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Practical Neurology Oct 2023Amantadine is an N-methyl-d-aspartate receptor agonist with secondary dopaminergic activity that is used to treat Parkinson's disease-related dyskinesia and to treat...
Amantadine is an N-methyl-d-aspartate receptor agonist with secondary dopaminergic activity that is used to treat Parkinson's disease-related dyskinesia and to treat fatigue in multiple sclerosis. It is primarily renally excreted and so impaired kidney function prolongs its half-life and may lead to toxicity. We describe a woman with multiple sclerosis taking amantadine who developed acute renal impairment, which triggered florid visual hallucinations that resolved on stopping the medication.
Topics: Female; Humans; Antiparkinson Agents; Levodopa; Amantadine; Hallucinations; Multiple Sclerosis
PubMed: 37419676
DOI: 10.1136/pn-2023-003723 -
Molecular Brain Apr 2024Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's...
Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Drugs that increase or maintain dopamine levels in the brain could be a therapeutic strategy for AD. However, the effects of dopamine and its precursor levodopa (L-DOPA) on Aβ/tau pathology in vivo and the underlying molecular mechanisms have not been studied in detail. Here, we investigated whether L-DOPA treatment alters neuroinflammation, Aβ pathology, and tau phosphorylation in 5xFAD mice, a model of AD. We found that L-DOPA administration significantly reduced microgliosis and astrogliosis in 5xFAD mice. In addition, L-DOPA treatment significantly decreased Aβ plaque number by upregulating NEP and ADAM17 levels in 5xFAD mice. However, L-DOPA-treated 5xFAD mice did not exhibit changes in tau hyperphosphorylation or tau kinase levels. These data suggest that L-DOPA alleviates neuroinflammatory responses and Aβ pathology but not tau pathology in this mouse model of AD.
Topics: Animals; Levodopa; Alzheimer Disease; Disease Models, Animal; ADAM17 Protein; Amyloid beta-Peptides; tau Proteins; Neuroinflammatory Diseases; Phosphorylation; Mice, Transgenic; Plaque, Amyloid; Mice; Brain
PubMed: 38685105
DOI: 10.1186/s13041-024-01092-8 -
Ageing Research Reviews Aug 2023Parkinson's disease (PD) is the second most common neurodegenerative disorder. The degeneration of dopaminergic neurons in the midbrain is primarily responsible for... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disorder. The degeneration of dopaminergic neurons in the midbrain is primarily responsible for the onset of the disease. The major challenge faced in the treatment of PD is the blood-brain barrier (BBB), which impedes the delivery of therapeutics to targeted locations. To address this issue, lipid nanosystems have been used for the precise delivery of therapeutic compounds in anti-PD therapy. In this review, we will discuss the application and clinical significance of lipid nanosystem in delivering therapeutic compounds for anti-PD treatment. These medicinal compounds include ropinirole, apomorphine, bromocriptine, astaxanthin, resveratrol, dopamine, glyceryl monooleate, levodopa, N-3,4-bis(pivaloyloxy)- dopamine and fibroblast growth factor, which have significant potential to treat PD in the early stage. This review, in a nutshell, will pave the way for researchers to develop diagnostic and potential therapeutic approaches using nanomedicine to overcome the challenges posed by the BBB in delivering therapeutic compounds for PD.
