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Current Opinion in Neurobiology Feb 2024L-DOPA-induced dyskinesia (LID) is the most common form of hyperkinetic movement disorder resulting from altered information processing in the cortico-basal ganglia... (Review)
Review
L-DOPA-induced dyskinesia (LID) is the most common form of hyperkinetic movement disorder resulting from altered information processing in the cortico-basal ganglia network. We here review recent advances clarifying the altered interplay between striatal output pathways in this movement disorder. We also review studies revealing structural and synaptic changes to the striatal microcircuitry and altered cortico-striatal activity dynamics in LID. We furthermore highlight the recent progress made in understanding the involvement of cerebellar and brain stem nuclei. These recent developments illustrate that dyskinesia research continues to provide key insights into cellular and circuit-level plasticity within the cortico-basal ganglia network and its interconnected brain regions.
Topics: Humans; Dyskinesia, Drug-Induced; Levodopa; Basal Ganglia; Corpus Striatum; Brain
PubMed: 38184982
DOI: 10.1016/j.conb.2023.102833 -
Cellular and Molecular Neurobiology Aug 2023Parkinson's disease (PD) is one of the most common degenerative brain disorders caused by the loss of dopaminergic neurons in the substantia nigra (SN). Lewy bodies and... (Review)
Review
Parkinson's disease (PD) is one of the most common degenerative brain disorders caused by the loss of dopaminergic neurons in the substantia nigra (SN). Lewy bodies and -synuclein accumulation in the SN are hallmarks of the neuropathology of PD. Due to lifestyle changes and prolonged L-dopa administration, patients with PD frequently have vitamin deficiencies, especially folate, vitamin B6, and vitamin B12. These disorders augment circulating levels of Homocysteine with the development of hyperhomocysteinemia, which may contribute to the pathogenesis of PD. Therefore, this review aimed to ascertain if hyperhomocysteinemia may play a part in oxidative and inflammatory signaling pathways that contribute to PD development. Hyperhomocysteinemia is implicated in the pathogenesis of neurodegenerative disorders, including PD. Hyperhomocysteinemia triggers the development and progression of PD by different mechanisms, including oxidative stress, mitochondrial dysfunction, apoptosis, and endothelial dysfunction. Particularly, the progression of PD is linked with high inflammatory changes and systemic inflammatory disorders. Hyperhomocysteinemia induces immune activation and oxidative stress. In turn, activated immune response promotes the development and progression of hyperhomocysteinemia. Therefore, hyperhomocysteinemia-induced immunoinflammatory disorders and abnormal immune response may aggravate abnormal immunoinflammatory in PD, leading to more progression of PD severity. Also, inflammatory signaling pathways like nuclear factor kappa B (NF-κB) and nod-like receptor pyrin 3 (NLRP3) inflammasome and other signaling pathways are intricate in the pathogenesis of PD. In conclusion, hyperhomocysteinemia is involved in the development and progression of PD neuropathology either directly via induction degeneration of dopaminergic neurons or indirectly via activation of inflammatory signaling pathways.
Topics: Humans; Parkinson Disease; Hyperhomocysteinemia; Levodopa; Substantia Nigra; Neurodegenerative Diseases; Dopaminergic Neurons
PubMed: 37074484
DOI: 10.1007/s10571-023-01350-8 -
Cerebellum (London, England) Oct 2023Multiple system atrophy (MSA) is a rare, adult-onset, progressive neurodegenerative disorder with major diagnostic challenges. Aiming for a better diagnostic accuracy... (Review)
Review
Multiple system atrophy (MSA) is a rare, adult-onset, progressive neurodegenerative disorder with major diagnostic challenges. Aiming for a better diagnostic accuracy particularly at early disease stages, novel Movement Disorder Society criteria for the diagnosis of MSA (MDS MSA criteria) have been recently developed. They introduce a neuropathologically established MSA category and three levels of clinical diagnostic certainty including clinically established MSA, clinically probable MSA, and the research category of possible prodromal MSA. The diagnosis of clinically established and clinically probable MSA is based on the presence of cardiovascular or urological autonomic failure, parkinsonism (poorly L-Dopa-responsive for the diagnosis of clinically established MSA), and cerebellar syndrome. These core clinical features need to be associated with supportive motor and non-motor features (MSA red flags) and absence of any exclusion criteria. Characteristic brain MRI markers are required for a diagnosis of clinically established MSA. A research category of possible prodromal MSA is devised to capture patients manifesting with autonomic failure or REM sleep behavior disorder and only mild motor signs at the earliest disease stage. There is a number of promising laboratory markers for MSA that may help increase the overall clinical diagnostic accuracy. In this review, we will discuss the core and supportive clinical features for a diagnosis of MSA in light of the new MDS MSA criteria, which laboratory tools may assist in the clinical diagnosis and which major differential diagnostic challenges should be borne in mind.
