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Molecular Medicine (Cambridge, Mass.) Mar 2024Loss of dopaminergic neurons underlies the motor symptoms of Parkinson's disease (PD). However stereotypical PD symptoms only manifest after approximately 80% of...
BACKGROUND
Loss of dopaminergic neurons underlies the motor symptoms of Parkinson's disease (PD). However stereotypical PD symptoms only manifest after approximately 80% of dopamine neurons have died making dopamine-related motor phenotypes unreliable markers of the earlier stages of the disease. There are other non-motor symptoms, such as depression, that may present decades before motor symptoms.
METHODS
Because serotonin is implicated in depression, here we use niche, fast electrochemistry paired with mathematical modelling and machine learning to, for the first time, robustly evaluate serotonin neurochemistry in vivo in real time in a toxicological model of Parkinsonism, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
RESULTS
Mice treated with acute MPTP had lower concentrations of in vivo, evoked and ambient serotonin in the hippocampus, consistent with the clinical comorbidity of depression with PD. These mice did not chemically respond to SSRI, as strongly as control animals did, following the clinical literature showing that antidepressant success during PD is highly variable. Following L-DOPA administration, using a novel machine learning analysis tool, we observed a dynamic shift from evoked serotonin release in the hippocampus to dopamine release. We hypothesize that this finding shows, in real time, that serotonergic neurons uptake L-DOPA and produce dopamine at the expense of serotonin, supporting the significant clinical correlation between L-DOPA and depression. Finally, we found that this post L-DOPA dopamine release was less regulated, staying in the synapse for longer. This finding is perhaps due to lack of autoreceptor control and may provide a ground from which to study L-DOPA induced dyskinesia.
CONCLUSIONS
These results validate key prior hypotheses about the roles of serotonin during PD and open an avenue to study to potentially improve therapeutics for levodopa-induced dyskinesia and depression.
Topics: Mice; Animals; Levodopa; Dopamine; Serotonin; Antiparkinson Agents; Dyskinesia, Drug-Induced; Parkinson Disease; Parkinsonian Disorders; Biomarkers
PubMed: 38429661
DOI: 10.1186/s10020-023-00773-9 -
International Journal of Molecular... Jul 2023Parkinson's Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We...
Parkinson's Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We investigated the pathophysiologic mechanisms of the lateral pterygoid muscles (LPMs) and the trigeminal system related to PD-induced orofacial manifestations. A PD rat model was produced by unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. Abnormal involuntary movements (dyskinesia) and nociceptive responses were determined. We analyzed the immunodetection of Fos-B and microglia/astrocytes in trigeminal and facial nuclei and morphological markers in the LPMs. Hyperalgesia response was increased in hemiparkinsonian and dyskinetic rats. Hemiparkinsonism increased slow skeletal myosin fibers in the LPMs, while in the dyskinetic ones, these fibers decreased in the contralateral side of the lesion. Bilateral increased glycolytic metabolism and an inflammatory muscle profile were detected in dyskinetic rats. There was increased Fos-B expression in the spinal nucleus of lesioned rats and in the motor and facial nucleus in L-DOPA-induced dyskinetic rats in the contralateral side of the lesion. Glial cells were increased in the facial nucleus on the contralateral side of the lesion. Overall, spinal trigeminal nucleus activation may be associated with orofacial sensorial impairment in Parkinsonian rats, while a fatigue profile on LPMs is suggested in L-DOPA-induced dyskinesia when the motor and facial nucleus are activated.
Topics: Rats; Animals; Levodopa; Dyskinesia, Drug-Induced; Corpus Striatum; Parkinsonian Disorders; Parkinson Disease; Oxidopamine; Brain Stem; Disease Models, Animal; Antiparkinson Agents
PubMed: 37569642
DOI: 10.3390/ijms241512270 -
Cell Reports. Medicine Oct 2023Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat...
Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.
Topics: Mice; Animals; Dopamine Agonists; Levodopa; Dopamine; Antiparkinson Agents; Parkinsonian Disorders; Dyskinesia, Drug-Induced; Oxidopamine; gamma-Aminobutyric Acid
PubMed: 37774703
DOI: 10.1016/j.xcrm.2023.101208 -
Medicina Aug 2023There is a wealth of information on early pharmacological supportive treatment for early rehabilitation following acute ischemic stroke. This review aims to provide... (Review)
Review
There is a wealth of information on early pharmacological supportive treatment for early rehabilitation following acute ischemic stroke. This review aims to provide healthcare professionals involved in rehabilitating patients with a summary of the available evidence to assist with decision-making in their daily clinical practice. A search for randomized clinical trials and observational studies published between 1/1/2000 and 28/8/2022 was performed using PubMed, Cochrane and Epistemonikos as search engines with language restriction to english and spanish. The selected studies included patients older than 18 with acute ischemic stroke undergoing early rehabilitation. The outcomes considered for efficacy were: motor function, language, and central pain. The selected pharmacological interventions were: cerebrolysin, levodopa, selegiline, amphetamines, fluoxetine, citalopram, escitalopram, antipsychotics, memantine, pregabalin, amitriptyline and lamotrigine. Evidence synthesis and evaluation were performed using the GRADE methodology. This review provided a summary of the evidence on pharmacological supportive care in early rehabilitation of post-acute ischemic stroke patients. This will make it possible to improve current recommendations with the aim of collaborating with health decision-making for this population.
