What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?

Abstract

Levodopa is the most effective medication for motor symptoms in Parkinson's disease. However, various motor and non-motor complications are associated with levodopa treatment, resulting from altered levodopa-dopamine metabolism with disease progression and long-term use of the drug. The present review emphasizes the role of monoamine transporters other than the dopamine transporter in uptake of extracellular dopamine in the dopamine-denervated striatum. When dopaminergic neurons are lost and dopamine transporters decreased, serotonin and norepinephrine transporters compensate by increasing uptake of excessive extracellular dopamine in the striatum. Organic cation transporter-3 and plasma membrane monoamine transporter, low affinity, and high capacity transporters, also potentially uptake dopamine when high-affinity transporters do not work normally. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are often administered to patients with Parkinson's disease presenting with depression, pain or other non-motor symptoms. Thus, it is important to address the potential of these drugs to modify dopamine metabolism and uptake through blockade of the compensatory function of these transporters, which could lead to changes in motor symptoms of Parkinson's disease.

Salidroside Protection Against Oxidative Stress Injury Through the Wnt/β-Catenin Signaling Pathway in Rats with Parkinson’s Disease

“…Parkinson’s disease (PD) is a progressive neurological disease that is linked to the progressive loss of nigrostriatal dopaminergic neurons [1]. PD affects approximately 1% of the population aged 55 years and older; a positive correlation was found between the risk of PD and age [2].…”

Effects of Genetic Variability in Dopaminergic Pathway on Treatment Response in Parkinson’s Disease

“…However, since the continuous dopaminergic treatment options for advanced PD became available (subcutaneous apomorphine infusion, levodopa/carbidopa intrajejunal gel infusion, and deep brain stimulation), physicians are less hesitant to prescribe L-Dopa early in the disease course. L-Dopa is usually administered in the form of tablets, which are taken a few times daily (3-6 times) to deliver L-Dopa as continuously as possible [3,13,16,17]. Furthermore, COMT inhibitors, especially entacapone, are commonly used concomitantly with L-Dopa when early motor fluctuations (wearing-off phenomena) occur.…”

“…Degradation of dopamine can either be carried out in the presynaptic neuron after reuptake via DAT or in the glial cells. COMT is predominantly expressed in the glial cells, MAOB in the astrocytes, and MAOA in the catecholaminergic neurons like dopaminergic neurons of SN [12][13][14].…”

“…Dopamine itself is not suitable for oral treatment, because it cannot be transported to the brain through the BBB due to its high polarity. Moreover, it is also not an amino acid compound and is thus not a transporter substrate [13].…”

The assessment of pharmacoeconomic studies quality of Levodopa’s use for the management of Parkinson’s diseases, 2010-2015

“…Moreover, with the technology advancements, the PD's neurophysiological deficit is due to an affectation in the dopaminergic neurogenesis without a fully elucidated etiology [1,2]. Since 1960's, Levodopa (LD) is part of the PD's treatment, and it is still a standard drug in the therapeutic arsenal for the disease's management [3][4][5][6][7]. Besides, it satisfies two of the most relevant aspect when assessing an anti-Parkinson's medication effectiveness, disability, and mortality.…”