Topics: Adult; Humans; Multiple System Atrophy; Diagnosis, Differential; Parkinsonian Disorders; Magnetic Resonance Imaging; Levodopa
PubMed: 35986227
DOI: 10.1007/s12311-022-01453-w -
Brain Sciences May 2024Levodopa (L-DOPA) treatment represents the gold standard therapy for Parkinson's disease (PD) patients. L-DOPA therapy shows many side effects, among them,... (Review)
Review
Levodopa (L-DOPA) treatment represents the gold standard therapy for Parkinson's disease (PD) patients. L-DOPA therapy shows many side effects, among them, L-DOPA-induced dyskinesias (LIDs) remain the most problematic. Several are the mechanisms underlying these processes: abnormal corticostriatal neurotransmission, pre- and post-synaptic neuronal events, changes in gene expression, and altered plasticity. In recent years, researchers have also suggested non-neuronal mechanisms as a possible cause for LIDs. We reviewed recent clinical and pre-clinical studies on neuroinflammation contribution to LIDs. Microglia and astrocytes seem to play a strategic role in LIDs phenomenon. In particular, their inflammatory response affects neuron-glia communication, synaptic activity and neuroplasticity, contributing to LIDs development. Finally, we describe possible new therapeutic interventions for dyskinesia prevention targeting glia cells.
PubMed: 38790492
DOI: 10.3390/brainsci14050514 -
CNS Neuroscience & Therapeutics Oct 2023Parkinson's disease (PD) is a pervasive neurodegenerative disease, and levodopa (L-dopa) is its preferred treatment. The pathophysiological mechanism of levodopa-induced...
AIM
Parkinson's disease (PD) is a pervasive neurodegenerative disease, and levodopa (L-dopa) is its preferred treatment. The pathophysiological mechanism of levodopa-induced dyskinesia (LID), the most common complication of long-term L-dopa administration, remains obscure. Accumulated evidence suggests that the dopaminergic as well as non-dopaminergic systems contribute to LID development. As a 5-hydroxytryptamine 1A/1B receptor agonist, eltoprazine ameliorates dyskinesia, although little is known about its electrophysiological mechanism. The aim of this study was to investigate the cumulative effects of chronic L-dopa administration and the potential mechanism of eltoprazine's amelioration of dyskinesia at the electrophysiological level in rats.
METHODS
Neural electrophysiological analysis techniques were conducted on the acquired local field potential (LFP) data from primary motor cortex (M1) and dorsolateral striatum (DLS) during different pathological states to obtain the information of power spectrum density, theta-gamma phase-amplitude coupling (PAC), and functional connectivity. Behavior tests and AIMs scoring were performed to verify PD model establishment and evaluate LID severity.
RESULTS
We detected exaggerated gamma activities in the dyskinetic state, with different features and impacts in distinct regions. Gamma oscillations in M1 were narrowband manner, whereas that in DLS had a broadband appearance. Striatal exaggerated theta-gamma PAC in the LID state contributed to broadband gamma oscillation, and aperiodic-corrected cortical beta power correlated robustly with aperiodic-corrected gamma power in M1. M1-DLS coherence and phase-locking values (PLVs) in the gamma band were enhanced following L-dopa administration. Eltoprazine intervention reduced gamma oscillations, theta-gamma PAC in the DLS, and coherence and PLVs in the gamma band to alleviate dyskinesia.
CONCLUSION
Excessive cortical gamma oscillation is a compelling clinical indicator of dyskinesia. The detection of enhanced PAC and functional connectivity of gamma-band oscillation can be used to guide and optimize deep brain stimulation parameters. Eltoprazine has potential clinical application for dyskinesia.
Topics: Serotonin Receptor Agonists; Piperazines; Gamma Rhythm; Levodopa; Dyskinesia, Drug-Induced; Antiparkinson Agents; Animals; Rats; Disease Models, Animal; Motor Cortex
PubMed: 37122156
DOI: 10.1111/cns.14241 -
Translational Neurodegeneration Sep 2023There is a need for biomarkers to support an accurate diagnosis of Parkinson's disease (PD). Cerebrospinal fluid (CSF) has been a successful biofluid for finding...
BACKGROUND
There is a need for biomarkers to support an accurate diagnosis of Parkinson's disease (PD). Cerebrospinal fluid (CSF) has been a successful biofluid for finding neurodegenerative biomarkers, and modern highly sensitive multiplexing methods offer the possibility to perform discovery studies. Using a large-scale multiplex proximity extension assay (PEA) approach, we aimed to discover novel diagnostic protein biomarkers allowing accurate discrimination of PD from both controls and atypical Parkinsonian disorders (APD).
METHODS
CSF from patients with PD, corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), multiple system atrophy and controls, were analysed with Olink PEA panels. Three cohorts were used in this study, comprising 192, 88 and 36 cases, respectively. All samples were run on the Cardiovascular II, Oncology II and Metabolism PEA panels.