Topics: Humans; Parkinson Disease; Dopamine; Levodopa; Neurodegenerative Diseases; Lipids
PubMed: 37268112
DOI: 10.1016/j.arr.2023.101965 -
Biochimica Et Biophysica Acta. Reviews... Nov 2023The skin containing melanin pigment acts as a protective barrier and counteracts the UVR and other environmental stressors to maintain or restore disrupted cutaneous... (Review)
Review
The skin containing melanin pigment acts as a protective barrier and counteracts the UVR and other environmental stressors to maintain or restore disrupted cutaneous homeostasis. The production of melanin pigment is dependent on tyrosine levels. L-tyrosine and L-dihydroxyphenylalanine (L-DOPA) can serve both as a substrates and intermediates of melanin synthetic pathway and as inducers and positive regulators of melanogenesis. The biosynthesis of melanin is stimulated upon exposure to UVR, which can also stimulate local production of hormonal factors, which can stimulate melanoma development by altering the chemical properties of eu- and pheomelanin. The process of melanogenesis can be altered by several pathways. One involves activation of POMC, with the production of POMC peptides including MSH and ACTH, which increase intracellular cAMP levels, which activates the MITF, and helps to stimulate tyrosinase (TYR) expression and activity. Defects in OCA1 to 4 affects melanogenic activity via posttranslational modifications resulting in proteasomal degradation and reducing pigmentation. Further, altering, the MITF factor, helps to regulate the expression of MRGE in melanoma, and helps to increase the TYR glycosylation in ER. CRH stimulates POMC peptides that regulate melanogenesis and also by itself can stimulate melanogenesis. The POMC, P53, ACTH, MSH, MC1R, MITF, and 6-BH4 are found to be important regulators for pigmentation. Melanogenesis can affect melanoma behaviour and inhibit immune responses. Therefore, we reviewed natural products that would alter melanin production. Our special focus was on targeting melanin synthesis and TYR enzyme activity to inhibit melanogenesis as an adjuvant therapy of melanotic melanoma. Furthermore, this review also outlines the current updated pharmacological studies targeting the TYR enzyme from natural sources and its consequential effects on melanin production.
Topics: Humans; Melanins; Melanoma; Monophenol Monooxygenase; Pro-Opiomelanocortin; Cell Line, Tumor; Tyrosine; Enzyme Inhibitors; Adrenocorticotropic Hormone
PubMed: 37657683
DOI: 10.1016/j.bbcan.2023.188968 -
Movement Disorders : Official Journal... Dec 2023Functional connectivity (FC) has shown promising results in assessing the pathophysiology and identifying early biomarkers of neurodegenerative disorders, such as...
BACKGROUND
Functional connectivity (FC) has shown promising results in assessing the pathophysiology and identifying early biomarkers of neurodegenerative disorders, such as Parkinson's disease (PD).
OBJECTIVES
In this study, we aimed to assess possible resting-state FC abnormalities in early-stage PD patients using high-density electroencephalography (EEG) and to detect their clinical relationship with motor and non-motor PD symptoms.
METHODS
We enrolled 26 early-stage levodopa naïve PD patients and a group of 20 healthy controls (HC). Data were recorded with 64-channels EEG system and a source-reconstruction method was used to identify brain-region activity. FC was calculated using the weighted phase-lag index in θ, α, and β bands. Additionally, we quantified the unbalancing between β and lower frequencies through a novel index (β-functional ratio [FR]). Statistical analysis was conducted using a network-based statistical approach.
RESULTS
PD patients showed hypoconnected networks in θ and α band, involving prefrontal-limbic-temporal and frontoparietal areas, respectively, and a hyperconnected network in the β frequency band, involving sensorimotor-frontal areas. The θ FC network was negatively related to Non-Motor Symptoms Scale scores and α FC to the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III gait subscore, whereas β FC and β-FR network were positively linked to the bradykinesia subscore. Changes in θ FC and β-FR showed substantial reliability and high accuracy, precision, sensitivity, and specificity in discriminating PD and HC.
CONCLUSIONS
Frequency-specific FC changes in PD likely reflect the dysfunction of distinct cortical networks, which occur from the early stage of the disease. These abnormalities are involved in the pathophysiology of specific motor and non-motor PD symptoms, including gait, bradykinesia, mood, and cognition. © 2023 International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Hypokinesia; Reproducibility of Results; Levodopa; Brain; Magnetic Resonance Imaging
PubMed: 37860930
DOI: 10.1002/mds.29615 -
Neurological Sciences : Official... Feb 2024Safinamide is a recent antiparkinsonian drug that modulates both dopaminergic and glutamatergic systems with positive effects on motor and nonmotor symptoms of... (Observational Study)
Observational Study
INTRODUCTION
Safinamide is a recent antiparkinsonian drug that modulates both dopaminergic and glutamatergic systems with positive effects on motor and nonmotor symptoms of Parkinson's disease (PD). Here, we aimed to describe the efficacy and safety of safinamide in the Italian PD patients in real-life conditions.
