Search Results (1,293)

Parkinson’s disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, for which effective treatments remain unavailable. Here, we report CL0179, a fungal-derived decahydrofluorene alkaloid with antioxidant-associated neuroprotective properties, and evaluate its effects across cellular and animal PD models. CL0179 exhibited a favorable safety profile and protected SHSY5Y against 6-hydroxydopamine- (6-OHDA), rotenone-, and 1-Methyl-4-phenylpyridinium-iodide (MPP⁺)-induced neurotoxicity by preserving mitochondrial membrane potential and network integrity. Transcriptomic analyses revealed selective restoration of gene-expression programs associated with oxidative phosphorylation, mitochondrial bioenergetics, and stress adaptation disrupted by MPP⁺. CL0179 also enhanced SIRT1 activity under MPP⁺ stress, whereas pharmacological SIRT1 inhibition partially attenuated protection of mitochondrial membrane potential and cell viability. In LRRK2-G2019S astrocytes, CL0179 reduced ROS and α-synuclein accumulation and restored mitochondrial organization, while in human dopaminergic neurons, it attenuated toxin-induced mitochondrial depolarization and preserved neuronal architecture. To overcome the low production of CL0179, we generated the structurally related analogue CL0670. Both compounds crossed the blood–brain barrier and protected mouse primary cortical neurons, while CL0670 improved motor deficits in a 6-OHDA mouse model. Collectively, these compounds promote mitochondrial resilience and stress-adaptive neuroprotection, supporting their potential for PD and related neurodegenerative disorders. Full article

Efflux pumps are essential components of cellular detoxification mechanisms, regulating the intracellular accumulation of xenobiotics and endogenous compounds. Among them, P-glycoprotein (P-gp) plays a role in protecting the brain from potentially toxic molecules, and alterations in its function have been associated with neurodegenerative disorders, including Parkinson’s disease (PD). Although P-gp inhibitors have been extensively investigated in the context of multidrug resistance, their effects on neuronal cells remain poorly characterized. In the present study, we investigated the biological effects of the pyridoquinoxaline-based efflux pump inhibitor 2,2′-(pyrido[2,3-g]quinoxaline-2,3-diylbis(methylene))bis(oxy)bis(N-phenylbenzamide) (10d) in PC12 cells, a widely used dopaminergic neuronal model. The effects of 10d were evaluated by an MTT-based cell viability assay, while intracellular and extracellular dopamine (DA) levels and DA metabolites were quantified by high-performance liquid chromatography (HPLC). In addition, the ability of 10d to modulate MPTP-induced neurotoxicity was assessed, alone and in combination with amantadine (AMA), a known antiparkinsonian drug. Exposure to 10d (5 and 10 μM) reduced PC12 cell viability and markedly enhanced MPTP-induced cytotoxicity. Furthermore, 10d altered dopaminergic homeostasis by decreasing intracellular DA levels and modifying DA metabolite profiles, with more pronounced effects following co-treatment with MPTP. The combined administration of 10d, MPTP and AMA produced a stronger disruption of DA metabolism compared with individual treatments or 10d/MPTP co-exposure. Full article

Trace amines (TAs) are endogenous biogenic amines present at low concentrations in the brain and were historically considered byproducts of monoamine metabolism. The discovery of trace amine-associated receptors (TAARs), a family of G protein-coupled receptors, has redefined their physiological and pharmacological relevance. TAAR1 regulates dopaminergic, serotonergic, and glutamatergic signaling and is increasingly implicated in neuropsychiatric disorders. Preclinical studies show that TAAR1 agonists normalize dopaminergic function and improve cognitive deficits in schizophrenia models. Early clinical evidence suggests potential antipsychotic efficacy with a favorable extrapyramidal and metabolic safety profile. However, the failure of subsequent phase III trials to meet their primary efficacy endpoints highlights the need to identify responsive patient subgroups, optimize trial design, and clarify the clinical settings in which TAAR1 agonism may provide the greatest therapeutic benefit. In depression, TAAR1 activation produces antidepressant-like effects in preclinical models, whereas findings in anxiety are variable and context-dependent. TAAR1 may also modulate reward-driven feeding and metabolic parameters. Mechanistically, TAAR1 agonists differ in their effects on dopamine transporter function and monoaminergic neuron activity, indicating that their pharmacological effects are compound-specific rather than class-wide. These properties distinguish TAAR1-targeting compounds from classical D2 receptor antagonists and may underlie their clinical profile. Further translational studies are required to confirm their efficacy across symptom domains and establish long-term clinical benefit. Full article

