the resulting enhanced Ca2+ load renders these channels more susceptible to neurotoxic effects and neurodegeneration as observed in Parkinson s disease. Preclinical evidence suggests that block of these with dihydropyridines causes a switch to a Cavl.3-independent pacemaker and protects these neurons from neurotoxicity. 

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... 

A synthetic neurotoxin that causes parkinsonism in human and nonhuman primates, mice, gold fish, and dogs. MPTP is inert but metabolized by MAO-B to the neurotoxin MPP+ (1,2-dihydropyridine ion). This neurotoxin causes depletion of dopamine and degeneration of nigrostriatal dopamine neurons similar to what is observed in Parkinson s disease. 

Figure 7.8 Dopamine and motor function. When nigrostriatal dopamine activity is normal so is motor function. Any reduction in this DA activity, as in Parkinson s disease, results in reduced motor activity, i.e. akinesia. By contrast, too much DA activity, as in Huntington s Chorea, produces abnormal motor function, i.e. dyskinesia. The latter may be controlled by neuroleptic drugs (DA antagonists) but they can swing the balance in DA activity sufficiently to produce akinesia (Parkinsonism). DA agonists (and levodopa) may overcome akinesia but can induce DA overactivity and dyskinesia (peak dose effect) (see Chapter 15)...

The beneficial effect of deprenyl in Parkinson s disease was su ested to be in part due to its effect on increasing the levels of SOD activity in several brain regions (Carrillo et al., 1993). Deprenyl is known to inhibit monoamine oxidase type B, which results in a reduction in hydrogen peroxide formation by blockade of the oxidative deamination of dopamine. That is believed to be the major mechanism of action of this drug in inhibiting the progression of Parkinson s disease. 

Brotsie JM. Adjuncts to dopamine replacement, a pragmatic approach to reducing the problem of dyskinesia in Parkinson s disease. Mot Disord 1998 13 871-876. 

Roth T., Rye D Borchert L. et al. (2003). Assessment of sleepiness and unintended sleep in Parkinson s disease patients taking dopamine agonists. Sleep Med. 4, 275-80. 

Schoemaker, H., Pimoule, C., Arbilla, S., Scatton, B., Javoy-Agid, R, and Langer, S.Z., Sodium dependent pH]cocaine binding associated with dopamine uptake sites in the rat striatum and human putamen decrease after dopamine denervation and in Parkinson s disease, Naunyn-Schmiedeberg s Arch. Pharmacol., 329, 227, 1985. 

Varrone, A., Marek, K. L., Jennings, D. et al. 123I 5-CIT SPECT imaging demonstrates reduced density of striatal dopamine transporters in Parkinson s disease and multiple system atrophy. Mov. Disord. 16 1023-1032, 2001. 

Asenbaum, S., Brucke, T., Pirker, W. etal. Imaging of dopamine transporters with iodine-123-beta-CIT and SPECT in Parkinson s disease. /. Nucl. Med. 38 1-6,1997. 

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.

Much attention has been paid to the catecholamines noradrenaline and dopamine following the discovery that their depletion in the brain leads to profound mood changes and locomotor deficits. Thus noradrenaline has been implicated in the mood changes associated with mania and depression, while an excess of dopamine has been implicated in schizophrenia and a deficit in Parkinson s disease. 

Bromocriptine is a dopamine agonist acting by direct stimulation of the dopamine receptors. In Parkinson s disease, it is reserved for use in patients who are intolerant to levodopa or in whom levodopa alone is not sufficient. Orphenadrine is an antimuscarinic indicated in Parkinson s disease. Antimuscarinics tend to be more effective than levodopa in targeting tremor rather than rigidity and bradykinesia. Moclobemide is an antidepressant referred to as a reversible monoamine oxidase inhibitor (RIAAA) type A. 

Domperidone is a dopamine antagonist that acts on the chemoreceptor trigger zone. It can therefore be used as an anti-emetic in nausea and vomiting, for example, to counteract side-effects of cytotoxic therapy and to treat nausea associated with dopaminergic drugs used in Parkinson s disease. Unlike hyoscine butlybromide and antihistamines, domperidone is ineffective in motion sickness. 

Corsini G Del Zompo M, Gessa G Mangoni A. (1979) Therapeutic efficacy of apomorphine combined with an extracerebral inhibitor of dopamine receptors in Parkinson s disease. Lancet 1 954-956. 

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