METHODS
We performed a sub-analysis of the Italian cohort of the SYNAPSES study, a multi-country, multi-center, retrospective-prospective cohort observational study, designed to investigate the use of safinamide in routine clinical practice. Patients received for the first time a treatment with safinamide and were followed up for 12 months. The analysis was conducted on the overall population and in subgroups of interest: i) patients > 75 years, ii) patients with relevant comorbidities and iii) patients affected by psychiatric symptoms.
RESULTS
Italy enrolled 616/1610 patients in 52 centers, accounting for 38% of the entire SYNAPSES cohort. Of the patients enrolled, 86.0% were evaluable at 12 months, with 23.3% being > 75 years, 42.4% with psychiatric conditions and 67.7% with relevant comorbidities. Safinamide was effective on motor symptoms and fluctuations as measured through the Unified PD rating scale III and IV scores, and on the total score, without safety issues in none of the subgroups considered.
CONCLUSION
The SYNAPSES data related to Italian patients confirms the good safety profile of safinamide even in special groups of patients. Motor fluctuations and motor impairment improved at the follow-up suggesting the significant role of safinamide in managing motor symptoms in PD patients.
Topics: Humans; Parkinson Disease; Retrospective Studies; Prospective Studies; Antiparkinson Agents; Alanine; Levodopa; Benzylamines
PubMed: 37684511
DOI: 10.1007/s10072-023-07001-6 -
Revue Neurologique 2024Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a sporadic atypical parkinsonian syndrome with levodopa-unresponsive axial-predominant parkinsonism, early... (Review)
Review
Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a sporadic atypical parkinsonian syndrome with levodopa-unresponsive axial-predominant parkinsonism, early postural instability, vertical supranuclear gaze palsy, dysarthria, executive dysfunction and behavioural changes. PSP-RS can be mimicked by numbers of other disorders, generally known as PSP mimics, or PSP-like syndromes. Their aetiological spectrum includes neurodegenerative (mostly genetic), vascular, infectious and drug-induced illnesses as well as other causes. Based on the available data, we have tried to create a definition of PSP-RS mimics: a syndrome resembling PSP-RS with at least one of the following red flags: 1) positive family history; 2) onset before 45 years of age; 3) rapid or stepwise progression; 4) acute or subacute onset; 5) atypical symptoms and/or signs; 6) normal or atypical brain MRI; 7) history of HIV or untreated syphilis, aortal surgery or recent therapy with dopamine-blocking agents. We have suggested a short diagnostic algorithm leading to the identification of PSP-RS mimics and the recommended diagnostic work-up. The key point of the diagnostic process is the early identification and treatment of potentially treatable PSP-RS mimics.
Topics: Humans; Supranuclear Palsy, Progressive; Movement Disorders; Parkinsonian Disorders; Syndrome; Levodopa
PubMed: 37543508
DOI: 10.1016/j.neurol.2023.02.070 -
European Journal of Neurology Nov 2023Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD).... (Review)
Review
Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD). Enzyme inhibitors in the form of peripheral dopa-decarboxylase inhibitors and monoamine oxidase type-B inhibitors have been successfully employed to maximize the utility of levodopa in both early- and late-stage PD. However, another major pathway of the peripheral metabolism of levodopa through catechol-O-methyltransferase (COMT) remains unchecked by those measures. Consequently, this becomes a major factor in determining the extent of delivery to the brain. The introduction of tolcapone as a potent and effective peripheral and central COMT inhibitor was frustrated by the emergence of hepatic toxicity. Only with the subsequent introduction of entacapone as an effective inhibitor of peripheral COMT activity has it become possible to fully control the peripheral metabolism of levodopa and to optimize its delivery to the brain. At a single-dose level of 200 mg, the efficacy of entacapone in reducing OFF time and increasing ON time has led to its widespread use for the treatment of "wearing off". To maximize the efficacy of entacapone and to time-lock its pharmacokinetic profile to that of levodopa, a triple combination of levodopa, carbidopa, and entacapone in the form of Stalevo that allowed for flexibility in levodopa dosing was introduced early in the 21st century. This pioneering development has been successfully used worldwide for the past 20 years. This review considers the role of all three classes of enzyme inhibitors in PD medicine.