Current Parkinson’s disease (PD) therapies like Levodopa (L-DOPA) only provide symptomatic relief, highlighting the need for multi-target neuroprotective agents. This study investigates the mechanisms and preclinical effects of trans-vitisin B (tVB), an oligomeric stilbene, in PD models. In LPS-stimulated HMC3 and RAW 264.7 cells, tVB (0.1–10.0 µM) significantly suppressed reactive oxygen species (ROS), nitric oxide (NO), COX-2, and pro-inflammatory cytokines (IL-1β, TNF-α), while restoring HSP70 chaperone levels to normalize proteostasis. These findings were validated in vivo using C57BL/6 mice with rotenone-induced chronic PD. Administration of tVB attenuated motor deficits (Cylinder test) and reduced pathological freezing (Open Field) and working memory impairments (Y-maze) in this model, without inducing the dyskinesia-like side effects of L-DOPA treatment in rodents. Histologically, tVB mitigated the loss of dopaminergic neurons (TH⁺) in the substantia nigra, reduced microglial activation (IBA-1⁺) and neuronal NO synthase, and suppressed pathological phosphorylated Tau protein (p-TauSer202) accumulation. Unlike L-DOPA’s direct dopaminergic stimulation, tVB’s neuroprotective efficacy is mediated through multilevel regulation of key PD pathogenetic pathways, including neuroinflammation, oxidative stress, and impaired proteostasis. Full article

Parkinson’s disease (PD) involves not only the loss of dopaminergic neurons in the substantia nigra but also spinal cord degeneration. However, the molecular mechanisms of spinal cord degeneration remain unclear. This study investigated the spinal cord transcriptomic characteristics of MPTP-induced PD mice via transcriptome sequencing and weighted gene co-expression network analysis (WGCNA) to identify key gene modules and potential therapeutic targets. An MPTP-induced PD mouse model was established, and spinal cord transcriptome sequencing was conducted to screen differentially expressed genes (DEGs). Functional enrichment analysis, WGCNA for phenotype-correlated modules, and protein–protein interaction analysis were subsequently conducted to identify key genes. In total, 3473 DEGs were identified (1775 upregulated, 1698 downregulated). Downregulated genes were predominantly enriched in pathways related to oxidative phosphorylation and post-transcriptional regulation, whereas upregulated genes were associated with glutamatergic synapses, axonogenesis, and negative regulation of neurogenesis. Among the five co-expression modules, the brown and yellow modules were most strongly correlated with the PD phenotype, enriched in calcium signaling, inflammation, and spliceosome pathways. Key genes like Akt1, Nlrp3, Tgfb1, Lingo1, and Olig2 were upregulated, whereas Vps35 and Omg were downregulated. This study characterizes the spinal transcriptome of PD mice, suggesting that dysregulated post-transcriptional processes, abnormal oxidative phosphorylation, glutamatergic excitotoxicity, and neuroinflammation may be potential candidate mechanisms and vital involved factors in spinal cord degeneration. These findings provide novel insights into the pathological mechanisms of spinal cord degeneration in PD and lay a foundation for targeted therapy, deserving further investigation. Full article

Arthropod-borne viruses such as Alphaviruses and Flaviviruses are the causative agents of severe human disease, highlighted by fatal encephalitis and neurological sequelae in survivors. The lack of FDA-approved vaccines and therapeutics that can prevent or treat these infections results in a significant global disease burden. An important unmet need to address this capability gap is the need for affordable, scalable, clinically relevant human-based neuronal models to study neuroinvasive viruses and evaluate therapeutic options. Here, we described the application of a human neuronal precursor cell model, LUHMES (Lund human mesencephalic) cells, that can be differentiated into dopaminergic midbrain neurons and used to study virus infections. In this study, we demonstrated the susceptibility of LUHMES cells to infection by three arthropod-borne neurotropic viruses: Venezuelan equine encephalitis virus, dengue virus serotype 2, and West Nile virus. We also demonstrated how the model may be applied to evaluate potential therapeutic options using an FDA-approved small molecule, Omaveloxolone. Finally, we analyzed host cell responses to infection and treatment using gene expression and phospho-signaling analyses. These findings highlight the value of this model to interpret the pathogenic mechanisms of neurotropic viral infections and evaluate potential therapeutic intervention strategies in a clinically relevant in vitro human neuronal model. Full article

