Search Results (85)

Plant-derived pharmaceuticals represent a highly compelling area of research and continue to attract significant interest from countries, regions, scientific communities, and pharmaceutical companies worldwide. Among these, α- and β-amyrins have been identified as high-value triterpenoid compounds with a broad spectrum of potential therapeutic properties, including anti-inflammatory, antidiabetic, antiatherosclerotic, analgesic, antigout, neuroprotective, anti-Parkinsonian, anticancer, antibacterial, and anti-HIV activities. Relevant information and data were obtained through comprehensive searches of major scientific databases, including Web of Science, Elsevier, and the National Library of Medicine. This study highlighted the pharmaceutical potential of α- and β-amyrins, supported by specific evidence from in vivo, in vitro, and clinical trials. Various extraction methods for α- and β-amyrins are discussed, followed by recommendations for future directions in the development of these compounds as pharmaceutical agents and functional food ingredients. This review highlights the therapeutic of α- and β-amyrin compounds in the prevention and treatment of various serious diseases worldwide, potentially opening new opportunities and directions for the pharmaceutical industry. Full article

Backgrounds and Objectives: This study aims to characterize the prevalence and severity of antidepressant-associated adverse drug events (ADEs) and to identify predictors strongly associated with serious adverse events (SAEs). Materials and Methods: Disproportionality analysis on antidepressant-related ADEs spontaneously reported to the Korea Adverse event Reporting System (KIDS KAERS DB) from 2014 to 2023 was performed. Multiple logistic regression was conducted to identify predictors associated with SAEs. Sensitivity analysis was performed to validate the overall findings and assess the robustness of associations across subgroups defined by completeness of demographic data (age and sex), elderly age-stratification, and causality assessment. The study protocol was approved by the Kyung Hee University institutional review board. Results: Among 21,103 antidepressant-related ADEs, duloxetine was the most etiologic medication, followed by amitriptyline and escitalopram. Fluoxetine is the only agent with a high likelihood of reporting SAEs. ADEs involving vascular (extracardiac) disorders (ROR 42.42, 95% CI 13.19–136.42) and liver and biliary system disorders (ROR 7.84, 95% CI 3.77–16.29) were most likely to be SAEs. The predictors associated with substantial increased SAE risk were fluoxetine use (OR 2.71, 95% CI 1.68–4.39), male sex (OR 1.48, 95% CI 1.11–1.98), and concomitant administration of antiparkinsonian treatment (OR 8.29, 95% CI 3.61–19.06) and antidementia treatment (OR 2.94, 95% CI 1.34–6.05). Sensitivity analyses demonstrated similar and consistent findings. However, reversed trends in the association between SOC-based ADEs and sex were observed in the sensitivity analysis restricted to cases with “certain” and “probable” causality. Conclusions: The type of antidepressant, concomitant medications, and sex are major predictors for SAE risk. Further controlled studies on the impact of comorbidities and polypharmacy on antidepressant-related SAEs are warranted. Full article

Stroke, the third leading cause of death worldwide, is a major cause of functional disability. Cerebral ischemia causes a rapid elevation of adenosine, the main neuromodulator in the brain. The inhibition of adenosine A2A receptors (A2ARs) has been introduced as a potential target in neurodegenerative disorders involving extracellular adenosine elevation. Istradefylline, a selective A2AR antagonist, has been approved for Parkinson’s disease (PD) adjunctive therapy and showed neuroprotective effects in PD and Alzheimer’s disease. However, the role of A2ARs in post-stroke neuronal damage and behavioral deficits remains unclear. We recently showed that A2AR antagonism prevented the adenosine-induced post-hypoxia synaptic potentiation of glutamatergic neurotransmission following the hypoxia/reperfusion of hippocampal slices. Here, we investigated the potential neuroprotective effects of istradefylline in male Sprague-Dawley rats subjected to pial vessel disruption (PVD) used to model a small-vessel stroke. Rats were treated with either a vehicle control or istradefylline (3 mg/kg i.p.) following PVD surgery for three days. Istradefylline administration prevented anxiety and depressive-like behaviors caused by PVD stroke. In addition, istradefylline significantly attenuated ischemia-induced cognitive impairment and motor deficits. Moreover, istradefylline markedly reduced hippocampal neurodegeneration, as well as GFAP/Iba-1, TNF-α, nNOS, and iNOS levels after PVD, but prevented the downregulation of anti-inflammatory markers TGF-β1 and IL-4. Together, these results suggest a molecular link between stroke and PD and that the anti-PD drug istradefylline displays translational potential for drug repurposing as a neuroprotective agent for cerebral ischemic damage. Full article