Topics: Humans; Ischemic Stroke; Medicine; Amitriptyline; Antipsychotic Agents; Citalopram
PubMed: 37624681
DOI: No ID Found -
Neuropharmacology Oct 2023Many patients with Parkinson's disease (PD) experiencing l-DOPA-induced dyskinesia (LID) receive adjunct treatment with dopamine agonists, whose functional impact on LID...
Many patients with Parkinson's disease (PD) experiencing l-DOPA-induced dyskinesia (LID) receive adjunct treatment with dopamine agonists, whose functional impact on LID is unknown. We set out to compare temporal and topographic profiles of abnormal involuntary movements (AIMs) after l-DOPA dose challenges including or not the dopamine agonist ropinirole. Twenty-five patients with PD and a history of dyskinesias were sequentially administered either l-DOPA alone (150% of usual morning dose) or an equipotent combination of l-DOPA and ropinirole in random order. Involuntary movements were assessed by two blinded raters prior and every 30 min after drug dosing using the Clinical Dyskinesia Rating Scale (CDRS). A sensor-recording smartphone was secured to the patients' abdomen during the test sessions. The two raters' CDRS scores were highly reliable and concordant with models of hyperkinesia presence and severity trained on accelerometer data. The dyskinesia time curves differed between treatments as the l-DOPA-ropinirole combination resulted in lower peak severity but longer duration of the AIMs compared with l-DOPA alone. At the peak of the AIMs curve (60-120 min), l-DOPA induced a significantly higher total hyperkinesia score, whereas in the end phase (240-270 min), both hyperkinesia and dystonia tended to be more severe after the l-DOPA-ropinirole combination (though reaching statistical significance only for the item, arm dystonia). Our results pave the way for the introduction of a combined l-DOPA-ropinirole challenge test in the early clinical evaluation of antidyskinetic treatments. Furthermore, we propose a machine-learning method to predict CDRS hyperkinesia severity using accelerometer data.
Topics: Humans; Antiparkinson Agents; Dopamine Agonists; Dyskinesia, Drug-Induced; Dystonia; Hyperkinesis; Levodopa; Oxidopamine; Parkinson Disease
PubMed: 37315840
DOI: 10.1016/j.neuropharm.2023.109630 -
Orphanet Journal of Rare Diseases Nov 2023Tetrahydrobiopterin (BH) deficiency caused by 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a rare disorder that is one of the major causes of... (Review)
Review
BACKGROUND
Tetrahydrobiopterin (BH) deficiency caused by 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a rare disorder that is one of the major causes of hyperphenylalaninemia in Taiwan.
METHODS
In this study, we reviewed the clinical courses of 12 adolescent and adult patients (7 females and 5 males) with PTPS deficiency.
RESULTS
The patients were treated shortly after diagnosis through newborn screening with a combination of BH, levodopa/carbidopa, and 5-OH-tryptophan. Their plasma phenylalanine and tyrosine levels were well controlled, and their prolactin levels were also decreased after treatment. However, their prolactin levels gradually rose as they grew into puberty, and at a current age of 27.5 [interquartile range (IQR 7.9)] years, five of the 12 patients had either highly elevated prolactin levels (> 100 ng/mL in one male patient, normal reference values, male < 11 ng/mL, female < 17 ng/mL) or symptoms, including irregular menstruation, amenorrhea, and breast swelling (in four female patients). The dosage of levodopa in these five patients (14.3 (IQR 3.0) mg/kg/day) was slightly higher than that in the other patients (p = 0.05). Magnetic resonance imaging studies did not reveal an increase in the size of the anterior pituitary gland, although a Rathke cleft cyst was found in one patient. Two patients received cabergoline treatment, which promptly lowered prolactin levels and relieved symptoms.
CONCLUSIONS
Hyperprolactinemia is common in female patients with PTPS deficiency, especially after puberty. A long-acting dopamine agonist, such as cabergoline, may be a necessary adjunctive treatment for most patients with BH deficiency.
Topics: Adolescent; Adult; Female; Humans; Infant, Newborn; Male; Cabergoline; Hyperprolactinemia; Levodopa; Phenylketonurias; Prolactin
PubMed: 37950276
DOI: 10.1186/s13023-023-02963-4 -
BMJ Open Oct 2023Experimental studies suggest a role of gut microbiota in the pathophysiology of Parkinson's disease (PD) via the gut-brain axis. The gut microbiota can also influence... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Experimental studies suggest a role of gut microbiota in the pathophysiology of Parkinson's disease (PD) via the gut-brain axis. The gut microbiota can also influence the metabolism of levodopa, which is the mainstay of treatment of PD. Therefore, modifying the gut microbiota by faecal microbiota transplantation (FMT) could be a supportive treatment strategy.
