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Journal of Neural Transmission (Vienna,... Nov 2023Dopamine was initially considered as a mere intermediate in the noradrenaline synthesis but was then found to be a neurotransmitter. Its depletion resulted in... (Review)
Review
Dopamine was initially considered as a mere intermediate in the noradrenaline synthesis but was then found to be a neurotransmitter. Its depletion resulted in characteristic symptoms in experimental studies and could be antagonized by DOPA (3,4-dihydroxyphenylalanin), suggesting a similarity to the human disorder Parkinson´s disease (PD) and a therapeutic potential which was successfully exploited from the 1970s on. This was due to the pioneering work of Arvid Carlsson and clinicians around the world who first worked on the breakthrough of L-DOPA therapy and then on its amendment and modification and on alternative therapies for PD patients. All these developments led to the establishment of PD therapy as we know it today. It is characterized by the availability of many different compounds which are mostly employed in combination and by different methods: orally, intravenously, transdermally, subcutaneously, or duodenally. Here, we present without claim of completeness some personal reflections about causal drug developments for PD patients and reflect on some personal interactions with leading clinicians and basic researchers who cooperated with us. Such interactions are crucial for the creation, sometimes serendipitously, of fresh ideas and to further develop existing concepts to make therapeutical progress.
Topics: Humans; Levodopa; Parkinson Disease; Antiparkinson Agents; Berlin; Dopamine
PubMed: 37796288
DOI: 10.1007/s00702-023-02692-9 -
Cells Nov 2023A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications... (Review)
Review
A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson's disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies.
Topics: Humans; Levodopa; Phosphoric Diester Hydrolases; Glutamic Acid; Dyskinesia, Drug-Induced; Nucleotides, Cyclic
PubMed: 38067182
DOI: 10.3390/cells12232754 -
Parkinsonism & Related Disorders Sep 2023Most patients with Parkinson's disease (PD) receiving levodopa (LD)/DOPA decarboxylase inhibitors develop motor fluctuations with an increasing amount of OFF time,... (Review)
Review
Most patients with Parkinson's disease (PD) receiving levodopa (LD)/DOPA decarboxylase inhibitors develop motor fluctuations with an increasing amount of OFF time, negatively impacting patient quality of life. Herein, we review the evidence supporting the substantial, yet underappreciated contribution of delays in time to ON (including delayed ON and no ON) to total daily OFF time. Most clinical studies use patient diaries that do not capture time to ON and wearing OFF separately as related to LD dosing, and consequently, most OFF time has generally been attributed to wearing OFF. Hence, most treatment regimens focus on reducing wearing OFF by changing LD dosing/formulations and/or using "ON-extenders" (eg, catechol-o-methyltransferase inhibitors, monoamine oxidase-B inhibitors, extended-release amantadine, and adenosine A receptor antagonists). However, the literature describing approved treatments for PD that has focused on delays in time to ON is sparse and suggests this type of OFF may comprise more than twice the amount of total daily OFF time as wearing OFF. Here, we advocate for the importance of measuring and adequately addressing delays in time to ON and build support for the consistent inclusion of the time to ON measurement in future clinical trials.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Quality of Life; Catechol O-Methyltransferase; Levodopa
PubMed: 37517986
DOI: 10.1016/j.parkreldis.2023.105495 -
International Journal of Molecular... Nov 2021Dopamine (DA) is an important signal mediator in the brain as well as in the periphery. The term "dopamine homeostasis" occasionally found in the literature refers to...
Dopamine (DA) is an important signal mediator in the brain as well as in the periphery. The term "dopamine homeostasis" occasionally found in the literature refers to the fact that abnormal DA levels can be associated with a variety of neuropsychiatric disorders. An analysis of the negative feedback inhibition of tyrosine hydroxylase (TH) by DA indicates, with support from the experimental data, that the TH-DA negative feedback loop has developed to exhibit 3,4-dihydroxyphenylalanine (DOPA) homeostasis by using DA as a derepression regulator. DA levels generally decline when DOPA is removed, for example, by increased oxidative stress. Robust DOPA regulation by DA further implies that maximum vesicular DA levels are established, which appear necessary for a reliable translation of neural activity into a corresponding chemical transmitter signal. An uncontrolled continuous rise (windup) in DA occurs when Levodopa treatment exceeds a critical dose. Increased oxidative stress leads to the successive breakdown of DOPA homeostasis and to a corresponding reduction in DA levels. To keep DOPA regulation robust, the vesicular DA loading requires close to zero-order kinetics combined with a sufficiently high compensatory flux provided by TH. The protection of DOPA and DA due to a channeling complex is discussed.
Topics: Aging; Dihydroxyphenylalanine; Dopamine; Homeostasis; Humans; Levodopa; Models, Neurological; Oxidative Stress; Tyrosine 3-Monooxygenase
PubMed: 34884667
DOI: 10.3390/ijms222312862 -
Methods in Molecular Biology (Clifton,... 2023Imaging mass spectrometry (IMS) allows for visualization of the spatial distribution of proteins, lipids, and other metabolites in a targeted or untargeted approach. The...