Monoterpenes (MTs) are plants’ secondary metabolites and major components of essential oils (EOs), widely used in the pharmaceutical industry. However, its neuroprotective effects, particularly in Parkinson’s disease (PD) have not been fully demonstrated. PD is a progressive neurological disorder marked by dopaminergic neuron loss in the substantia nigra, motor symptoms being the most reported ones. This review evaluates the evidence supporting the use of MTs as potential neuroprotective agents. PubMed, SCOPUS, Google Scholar, and ScienceDirect databases were searched for articles on MTs in murine models with any type of administration. The PRISMA guidelines were followed. After screening 405 records, 32 were included in the systematic review and 30 were included in the meta-analysis. Fifteen MTs, commonly found in EOs, were identified as potential therapeutic agents for PD. The meta-analysis revealed that MTs administration improved motor performance, increased tyrosine hydroxylase levels, reduced oxidative stress markers (malondialdehyde) and proinflammatory cytokines (IL-6, IL-1, TNF-α), and enhanced antioxidant enzymes (catalase, superoxide dismutase) in parkinsonian animals. The antioxidant and anti-inflammatory properties of MTs appear to be key mechanisms in mitigating dopaminergic neurodegeneration. However, further clinical research is essential to translate these findings into practical applications. Full article

Parkinson’s disease (PD) represents a growing challenge to global health, as it involves millions of people. The high grade of disability is due to the loss of dopaminergic neuron activity, and levodopa is the gold-standard therapy used to restore dopamine in the dopamine-denervated regions. Another therapeutic approach is the use of A_2A adenosine receptor antagonists and, among them, istradefylline is the only one currently approved for therapy in association with levodopa. In this work, we synthesized A_2A adenosine receptor antagonists represented by 9-ethyl-2,8-disubstituted adenine derivatives, which were tested at human adenosine receptors in binding and functional assays. These compounds showed A_2A adenosine receptor-binding affinities in the low nanomolar range and 1, 4, and 5 exhibited good potency in the functional assays. Hence, they were evaluated in in vivo rat models of PD, where they were demonstrated to revert haloperidol-induced catalepsy and potentiate levodopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats. The most potent derivative, 4, was then evaluated in the tacrine model, where it reduced the tremulous jaw movements, therefore demonstrating an action on parkinsonian tremor. These data revealed 8-ethoxy-2-phenethoxy-9-ethyladenine (4) as an A_2A adenosine receptor antagonist endowed with antiparkinsonian effects and as a good candidate to treat the disease. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction, oxidative stress, and neuroinflammation are recognized as critical pathological mechanisms driving neurodegeneration in PD. Exosome (Exo)-based therapies, particularly those derived from human neural stem cells (hNSCs), offer promising neuroprotective effects due to their ability to transfer bioactive molecules that modulate cellular processes. Resveratrol (RES), a polyphenolic compound with potent antioxidant and anti-inflammatory properties, has been shown to enhance the therapeutic potential of stem cell (SC)-derived Exos. This study investigated the neuroprotective effects of RES-treated hNSCs-derived Exos (RES-hNSCs-Exos) on SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP⁺), a neurotoxin commonly used to model Parkinsonian neurotoxicity. Treating SH-SY5Y cells with MPP⁺ led to significant reductions in cell viability, mitochondrial dysfunction, increased oxidative stress, and the activation of inflammatory pathways. Treatment with RES-hNSCs-Exos rescued SH-SY5Y cells from MPP⁺-induced toxicity by improving cell viability, enhancing ATP production, increasing mitochondrial biogenesis, and reducing reactive oxygen species (ROS) generation. The findings also demonstrated the increased expression of essential genes involved in mitochondrial biogenesis, such as PGC1α, NRF1, and Tfam, indicating improved mitochondrial function in the presence of RES-hNSCs-Exos. Further analysis revealed that these protective effects were mediated by activating the AMP-activated protein kinase (AMPK) and Nrf2 signaling pathways, which promoted mitochondrial health and reduced oxidative stress. Moreover, RES-hNSCs-Exos treatment suppressed neuroinflammation by downregulating NLRP3 inflammasome activation and reducing the secretion of pro-inflammatory cytokines IL-1β and IL-18. In conclusion, the results suggest that RES-hNSCs-Exos exhibit potent neuroprotective effects against MPP⁺-induced neurotoxicity by enhancing mitochondrial function, reducing oxidative stress, and inhibiting neuroinflammation. These findings highlight the potential of hNSCs-Exos as a novel therapeutic strategy for neurodegenerative diseases like PD, with RES as a valuable enhancer of Exos efficacy. Full article

