Page 39 - GALENIKA MEDICAL JOURNAL

Abstract

January 2023 marks the 100th anniversary of the birth of Arvid Carlsson, a Swedish scientist, one of the three winners
of the Nobel Prize in Medicine in 2000 "for proving that dopamine is a brain neurotransmitter whose deficiency leads to
the symptoms of Parkinson's disease". Levodopa therapy is one of the main achievements of neurology in the twentieth
century, and Parkinson' s disease was the first disease in which a specific neurochemical deficiency was confirmed in
defined regions of the brain, which forms the basis for rational, chemically supported therapy.

The paper briefly reviews the most important achievements in the discovery of dopamine and levodopa, as well as their
functions in the development of Parkinson's disease. Dopamine synthesis, understanding of levodopa synthesis method,
possibility of measuring dopamine concentration in putamen and caudate and its loss in Parkinson' s disease, along
with histochemical visualization of nigrostriatal pathway and animal lesion model, enabled understanding of the role of
nigrostriatal dopamine system in the development of Parkinson's disease symptoms.

Part of the work is devoted to the metabolism of dopamine in healthy dopaminergic neurons, and then to its functioning
in dopaminergic neurons of Parkinson's disease patients. It is known that in Parkinson's disease, dopamine deficiency
occurs due to selective degeneration of nigrostriatal dopaminergic neurons. Their suffering is triggered by a cascade of
events that included the action of potential toxins, the influence of susceptibility genes on the body's response to them,
oxidative stress caused by mitochondrial dysfunction, dysfunction of the ubiquitous proteasomal system that leads to the
accumulation of incorrectly "packaged" proteins, the exhaustion of the endoplasmic reticulum system and the activation of
mycoglia that follows inflammatory process. These changes can lead to programmed cell death of dopaminergic neurons
with consequent dopamine deficiency and the development of PD.

Special attention is paid to the consequences of neuron loss on the functioning of the remaining dopaminergic neurons
and dopamine receptors, with reference to the therapeutic motor complications that may arise on that occasion. The
basic assumptions about the occurrence of therapeutic complications are still related to the pharmacokinetics of levodopa
and the model of its delivery to the brain, which results in non-physiological, pulsatile stimulation of dopamine receptors.
Today's possibilities in achieving a more stable concentration of levodopa with existing strategies are presented, with
an answer to the question of whether continuous stimulation can be achieved under the conditions of standard, regular
patients' levodopa therapy. In the short final part, the position of levodopa in the guidelines and recommendations for
treatment is commented.

It is expected that L-dopa will remain the "gold standard" for the treatment of PD at least until the development of more
potent and safer dopamine agonists or the development of neuroprotective or neurorestorative therapies.

Keywords: dopamine, levodopa, Parkinson's disease

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REVIJALNI RADOVI Galenika Medical Journal, 2023; 2(5):31-39. 37