PubMed: 37500177
DOI: 10.1111/ene.15994 -
Inflammopharmacology Aug 2023Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta,... (Review)
Review
Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor and non-motor symptoms. Although levodopa is the primary medication for PD, its long-term use is associated with complications such as dyskinesia and drug resistance, necessitating novel therapeutic approaches. Recent research has highlighted the potential of targeting opioid and cannabinoid receptors as innovative strategies for PD treatment. Modulating opioid transmission, particularly through activating µ (MOR) and δ (DOR) receptors while inhibiting κ (KOR) receptors, shows promise in preventing motor complications and reducing L-DOPA-induced dyskinesia. Opioids also possess neuroprotective properties and play a role in neuroprotection and seizure control. Similar to this, endocannabinoid signalling via CB1 and CB2 receptors influences the basal ganglia and may contribute to PD pathophysiology, making it a potential therapeutic target. In addition to opioid and cannabinoid receptor targeting, the NLRP3 pathway, implicated in neuroinflammation and neurodegeneration, emerges as another potential therapeutic avenue for PD. Recent studies suggest that targeting this pathway holds promise as a therapeutic strategy for PD management. This comprehensive review focuses on neuromodulation and novel therapeutic approaches for PD, specifically highlighting the targeting of opioid and cannabinoid receptors and the NLRP3 pathway. A better understanding of these mechanisms has the potential to enhance the quality of life for PD patients.
Topics: Humans; Parkinson Disease; Receptors, Cannabinoid; Analgesics, Opioid; NLR Family, Pyrin Domain-Containing 3 Protein; Quality of Life; Levodopa; Dyskinesias
PubMed: 37318694
DOI: 10.1007/s10787-023-01259-0 -
Genomics Nov 2023Scleroderma yunnanense, an ectomycorrhizal fungus, is a popular edible mushroom within the Yunnan Province of Southwest China that holds great ecological and economic... (Review)
Review
Scleroderma yunnanense, an ectomycorrhizal fungus, is a popular edible mushroom within the Yunnan Province of Southwest China that holds great ecological and economic implications. However, despite its significance, there remains limited information about this species. Therefore, we sequenced S. yunnanense genome to identify the functional genes of S. yunnanense involved in secondary metabolite and carbohydrate production pathways. First, we present the 40.43 Mb high-quality reference genome for S. yunnanense, distributed across 35 contigs; moreover, the N50 contig size was found to reach 3.31 Mb and contained 8877 functional genes. Finally, genome annotation was conducted to compare the functional genes of S. yunnanense with protein sequences from different publicly available databases. Taken together, we identified 12 biosynthetic gene clusters across 10 contigs; among these were 13 key mevalonate (MVA) pathway enzymes, a key tyrosinase enzyme in the 3,4-dihydroxyphenylalanine (DOPA) pathway that is responsible for producing DOPA melanins, and 16 enzymes involved in uridine diphosphate glucose biosynthesis. Overall, this study presents the first genome assembly and annotation of S. yunnanense; ultimately, this information will be important in the elucidation of the biological activities and artificial domestication of this fungus.
Topics: Genome, Fungal; Molecular Sequence Annotation; China; Whole Genome Sequencing; Dihydroxyphenylalanine; Phylogeny
PubMed: 37839651
DOI: 10.1016/j.ygeno.2023.110727