Monoamine oxidase inhibitors are widely used for the symptomatic treatment of Parkinson’s disease (PD). They demonstrate antiparkinsonian activity in different toxin-based models induced by 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and pesticides (rotenone and paraquat). In some models, such as MPTP-induced PD, MAO inhibitors prevent the formation of the neurotoxin MPP⁺ from the protoxin MPTP. Regardless of the toxin’s nature, potent MAO inhibitors prevent dopamine loss reduction, the formation of hydrogen peroxide, hydrogen peroxide signaling, and the accumulation of hydrogen peroxide-derived reactive oxygen species responsible for the development of oxidative stress. It becomes increasingly clear that some metabolites of MAO inhibitors (e.g., the rasagiline metabolite 1-R-aminoindan) possess their own bio-pharmacological activities unrelated to the parent compound. In addition, various MAO inhibitors exhibit multitarget action, in which MAO-independent effects prevail. This opens new prospects in the development of novel therapeutics based on simultaneous actions on several prospective targets for the therapy of PD. Full article

Monoamine oxidase B (MAO-B) inhibitors are widely used as part of combination drug therapy for Parkinson’s disease. As demonstrated in both in vitro and in vivo experiments, the monoterpenoid Prottremine and some of its derivatives exhibit high antiparkinsonian activity. In this study, the inhibitory activity of Prottremine and its derivatives (including 14 new 9-N- and S-derivatives) against MAO-A and MAO-B enzymes has been investigated for the first time. Compounds containing fragments of substituted anilines have demonstrated the highest activity against MAO-A; for example, compound 28 had an IC₅₀ of 178 ± 44 μM. A significant proportion of the compounds tested, including Prottremine, exhibited moderate inhibitory activity towards MAO-B, with the most active being the o-aminoacetophenone derivative, which had an IC₅₀ of 95 ± 5 μM. A molecular docking method for studying murine MAO-A and -B enzymes was developed using AlphaFold2 (v2.3.2), with further improvements. For the MAO-B enzyme, a strong correlation was observed between the molecular docking data and the measured activity of the compounds, with the maximum binding affinity registered for the most active compound. It is conceivable that the antiparkinsonian activity of Prottremine and some of its derivatives may be partially mediated, among other mechanisms, by MAO-B enzyme inhibition. Full article

Background: Paraneoplastic neurological syndromes (PNSs) are rare conditions characterized by immune-mediated pathogenesis, frequently associated with the presence of a neoplasm. Although a single antineuronal antibody mediates a specific syndrome, atypical manifestations mediated by the same antibody have been described. Methods: The aim of this study was to report on an atypical case of PNS with dual positivity for anti-GAD65 and anti-CRMP5/CV2 antibodies, simultaneously characterized by cognitive decline associated with progressive ataxia and parkinsonism. We also reviewed the current literature for published cases of PNSs with parkinsonism associated with anti-GAD65 and anti- CRMP5/CV2 antibodies. Results: A 68-year-old man with an insidious onset of bradykinesia, cognitive decline, and gait instability that began the year before our evaluation had been diagnosed with parkinsonian syndrome. Analysis of the cerebrospinal fluid showed lymphocytic pleocytosis, and a panel for PNS tested positive for anti-GAD65 and anti- CRMP5/CV2 antibodies. After investigation, a microcitoma was found in the lung. Conclusions: In light of our findings, we suggest considering PNS as an alternative diagnosis to parkinsonism-plus syndromes, in particular if bradykinetic syndrome is accompanied by other clinical manifestations including cognitive decline or ataxia in rapidly deteriorating patients. Earlier detection of PNS would lead to timelier identification of any occult tumors, therein promising improvement in the patient’s prognosis. Full article