Parkinson’s disease (PD) is characterized by progressive dopaminergic degeneration and maladaptive motor cortical plasticity. However, the cellular pathways underlying cortical surface activity in the primary motor cortex (M1) remain unclear, despite serving as a potential target for electrotherapy. We investigated the excitatory–inhibitory (E-I) balance and synaptic plasticity of superficial M1 circuits in a unilateral 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Using extracellular local field potential and whole-cell patch recordings from the contralateral and ipsilateral M1 hemispheres of hemi-parkinsonian rats, we observed a significantly elevated field excitatory postsynaptic potential (fEPSP) input–output function but unchanged intrinsic neuronal excitability in the M1 superficial layer. An altered relative contribution between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated transmission was reflected by a significantly increased AMPA/NMDA ratio. Markedly reduced inhibitory synaptic tone was also evidenced by the decreased amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), supporting an E-I imbalance favoring excitation in PD. Furthermore, group I metabotropic glutamate receptor (mGluR_1/5)-dependent long-term depression (LTD) was abolished in the ipsilateral PD hemisphere, whereas NMDAR-dependent LTD remained intact. In summary, dopamine depletion appears to enhance network excitation and disrupt mGluR_1/5-mediated control of M1 surface circuitry. Our findings identify altered cortical surface mGluR-dependent plasticity in the hemi-parkinsonian model; however, the relationship between these electrophysiological alterations and individual motor outcomes remains to be determined. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons. Its symptoms affect both motor functions—such as bradykinesia, rigidity, resting tremor, and postural instability—and non-motor functions, including neuropsychiatric issues, sleep disorders, and constipation. Drawing on the literature, the following topics were developed and presented: Pathophysiology; Treatment; Neuropsychiatric and Cognitive Function; Sleep Challenges; Exercise and Movement; Striving for Wellness; and Obstacles/Paths Forward. These seven categories form the foundation of this review, which centers on four main areas related to PD: dopamine biology and pathophysiology; management of key motor and non-motor symptoms; strategies for achieving wellness; and unresolved issues in PD. The complexity of PD’s clinical features is highlighted by describing patient–healthcare provider interactions, elucidating disease mechanisms, managing motor and non-motor symptoms, highlighting the benefits of exercise, emphasizing the importance of sleep, addressing mental health challenges and cognitive changes, fostering a hopeful and resilient mindset, potentially slowing disease progression, treating comorbidities, and promoting overall wellness. Although there have been tremendous advances in the basic science and clinical management of PD in recent years, PD remains incurable. Thus, we describe several roadblocks that have hindered progress in understanding PD. Only by integrating historical insights with the latest PD advances can we acquire the knowledge needed to change the disease’s trajectory. Finally, this review aims to provide a meaningful summary for healthcare professionals (and students) caring for patients with PD. Full article

Parkinson’s disease (PD) is widely regarded as a disorder of dopaminergic neurons that involves mitochondrial dysfunction, impaired mitophagy, and oxidative stress. However, the nature and significance of skeletal muscle pathology remain unclear. In this study, we used Caenorhabditis elegans, which lack muscle stem cells in adulthood, to examine the effects of PDR-1/Parkin deficiency on mitochondrial homeostasis and motor function under conditions where muscle regeneration does not occur. Silencing of pdr-1 attenuated age-related mitochondrial fragmentation in body-wall muscle cells but was associated with later impairments in locomotor activity and loss of nuclear GFP signals, suggesting progressive muscle cell damage. By day 2 of adulthood, mitochondrial reactive oxygen species (mtROS) levels were elevated in muscle cells subjected to pdr-1 RNAi, and in the pdr-1(gk448) mutant this mtROS elevation was accompanied by a reduction in mitochondrial membrane potential (ΔΨm). In vivo imaging further revealed elevated mitochondrial Ca²⁺ levels ([Ca²⁺]_mito) in PDR-1-deficient muscle cells. Moreover, the mtROS increase associated with PDR-1 deficiency was suppressed in mcu-1 mutants. These findings support a model in which MCU-1-dependent elevation of [Ca²⁺]_mito contributes to oxidative mitochondrial defects in PDR-1/Parkin-deficient muscle. Full article