RESULTS
Our analysis revealed that 26 and 39 proteins were differentially expressed in the CSF of test and validation PD cohorts, respectively, compared to controls. Among them, 6 proteins were changed in both cohorts. Midkine (MK) was increased in PD with the strongest effect size and results were validated with ELISA. Another most increased protein in PD, DOPA decarboxylase (DDC), which catalyses the decarboxylation of DOPA (L-3,4-dihydroxyphenylalanine) to dopamine, was strongly correlated with dopaminergic treatment. Moreover, Kallikrein 10 was specifically changed in APD compared with both PD and controls, but unchanged between PD and controls. Wnt inhibitory factor 1 was consistently downregulated in CBS and PSP patients in two independent cohorts.
CONCLUSIONS
Using the large-scale PEA approach, we have identified potential novel PD diagnostic biomarkers, most notably MK and DDC, in the CSF of PD patients.
Topics: Humans; Dopa Decarboxylase; Dopamine; Midkine; Parkinson Disease
PubMed: 37667404
DOI: 10.1186/s40035-023-00374-w -
Plants (Basel, Switzerland) Nov 2023The broad bean plant contains L-DOPA, a compound that is essential for patients with Parkinson's disease. However, little has been reported on other broad bean compounds...
The broad bean plant contains L-DOPA, a compound that is essential for patients with Parkinson's disease. However, little has been reported on other broad bean compounds that have beneficial effects on health. The objective was to evaluate plants of four Mexican broad bean varieties to determine the content and yield of total phenolic compounds (TPC), total flavonoids (TF), and L-DOPA, as well as to analyze the flavonoid profile and antioxidant (AA) and anti-inflammatory (AANTI) activity in vitro. Broad bean seeds were sown in the field and plants were harvested 20 days after emergence. The analyses were performed with visible UV spectrophotometry and HPLC. The variety José María produced the highest yield of TPC (9.30 g m), TF (8.08 g m), and L-DOPA (5.64 g m) per unit of area. The highest yields per plant were obtained with the Rojita variety: TPC (0.25 g plant), TF (0.21 g plant), and L-DOPA (0.17 g plant). This variety also had the highest antioxidant (IC = 87.68 µg mL) and anti-inflammatory (IC = 74.40 mg mL) activity, which was attributed to the L-DOPA compounds and to rutin and isoorientins, respectively. The flavonoid profile revealed the presence of rutin and isoorientins, which had not been previously detected in the broad bean plant.
PubMed: 38068555
DOI: 10.3390/plants12233918 -
Journal of Pharmacological Sciences Jul 2023Methylphenidate (MPH) and methamphetamine (METH) are the current treatments of choice for attention deficit/hyperactivity disorder. We previously reported that METH...
Methylphenidate (MPH) and methamphetamine (METH) are the current treatments of choice for attention deficit/hyperactivity disorder. We previously reported that METH induces the release of dopamine (DA) and of the neurotransmitter candidate L-3,4-dihydroxyphenylalanine (L-DOPA). In contrast, we here found that MPH increased the DA release while it did not affect the L-DOPA release from the dorsolateral striatum. Nevertheless, MPH-induced hyperlocomotion was reduced in Gpr143 (L-DOPA receptor) gene-deficient (Gpr143) mice. The rewarding effect and increased c-fos expression induced by MPH were also attenuated in Gpr143 mice. Together, these findings suggest that GPR143 is involved in the acute and chronic actions of MPH.
Topics: Mice; Animals; Methylphenidate; Levodopa; Receptors, Neurotransmitter; Dopamine; Methamphetamine; Central Nervous System Stimulants
PubMed: 37257945
DOI: 10.1016/j.jphs.2023.04.006 -
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 -
Frontiers in Microbiology 2023Ongoing extensive research in the field of gut microbiota (GM) has highlighted the crucial role of gut-dwelling microbes in human health. These microbes possess 100... (Review)
Review
Ongoing extensive research in the field of gut microbiota (GM) has highlighted the crucial role of gut-dwelling microbes in human health. These microbes possess 100 times more genes than the human genome and offer significant biochemical advantages to the host in nutrient and drug absorption, metabolism, and excretion. It is increasingly clear that GM modulates the efficacy and toxicity of drugs, especially those taken orally. In addition, intra-individual variability of GM has been shown to contribute to drug response biases for certain therapeutics. For instance, the efficacy of cyclophosphamide depends on the presence of and in the host intestine. Conversely, the presence of inappropriate or unwanted gut bacteria can inactivate a drug. For example, dehydroxylase of and A2 can metabolize L-dopa before it converts into the active form (dopamine) and crosses the blood-brain barrier to treat Parkinson's disease patients. Moreover, GM is emerging as a new player in personalized medicine, and various methods are being developed to treat diseases by remodeling patients' GM composition, such as prebiotic and probiotic interventions, microbiota transplants, and the introduction of synthetic GM. This review aims to highlight how the host's GM can improve drug efficacy and discuss how an unwanted bug can cause the inactivation of medicine.
PubMed: 38098666
DOI: 10.3389/fmicb.2023.1274925