Background: Parkinson’s disease (PD) is a neurodegenerative disorder that progressively damages the autonomic and central nervous systems, leading to hallmark symptoms such as resting tremor, bradykinesia, and rigidity. Despite extensive research, the underlying cause of PD remains unclear, and current treatments are unable to halt the progression of the disease. In this retrospective study, based on historical electronic health records (EHR) from a national health provider covering the period from 2003 to 2023, we investigated the impact of vaccination and medication purchases on PD occurrence and severity. Methods: Using a case–control design, we compared the vaccination histories of 1446 PD patients with 7230 matched controls to assess the association between vaccination and PD onset. Additionally, we explored statistical associations between vaccination, medication purchases, and PD severity over an average of 9 years of follow-up, utilizing a machine learning algorithm to quantify disease severity based on annual antiparkinsonian medication purchases. Results: Our analysis revealed a significant reduction in PD occurrence following tetanus–diphtheria (Td) vaccination, with an adjusted odds ratio of 0.17 (95% CI [0.04, 0.70]) for PD onset within 5 years post-vaccination. Furthermore, a time-dependent relationship was identified between the duration since vaccination and both the rate of PD onset and disease progression. Notably, we observed that antimicrobial treatments significantly influenced disease severity, consistent with the antibiotic sensitivity profile of Clostridium tetani. Conclusions: These findings support the hypothesis that tetanus vaccination and/or C. tetani eradication may reduce PD occurrence and slow its progression, suggesting promising directions for future research in PD prevention and treatment. Full article

Monoamine oxidase (MAO) plays a key role in the pathogenesis of central nervous system disorders, and MAO inhibitors have been used in the treatment of depression and Parkinson’s disease. In the search for new classes of MAO inhibitors, the present study investigated a series of 1,2,4-oxadiazin-5(6H)-one derivatives. This study provides the first optimization of the reaction conditions for the condensation of amidoximes with alkyl 2-halocarboxylates to yield the desired 1,2,4-oxadiazin-5(6H)-ones. The results of the in vitro MAO inhibition studies showed that the 1,2,4-oxadiazin-5(6H)-ones were indeed inhibitors of human MAO with the most potent inhibition observed for 5f (IC₅₀ = 0.900 µM) and 7c (IC₅₀ = 0.371 µM). It was concluded that, with appropriate substitution, 1,2,4-oxadiazin-5(6H)-one derivatives would act as good potency MAO-B inhibitors and lead compounds for the development of antiparkinsonian drugs. In Parkinson’s disease, MAO-B inhibitors enhance central dopamine levels and reduce MAO-mediated production of hydrogen peroxide and resultant oxidative injury. This study represents one of few works to investigate synthetic approaches and biological activities of the 1,2,4-oxadiazin-5(6H)-one class of heterocycles. Full article

Introduction. Previous studies have shown that probiotics have positive effects on both motor and non-motor symptoms in Parkinson’s disease (PD). Additionally, in preclinical settings, probiotics have demonstrated the ability to counteract neuronal loss and alpha-synuclein aggregation, important pathological hallmarks of PD. Notably, preliminary in vitro studies have revealed the immunomodulatory properties of probiotics. This study aims to evaluate the impact of probiotics on symptoms and peripheral cytokines levels in PD patients compared to placebo. Methods. Patients were enrolled and blindly randomized to receive either active probiotics (comprising Bifidobacterium animalis subsp. lactis BS01 LMG P-21384, Bifidobacterium longum BL03 DSM 16603, Bifidobacterium adolescentis BA02 DSM 18351, Fructo-oligosaccharides and Maltodextrin-Group A) or placebo (Maltodextrin-Group B). Clinical evaluations and plasma levels cytokines (TNF-α, IFN-γ, IL-6, and TGF-β) were also assessed at enrollment and after 12 weeks. Anti-parkinsonian therapy remained stable throughout the study. Results. Forty PD patients were recruited. After 12 weeks, Group A showed significant improvement in motor symptoms (UPDRS III: 13.89 ± 4.08 vs. 12.74 ± 4.57, p = 0.028) and non-motor symptoms (NMSS: 34.32 ± 21.41 vs. 30.11 ± 19.89, p = 0.041), with notable improvement in the gastrointestinal sub-item (3.79 ± 4.14 vs. 1.89 ± 2.54, p = 0.021). A reduction of IFN-γ levels was observed in both groups, but group A also showed a significant decrease in IL-6 and a slight increase in the anti-inflammatory cytokine TGF-β. Conclusions. Our data suggest that probiotics may modulate peripheral cytokines levels and improve clinical symptoms in PD patients. Probiotics may, therefore, represent a valuable adjunctive therapy to conventional anti-parkinsonian drugs. Full article