Background/Objectives: The aim of the present study was to investigate the mechanisms in Parkinson’s disease (PD), a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, aggregation of α-synuclein, mitochondrial dysfunction, oxidative stress, neuroinflammation, gut dysbiosis, and blood–brain barrier (BBB) impairment. Although there are several approved therapies that have been developed, their aqueous solubility, oral bioavailability, first-pass metabolism, and inability to penetrate the BBB make them less effective over time. This review is intended to critically analyze the potential of self-nanoemulsifying drug delivery systems (SNEDDSs) as a pathogenesis-related approach to enhance the delivery and therapeutic activity of repurposed drugs and conventional drugs for PD. Methods: A comprehensive literature search was conducted to address the pathogenic mechanisms of PD, the deficiencies of current pharmacotherapy, recent developments in SNEDDS formulation strategies and their application in improving oral bioavailability, lymphatic transport, BBB penetration and targeted brain delivery. A special focus was dedicated to drug repurposing, functionalized SNEDDSs, PEGylation, and gut–brain axis modulation. Results: SNEDDSs significantly enhance the water solubility, stability, intestinal absorption and systemic exposure of poorly water-soluble therapeutic agents and, to a certain extent, lymphatic uptake to avoid first-pass metabolism. These systems include improved brain delivery, decreased pharmacokinetic variability, and prolonged drug levels within the therapeutic range. Moreover, SNEDDSs can be used to deliver multiple molecules that are found to be neuroprotective, antioxidant, anti-inflammatory and probiotic, all at once, which can act on multiple pathogenic mechanisms associated with PD. Functionalized and PEGylated SNEDDSs add further to formulation stability, extend systemic circulation and increase efficiency of brain targeting. Conclusions: SNEDDSs are a promising translational nanomedicine platform for enhancing the effectiveness of conventional and repurposed therapeutics in PD, which address key pharmacokinetic and biological challenges. The next generation of oral therapies with targeted surface engineering, precision drug repurposing and clinical validation will be expected to bring about a faster advancement of drugs that can alter the course of disease rather than giving only symptomatic relief. Full article

Currently, effective disease-modifying treatments for Parkinson’s disease (PD) remain lacking. Although exercise has been confirmed to exert neuroprotective effects against PD, its specific molecular mechanisms remain unclear. In particular, the causal role of the Nuclear Factor E2-related Factor 2 (Nrf2)–antioxidant response element (ARE) signaling axis in this process has not been clearly elucidated. This study aimed to provide direct causal evidence that regular treadmill exercise protects the substantia nigra pars compacta (SNc)–striatal dopaminergic system by activating the Nrf2-ARE pathway. The results showed that exercise significantly improved motor function deficits in PD mice, preserved the number of TH-positive neurons, and restored striatal dopamine homeostasis. Mechanistically, exercise activated the Nrf2-ARE pathway, thereby inhibiting the accumulation of mitochondrial ROS (mtROS) and the activation of pro-inflammatory amoeboid microglia in the substantia nigra. Crucially, the improvements in behavioral, neuropathological, and neurochemical indicators induced by exercise were completely reversed, returning to levels comparable to those in the sedentary model group. In conclusion, this study provides clear pharmacological evidence that the neuroprotective effect of regular treadmill exercise against chronic PD strictly depends on the Nrf2-ARE pathway. These findings indicate that Nrf2 is a key mechanistic node linking exercise and neuroprotection, providing reliable preclinical evidence for Nrf2-targeted disease-modifying strategies in PD rehabilitation. Full article

Tobacco use remains one of the leading preventable causes of morbidity and mortality worldwide, contributing to more than 7 million deaths annually and imposing a substantial economic burden on healthcare systems and global productivity. The addictive properties of tobacco are primarily mediated by nicotine, which exerts its effects through neuronal nicotinic acetylcholine receptors (nAChRs) within brain reward circuits. Among these receptor subtypes, α4β2-containing nAChRs play a central role in nicotine dependence by regulating dopaminergic signaling associated with reinforcement, craving, withdrawal, and relapse. Repeated nicotine exposure induces neuroadaptive changes in receptor expression and neural circuitry, contributing to the chronic and relapsing nature of addiction. Advances in addiction neuroscience and receptor pharmacology have enhanced the understanding of nicotine-mediated signaling and facilitated the development of evidence-based smoking cessation therapies. Current treatment approaches include nicotine replacement therapies, antidepressant-based interventions, and partial nAChR agonists such as varenicline and cytisine. Emerging strategies encompass subtype-selective ligands, allosteric modulators, immunotherapeutics, neuromodulation techniques, and digital health technologies aimed at improving cessation outcomes. This review summarizes the neuropharmacological mechanisms underlying nicotine addiction and critically examines current and emerging therapeutic strategies, highlighting their mechanisms of action, clinical efficacy, limitations, and future potential for tobacco cessation. Full article