Imaging mass spectrometry (IMS) allows for visualization of the spatial distribution of proteins, lipids, and other metabolites in a targeted or untargeted approach. The identification of compounds through mass spectrometry combined with the mapping of compound distribution in the sample establishes IMS as a powerful tool for metabolomics. IMS analysis for serotonin will allow researchers to pinpoint areas of deficiencies or accumulations associated with ocular disorders such as serotonin selective reuptake inhibitor optic neuropathy. Furthermore, L-DOPA has shown great promise as a therapeutic approach for disorders such as age-related macular degeneration, and IMS allows for localization, and relative magnitudes, of L-DOPA in the eye. We describe here an end-to-end approach of IMS from sample preparation to data analysis for serotonin and L-DOPA analysis.
Topics: Levodopa; Lipids; Metabolomics; Serotonin; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 36152160
DOI: 10.1007/978-1-0716-2699-3_16 -
Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa-Induced Dyskinesia.Movement Disorders : Official Journal... Mar 2023Current models of levodopa (L-dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-dopa. However, patients with LID receive...
BACKGROUND
Current models of levodopa (L-dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-dopa. However, patients with LID receive combination therapies that often include dopamine agonists.
OBJECTIVE
Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether an adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses.
METHODS
Different regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L-dopa monotreatment or L-dopa combined with ropinirole.
RESULTS
We defined chronic regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared with the monotreatment group, animals receiving the L-dopa-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood-brain barrier hyperpermeability was markedly reduced after L-dopa-ropinirole cotreatment compared with L-dopa monotreatment. Moreover, significant group differences were detected upon examining the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L-dopa-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L-dopa-ropinirole cotreated animals.
CONCLUSIONS
Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms and candidate interventions in both clinical and experimental settings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Rats; Animals; Levodopa; Dopamine Agonists; Antiparkinson Agents; Rats, Sprague-Dawley; Dyskinesia, Drug-Induced; Oxidopamine; Disease Models, Animal
PubMed: 36656044
DOI: 10.1002/mds.29301 -
The New Phytologist Aug 2020
Topics: Betalains; Caryophyllales; Dioxygenases; Levodopa; Pigmentation
PubMed: 31782527
DOI: 10.1111/nph.16295 -
Stem Cells (Dayton, Ohio) Mar 2022Neurogenesis occurs in the hippocampus throughout life and is implicated in various physiological brain functions such as memory encoding and mood regulation....
Neurogenesis occurs in the hippocampus throughout life and is implicated in various physiological brain functions such as memory encoding and mood regulation. L-3,4-dihydroxyphenylalanine (L-DOPA) has long been believed to be an inert precursor of dopamine. Here, we show that L-DOPA and its receptor, GPR143, the gene product of ocular albinism 1, regulate neurogenesis in the dentate gyrus (DG) in a dopamine-independent manner. L-DOPA at concentrations far lower than that of dopamine promoted proliferation of neural stem and progenitor cells in wild-type mice under the inhibition of its conversion to dopamine; this effect was abolished in GPR143 gene-deficient (Gpr143-/y) mice. Hippocampal neurogenesis decreased during development and adulthood, and exacerbated depression-like behavior was observed in adult Gpr143-/y mice. Replenishment of GPR143 in the DG attenuated the impaired neurogenesis and depression-like behavior. Our findings suggest that L-DOPA through GPR143 modulates hippocampal neurogenesis, thereby playing a role in mood regulation in the hippocampus.
Topics: Animals; Dopamine; Hippocampus; Levodopa; Mice; Mice, Inbred C57BL; Neurogenesis; Receptors, G-Protein-Coupled
PubMed: 35257172
DOI: 10.1093/stmcls/sxab013 -
Biochemistry Aug 2021Dioxygenase enzymes are essential protein catalysts for the breakdown of catecholic rings, structural components of plant woody tissue. This powerful chemistry is used...
Dioxygenase enzymes are essential protein catalysts for the breakdown of catecholic rings, structural components of plant woody tissue. This powerful chemistry is used in nature to make antibiotics and other bioactive materials or degrade plant material, but we have a limited understanding of the breadth and depth of substrate space for these potent catalysts. Here we report steady-state and pre-steady-state kinetic analysis of dopamine derivatives substituted at the 6-position as substrates of L-DOPA dioxygenase, and an analysis of that activity as a function of the electron-withdrawing nature of the substituent. Steady-state and pre-steady-state kinetic data demonstrate the dopamines are impaired in binding and catalysis with respect to the cosubstrate molecular oxygen, which likely afforded spectroscopic observation of an early reaction intermediate, the semiquinone of dopamine. The reaction pathway of dopamine in the pre-steady state is consistent with a nonproductive mode of binding of oxygen at the active site. Despite these limitations, L-DOPA dioxygenase is capable of binding all of the dopamine derivatives and catalyzing multiple turnovers of ring cleavage for dopamine, 6-bromodopamine, 6-carboxydopamine, and 6-cyanodopamine. 6-Nitrodopamine was a single-turnover substrate. The variety of substrates accepted by the enzyme is consistent with an interplay of factors, including the capacity of the active site to bind large, negatively charged groups at the 6-position and the overall oxidizability of each catecholamine, and is indicative of the utility of extradiol cleavage in semisynthetic and bioremediation applications.
Topics: Catalysis; Catalytic Domain; Catechols; Cyclization; Dioxygenases; Dopamine; Kinetics; Levodopa; Models, Molecular; Molecular Docking Simulation; Oxygenases; Substrate Specificity
PubMed: 34324302
DOI: 10.1021/acs.biochem.1c00310 -
Neurology Sep 2022
Topics: Humans; Levodopa
PubMed: 35715203
DOI: 10.1212/WNL.0000000000200982