Background: Monoamine oxidases (MAO) are flavoenzymes that metabolize a range of brain neurotransmitters, whose dysregulation is closely associated with the development of various neurological disorders. This is why MAOs have been the central target in pharmacological interventions for neurodegeneration for more than 60 years. Still, existing drugs only address symptoms and not the cause of the disease, which underlines the need to develop more efficient inhibitors without adverse effects. Methods: Our drug design strategy relied on docking 25 organic scaffolds to MAO-B, which were extracted from the ChEMBL20 database with the highest cumulative counts of unique member compounds and bioactivity assays. The most promising candidates were substituted with the inactivating propargylamine group, while further affinity adjustment was made by its N-methylation. A total of 46 propargylamines were submitted to the docking and molecular dynamics simulations, while the best binders underwent mechanistic DFT analysis that confirmed the hydride abstraction mechanism of the covalent inhibition reaction. Results: We identified indole-2-propargylamine 4fH and indole-2-N-methylpropargylamine 4fMe as superior MAO-B binders over the clinical drugs rasagiline and selegiline. DFT calculations highlighted 4fMe as more potent over selegiline, evident in a reduced kinetic requirement (ΔΔG^‡ = −2.5 kcal mol⁻¹) and an improved reaction exergonicity (ΔΔG_R = −4.3 kcal mol⁻¹), together with its higher binding affinity, consistently determined by docking (ΔΔG_BIND = −0.1 kcal mol⁻¹) and MM-PBSA analysis (ΔΔG_BIND = −1.5 kcal mol⁻¹). Conclusions: Our findings strongly advocate 4fMe as an excellent drug candidate, whose synthesis and biological evaluation are highly recommended. Also, our results reveal the structural determinants that influenced the affinity and inhibition rates that should cooperate when designing further MAO inhibitors, which are of utmost significance and urgency with the increasing prevalence of brain diseases. Full article

The novel antiparkinsonian agent PA-96 is the focus of our research. PA-96 supported the survival of cultured naïve dopamine neurons, alleviated motor deficits in MPTP and haloperidol-based mice models of Parkinson’s disease, and increased the density of tyrosine hydroxylase positive neurons and dopamine concentration in the midbrain of an MPTP-damaged brain. In this work, an HPLC–MS/MS method was developed and validated, and the pharmacokinetics of the agent was investigated in mice after a single or multiple oral administration (p.o.) and intravenous injection (i.v.) at various doses. The dose proportionality was also evaluated after a single p.o. administration of three ascending doses (1, 5, and 10 mg/kg) and a single i.v. injection of two doses (1 and 10 mg/kg); also, the bioavailability was estimated. The disproportionality of pharmacokinetic parameters could be explained by the saturation of active centres of enzymes or receptors binding the substance: at low doses, part of the compound is bound, leaving a small amount circulating in blood, and rapidly metabolised and/or bound too. The bioavailability of PA-96 was c.a. 7 and 35% for the doses of 5 and 10 mg/kg, correspondingly. Full article

Neurodegenerative diseases such as Parkinson’s and Alzheimer’s continue to be some of the most significant challenges in modern medicine. Recent research related to the molecular mechanisms of parkinsonism has opened up new approaches to antiparkinsonian therapy. In response to this, we present the evaluation of the potential neuroprotective and MAOA/MAOB inhibitory effects of newly synthesized hydrazones, containing a pyrrole moiety in the carboxyl fragment of the structure. The substances were studied on different brain subcellular fractions, including rat brain synaptosomes, mitochondria, and microsomes. The single application of 50 µM of each compound to the subcellular fractions showed that all substances exhibit a weak neurotoxic effect, with 7b, 7d, and 8d being the least neurotoxic representatives. The corresponding neuroprotective and antioxidant effects were also evaluated in different injury models on subcellular fractions, single out 7b, 7d, and 8d as the most prominent derivatives. A 1 µM concentration of each molecule from the series was also studied for potential hMAOA/hMAOB inhibitory effects. The results revealed a lack of hMAOA activity for all evaluated structures and the appearance of hMAOB effects, with compounds 7b, 7d, and 8d showing effects similar to those of selegiline. The best hMAOB selectivity index (>204) was determined for 7d and 8d, distinguishing these two representatives as the most promising molecules for further studies as potential selective MAOB inhibitors. The performed molecular docking simulations defined the appearance of selective MAOB inhibitory effects based on the interaction of the tested molecules with Tyr398, which is one of the components of the aromatic cage of MAOB and participated in π–π stabilization with the aromatic pyrrole ring. The preliminary PAMPA testing indicated that in relation to the blood–brain barrier (BBB) permeability, the tested pyrrole-based hydrazones may be considered as high permeable, except for 8a and 8e, which were established to be permeable in the medium range with −logP of 5.268 and 5.714, respectively, compared to the applied references. Full article