Levodopa treatment: impacts and mechanisms throughout Parkinson's disease progression

Abstract

Treatment with levodopa, a precursor of dopamine (DA), to compensate for the loss of endogenous DA in Parkinson's disease (PD), has been a success story for over 50 years. However, in late stages of PD, the progressive degeneration of dopaminergic neurons and the ongoing reduction in endogenous DA concentrations make it increasingly difficult to maintain normal-like DA function. Typically, in late PD, higher doses of levodopa are required, and the fluctuations in striatal DA concentrations-reflecting the timing pattern of levodopa administrations-become more pronounced. These DA fluctuations can include highs that induce involuntary movements (levodopa-induced dyskinesia, LID) or lows that result in insufficient suppression of PD symptoms ("OFF" phases). The enhanced fluctuations primarily arise from the loss of DA buffering capacity, resulting from the degeneration of DA neurons, and an increased reliance on levodopa-derived DA release as a "false neurotransmitter" by serotonergic neurons. In many patients, the LID and OFF-phases can be alleviated by modifying the levodopa therapy to provide a more continuous delivery or by using additional medications, such as monoamine oxidase-B (MAO-B) inhibitors, amantadine, or dopaminergic receptor agonists. Understanding the challenges faced by levodopa therapy also requires considering that the PD striatum is characterized not only by the loss of DA neurons but also by neuroplastic adaptations and PD-induced degenerations of other neural populations. This review provides a broad overview on the use of levodopa in treating PD, with a focus on the underlying science of the challenges encountered in late stages of the disease.

Keywords: Levodopa; Levodopa-induced dyskinesia (LID); Long duration response (LDR); Mode of action; OFF-phase; Parkinson’s disease; Progression.

Fig. 1

Overview of the synthesis of DA as an endogenous neurotransmitter or after conversion of exogenously administered levodopa. A DA is synthesized from tyrosine (Tyr) by a channelling mechanism with the enzymes tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (abbreviated as either AADC or DDC), and the transporter VMAT2 forming a complex at the vesicular membrane. The synthesized DA is stored in synaptic vesicles for release. Significant leakage of transmitter molecules out from vesicles has been observed. Upon arrival of an action potential, vesicles are emptied, and DA is released into the intercellular space. There, DA diffuses to DA-responsive target sites or is taken up by DA transporters (DAT). TH is inhibited by DA, and there is also an inhibition of TH from extracellular DA via D2 autoreceptor signalling. Monoamine oxidase (MAO) forms hydrogen peroxide (a reactive oxygen species (ROS)) during the metabolization of DA, and also autoxidation of DA leads to the production of ROS. The formulas on the right show the biochemistry of some of the ROS and quinone-generating reactions that DA(-synthesis) can be involved in and that are believed to contribute to the sensitivity of DA neurons to PD. This figure and its legend were adapted with permission from Segura Aguilar et al. , Kleppe et al. , and Watanabe et al. . B An advantage of L-DOPA over DA as a drug for treating PD is that it can pass the BBB. The transporter molecule LAT1 plays a role in this. Administered carbidopa blocks the conversion of L-DOPA to DA in the periphery. C In the striatum, the axons of 5HT neurons can take up exogenous L-DOPA and convert it into DA that increases the concentration of extracellular DA, at least if the number of DA neurons has diminished so that they can’t regulate those concentrations. While it has been proven that either exogenous levodopa itself or its derived DA can end up in DA neurons, there probably is no evidence showing that this leads to increased extracellular DA concentrations in the striatum, and DA neuron autoregulation mechanisms may keep a possible rise in check. This figure was adapted with permission from Farajdokht et al. (2020). Levodopa is believed to enter various cells, including neurons, involving large neutral amino acid (LNAA) transporter molecules, but the precise LNAA transporters used for entering serotonergic (5HT) or SNc DA neurons in the striatum seem not to be known (Kageyama et al. ; Mosharov et al. 2015)

Fig. 2

Risks of LID and OFF-phase after levodopa treatment increase in late PD. In early PD, in the striatum, if supported by some extra DA production from 5HT neurons that convert exogenous levodopa to DA as a false neurotransmitter, the remaining DA neurons are still sufficient to homogenize extracellular DA concentrations (they have a “buffering capacity”) and provide natural DA signals. In late PD, however, when the DA neurons diminish, more levodopa needs to be given so the 5HT neurons can produce more DA. Because these 5HT neurons do not reuptake DA or have any other DA-specific regulatory function, the wave of highs and lows in striatal DA concentrations starts to more exactly follow the timings of levodopa administration. These increased fluctuations increase the risk of LID and OFF-phase

Fig. 3

Increases in DA levels in the striatum promote activities by stimulating circuits that include D1 MSNs and inhibiting circuits that include D2 MSNs. Glutamatergic (stimulatory) neurons from different brain regions and from many different neurocircuits innervate the striatum. Here, neural activities are validated by DA that is released by dopaminergic neurons innervating from the ventral tegmental area (VTA) or the substantia nigra (SN). In the striatum, DA stimulates medium spiny neurons (MSNs) that express dopamine receptor D1, so-called D1-MSNs, and inhibits D2-MSNs. The activated D1-MSNs, which are GABAergic (inhibitory), relay through the substantia nigra pars reticulata (SNr) or globus pallidus externa (GPe) to inhibit the inhibition of neural activities that here are described as “Action/Process”; this stimulatory pathway is called the “direct pathway.” If striatal DA levels decrease, this stimulates D2-MSNs, which are also GABAergic and relay through the globus pallidus externa (GPe), subthalamic nuclei (STM), and GPi/SNr to form the “indirect pathway” that inhibits (because “ − − + − ” equals “ − ”) neural activities (“Action/Process”) that can be stimulated by the direct pathway. This figure and its legend were adapted with permission from Dijkstra and Nagatsu

Fig. 4

The major changes in the striatum during PD progression, including the changing responses to levodopa treatment