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Neuropharmacology Sep 2023Cellular responses to metabotropic glutamate (mGlu) receptor activation are shaped by mechanisms of receptor-receptor interaction. mGlu receptor subtypes form... (Review)
Review
Cellular responses to metabotropic glutamate (mGlu) receptor activation are shaped by mechanisms of receptor-receptor interaction. mGlu receptor subtypes form homodimers, intra- or inter-group heterodimers, and heteromeric complexes with other G protein-coupled receptors (GPCRs). In addition, mGlu receptors may functionally interact with other receptors through the βγ subunits released from G proteins in response to receptor activation or other mechanisms. Here, we discuss the interactions between (i) mGlu and GABA receptors in cerebellar Purkinje cells; (ii) mGlu and 5-HTserotonergic receptors in the prefrontal cortex; (iii) mGlu and A receptors or mGlu and D dopamine receptors in medium spiny projection neurons of the indirect and direct pathways of the basal ganglia motor circuit; (iv) mGlu and A receptors in relation to the pathophysiology of Alzheimer's disease; and (v) mGlu and A adenosine or α- or β adrenergic receptors. In addition, we describe in detail a novel form of non-heterodimeric interaction between mGlu and mGlu receptors, which appears to be critically involved in mechanisms of activity-dependent synaptic plasticity in the prefrontal cortex and hippocampus. Finally, we highlight the potential implication of these interactions in the pathophysiology and treatment of cerebellar disorders, schizophrenia, Alzheimer's disease, Parkinson's disease, l-DOPA-induced dyskinesias, stress-related disorders, and cognitive dysfunctions. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".
Topics: Humans; Alzheimer Disease; Levodopa; Parkinson Disease; Receptor, Metabotropic Glutamate 5; Basal Ganglia
PubMed: 37142158
DOI: 10.1016/j.neuropharm.2023.109569 -
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 -
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 -
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 -
Journal of Neural Transmission (Vienna,... Nov 2023Emerging studies suggest a correlation between elevated plasma homocysteine (hcy) levels and the risk of atherosclerosis, vascular disorders, and neurodegenerative... (Review)
Review
Emerging studies suggest a correlation between elevated plasma homocysteine (hcy) levels and the risk of atherosclerosis, vascular disorders, and neurodegenerative diseases, including Parkinson's disease (PD). This narrative review delves into the intricate relationships between Hcy, vitamin B metabolites, dopamine-substituting compounds, and various symptoms of PD. Patients undergoing a long-term L-dopa/dopa-decarboxylase inhibitor (DDI) regimen, especially without a concurrent catechol-O-methyl transferase (COMT) inhibitor or methyl group-donating vitamin supplementation, such as vitamins B6 and B12, exhibit an elevation in Hcy and a decline in vitamin B metabolites. These altered concentrations appear to be associated with heightened risks of developing non-motor symptoms, including peripheral neuropathy and cognitive disturbances. The review underscores the impact of levodopa metabolism via COMT on homocysteine levels. In light of these findings, we advocate for the supplementation of methyl group-donating vitamins, notably B6 and B12, in patients undergoing a high-dose L-dopa/DDI regimen, particularly those treated with L-dopa/carbidopa intestinal gel (LCIG) infusion.
Topics: Humans; Levodopa; Parkinson Disease; Antiparkinson Agents; Dopamine; Catechol O-Methyltransferase; Homocysteine; Vitamins; Vitamin B 12
PubMed: 37603058
DOI: 10.1007/s00702-023-02684-9 -
Annals of Medicine Dec 2024Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can... (Observational Study)
Observational Study
BACKGROUND
Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD.
PATIENTS AND METHODS
PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) patient chart review/interview.
RESULTS
Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%).
CONCLUSION
This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life.
Topics: Humans; Male; Aged; Female; Parkinson Disease; Levodopa; Antiparkinson Agents; Retrospective Studies; Catechol O-Methyltransferase; Quality of Life; Prospective Studies; Catechol O-Methyltransferase Inhibitors
PubMed: 38381654
DOI: 10.1080/07853890.2024.2315226 -
Investigative Ophthalmology & Visual... Sep 2023Wet AMD (wAMD) is associated with cellular senescence. However, senescent cell-targeted therapies for wAMD have rarely been comprehensively studied. This study aimed to...
PURPOSE
Wet AMD (wAMD) is associated with cellular senescence. However, senescent cell-targeted therapies for wAMD have rarely been comprehensively studied. This study aimed to explore the therapeutic effects of senolytic agents on choroidal neovascularization (CNV).
METHODS
RNA sequencing datasets were obtained from the Gene Expression Omnibus database and used to explore the association between senescence and wAMD. We explored the effects of senescent adult RPE cell line-19 cells on the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells. A laser-induced CNV animal model was used to study wAMD. We studied a senescent cell elimination therapy for CNV progression using two types of senolytics and a transgenic method.
RESULTS
Cells in the retinal pigment epithelium-choroid of the CNV model were enriched in senescence, inflammation, and angiogenesis gene sets. AP20187 was used to specifically eliminate senescent cells and proven to alleviate CNV progression in INK-ATTAC transgenic mice. Senescent adult RPE cell line-1 cells produced elevated levels of senescence-associated secretory phenotypes, including VEGFs; they also demonstrated increased proliferation, migration, invasion, and tube formation in human umbilical vein endothelial cells. The number of senescent cells increased in the laser-induced CNV rat model, and intravitreal injections of dasatinib with quercetin reduced the expression of p16 in CNV and alleviated neovascularization.
CONCLUSIONS
Senescent RPE cells can accelerate pathological neovascularization; thus, senescent cell-targeting therapy has great clinical potential for wAMD.
Topics: Adult; Humans; Mice; Animals; Rats; Dasatinib; Quercetin; Retinal Pigment Epithelium; Choroidal Neovascularization; Cellular Senescence; Choroid; Human Umbilical Vein Endothelial Cells; Methyldopa
PubMed: 37750741
DOI: 10.1167/iovs.64.12.39 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2024The article is of a review nature and is devoted to tremor, one of the maladaptive and difficult-to-treat symptoms of Parkinson's disease (PD). Along with the classic... (Review)
Review
The article is of a review nature and is devoted to tremor, one of the maladaptive and difficult-to-treat symptoms of Parkinson's disease (PD). Along with the classic rest tremor, patients with PD may experience tremor of other modalities: postural tremor, kinetic tremor, which reflects a multimodal mechanism of tremor formation involving multiple neurotransmitter systems. The unpredictable response to therapeutic options, the ambiguous response to levodopa, also reflects the role of multiple underlying pathophysiological processes. Among the drug methods of tremor correction, preference is given to dopamine receptor agonists - due to the spectrum of their pharmaceutical action, high efficiency in relation to all leading motor and a number of non-motor manifestations. The evidence for advanced neurosurgical, non-invasive modalities is mixed, and there are insufficient comparative studies to assess their efficacy in patients with tremor-dominant forms of PD.
Topics: Humans; Parkinson Disease; Tremor; Levodopa; Dopamine Agonists; Antiparkinson Agents
PubMed: 38676674
DOI: 10.17116/jnevro202412404128 -
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