METHODS AND ANALYSIS
We have developed a study protocol for a single-centre, prospective, self-controlled, interventional, safety and feasibility donor-FMT pilot study with randomisation and double-blinded allocation of donor faeces. The primary objectives are feasibility and safety of FMT in patients with PD. Secondary objectives include exploring whether FMT leads to alterations in motor complications (fluctuations and dyskinesias) and PD motor and non-motor symptoms (including constipation), determining alterations in gut microbiota composition, assessing donor-recipient microbiota similarities and their association with PD symptoms and motor complications, evaluating the ease of the study protocol and examining FMT-related adverse events in patients with PD. The study population will consist of 16 patients with idiopathic PD that use levodopa and experience motor complications. They will receive FMT with faeces from one of two selected healthy human donors. FMT will be administered via a gastroscope into the duodenum, after treatment with oral vancomycin, bowel lavage and domperidone. There will be seven follow-up moments during 12 months.
ETHICS AND DISSEMINATION
This study was approved by the Medical Ethical Committee Leiden Den Haag Delft (ref. P20.087). Study results will be disseminated through publication in peer-reviewed journals and international conferences.
TRIAL REGISTRATION NUMBER
International Clinical Trial Registry Platform: NL9438.
Topics: Humans; Feasibility Studies; Fecal Microbiota Transplantation; Feces; Levodopa; Parkinson Disease; Pilot Projects; Prospective Studies; Treatment Outcome
PubMed: 37798034
DOI: 10.1136/bmjopen-2023-071766 -
Molecules (Basel, Switzerland) Jan 2024Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis Sativa, has garnered increasing attention for its diverse therapeutic potential. This comprehensive... (Review)
Review
Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis Sativa, has garnered increasing attention for its diverse therapeutic potential. This comprehensive review delves into the complex pharmacokinetics of CBD, including factors such as bioavailability, distribution, safety profile, and dosage recommendations, which contribute to the compound's pharmacological profile. CBD's role as a pharmacological inhibitor is explored, encompassing interactions with the endocannabinoid system and ion channels. The compound's anti-inflammatory effects, influencing the Interferon-beta and NF-κB, position it as a versatile candidate for immune system regulation and interventions in inflammatory processes. The historical context of Cannabis Sativa's use for recreational and medicinal purposes adds depth to the discussion, emphasizing CBD's emergence as a pivotal phytocannabinoid. As research continues, CBD's integration into clinical practice holds promise for revolutionizing treatment approaches and enhancing patient outcomes. The evolution in CBD research encourages ongoing exploration, offering the prospect of unlocking new therapeutic utility.
Topics: Humans; Cannabidiol; Biological Availability; Hallucinogens; Cannabinoid Receptor Agonists; Cannabis; Carbidopa
PubMed: 38257386
DOI: 10.3390/molecules29020473 -
Patient Related Outcome Measures 2023Parkinson's disease (PD) is a chronic and progressive neurodegenerative condition due to the degeneration of nigral dopaminergic cells. Both motor and non-motor symptoms... (Review)
Review
INTRODUCTION
Parkinson's disease (PD) is a chronic and progressive neurodegenerative condition due to the degeneration of nigral dopaminergic cells. Both motor and non-motor symptoms (NMS) of PD produce a marked impairment in PD patients' quality of life (QoL), but contrary to motor features, NMS do not improve with dopamine replacement. Novel therapeutic interventions for PD have successfully controlled most motor manifestations of PD, but the management of NMS is still challenging. Since NMS have a negative impact on the QoL of PD patients, researchers are currently looking for drugs that can modulate the activity of neurotransmitter systems other than dopamine in the hope that can alleviate NMS in PD. Among the recently approved drugs for patients experiencing fluctuations in motor symptoms, safinamide stands out as an effective add-on therapy to levodopa. Safinamide is a monoamine oxidase type-B inhibitor (MAOB-I), with proven efficacy in reducing motor fluctuations. Its distinctive mechanism of action impacts dopaminergic pathways via MAOB inhibition and glutamatergic pathways by blocking sodium and calcium channels. Findings from Phase III clinical trials, meta-analysis, post-hoc analysis, and real-life experiences indicate that safinamide benefits motor symptoms such as tremor, bradykinesia, rigidity, and gait. Additionally, it shows promise for improving NMS like fatigue, pain, mood, and sleep disturbances in patients with PD.
AREAS COVERED
In this article, the authors explore the impact of safinamide on patient-reported outcomes in PD. A thorough search was conducted on PubMed focusing on studies published between 2018 and 2023 in English. The inclusion criteria encompassed clinical trials, randomized controlled trials, systematic reviews, meta-analyses, and reviews. The search strategy revolved around the implementation of MeSH terms related to safinamide and its impact on the quality of life in PD.
CONCLUSION
Our data strongly support the improving effect on QoL, reducing the disabling NMS reported in patients with PD.
PubMed: 37840836
DOI: 10.2147/PROM.S369590