Neurons of the arcuate nucleus (AN) produce dopamine, which inhibits prolactin secretion. Tyrosine hydroxylase (TH), the key enzyme of dopamine synthesis, is expressed in AN in dopaminergic neurons and in neurons expressing only TH or both enzymes but lacking the dopamine transporter. These neurons are distributed differently between the ventrolateral and dorsomedial regions of the AN (further—ventrolateral or dorsomedial AN). We hypothesized that noradrenaline released by noradrenergic afferents inhibits TH synthesis in AN neurons postnatally. To test this hypothesis, we assessed: (i) adrenoreceptors gene expression in the ventrolateral and dorsomedial AN of intact rats at postnatal days (P) 5 and 60 and (ii) TH levels in sections of each AN region from rats at P5 and P60 after 6 h incubation in the absence or presence of noradrenaline, as well as noradrenaline with adrenoreceptor antagonists. It was shown that (i) AN neurons express genes for all types of adrenoreceptors in each region of AN on P5 and P60; (ii) neurons in both regions of AN synthesize TH, but to a greater extent at P60 than at P5; and (iii) noradrenaline inhibits TH synthesis, but only in the ventrolateral AN at P60—this action is mediated via α1-adrenoreceptors. Full article

Parkinson’s disease (PD) is a multisystem disorder in which gastrointestinal dysfunction often precedes motor symptoms, yet the molecular links between peripheral stress and central neurodegeneration remain unclear. We investigated whether genes commonly dysregulated in PD and a classic model of intestinal inflammation (IBD) might reveal conserved stress-responsive molecules relevant to brain pathology. Shared gene signatures between PD and inflammatory bowel disease (IBD) were identified from peripheral blood transcriptomes using weighted gene co-expression network analysis (WGCNA). Hub genes were prioritized via protein–protein interaction (PPI) analysis and evaluated for expression consistency in independent brain tissue transcriptomic datasets. Single-cell RNA sequencing (scRNA-seq) of the PD substantia nigra was used to define the cellular context of the key hub gene, and CellChat analysis assessed intercellular communication changes. Immunofluorescence validation was performed in an MPTP-induced PD mouse model. We identified 79 shared genes and 6 hub genes, among which only HSP90AA1 showed consistent upregulation across independent PD transcriptomic validation datasets. Functional enrichment highlighted inflammation-related pathways. Because peripheral immune infiltration showed only minor changes, we further investigated the cellular context of HSP90AA1 within the PD brain. ScRNA-seq analysis of the PD substantia nigra demonstrated that HSP90AA1 was expressed across multiple cell populations. Integration with transcriptional regulatory analysis identified TP53 as a potential upstream regulator, and the strongest TP53–HSP90AA1 co-expression and cellular colocalization signals were observed in astrocytes, prompting further astrocyte-focused investigation. CellChat analysis revealed altered intercellular communication patterns in PD substantia nigra, including changes in synapse-associated ligand–receptor interaction signatures, particularly involving NCAM-related pathways. In the MPTP-induced PD mouse model, immunofluorescence identified astrocytic HSP90α upregulation, and increased nuclear p53 signal in astrocytes, accompanied by dopaminergic neuron loss. Conclusion: Astrocytic upregulation of HSP90AA1 is associated with altered synapse-related intercellular communication patterns in the PD substantia nigra, potentially involving a predicted TP53 associated regulatory component. These findings, validated in an MPTP mouse model, identify HSP90AA1 as a candidate stress-responsive hub linking peripheral inflammatory states with astrocyte-associated molecular alterations in PD, providing a framework for further experimental investigation. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the intracellular accumulation of alpha-synuclein (α-syn) aggregates. Historically, research has focused on neuronal mechanisms; however, growing evidence indicates that the progression of neurodegeneration is influenced by changes in the brain microenvironment, particularly through the dynamic interplay between microglia and the extracellular matrix (ECM). ECM in the central nervous system is an organized network of structural proteins, glycoproteins, and proteoglycans that encases neurons and glial cells, regulating processes such as synaptic stability, neural plasticity, and intercellular signaling. In PD, the aggregation of α-syn and neuronal damage induce sustained microglial activation, which can alter ECM structure. Activated microglia release proteases, including matrix metalloproteinases and cathepsins, which can degrade critical ECM components such as collagens, laminins, and proteoglycans. This remodeling can modify synaptic architecture, regulate cellular signaling, and disrupt neuron-glia interactions, fostering an environment conducive to dopaminergic degeneration. Furthermore, ECM remodeling and microglial activation exhibit regional variability within the brain. Regions notably prone to degeneration, such as the SNpc and striatum, display significant alterations in matrix organization and inflammatory activity, while other dopaminergic regions, including the ventral tegmental area, show increased resilience. We suggest that microglia-mediated ECM remodeling serves as a mechanistic link between neuroinflammation and neuronal susceptibility in PD. This review consolidates the existing knowledge on microglial modulation of ECM dynamics during neurodegeneration, explores regional differences in these processes, and evaluates their significance as possible treatment targets. Full article