Parkinson's Disease Model Research Articles

The effect of AKT inhibition in α-synuclein-dependent neurodegeneration

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting millions of individuals worldwide. A hallmark of PD pathology is the accumulation of α-synuclein (α-Syn), a small protein known to support neuronal development and function. However, in PD, α-Syn cumulatively misfolds into toxic aggregates that disrupt cellular processes and contribute to neuronal damage and neurodegeneration. Previous studies implicated the AKT signaling pathway in α-Syn toxicity in cellular models of PD, suggesting AKT as a potential therapeutic target. Here, we investigated the effect of AKT inhibition in a Drosophila model of synucleinopathy. We observed that administration of the AKT inhibitor, A-443654 led to mild improvements in both survival and motor function in flies expressing human α-Syn. Genetic studies revealed that reduction of AKT levels decreased α-Syn protein levels, concomitant with improved physiological outcomes. The protective effects of AKT reduction appear to operate through the fly ortholog of NF-κB, Relish, suggesting a link between AKT and NF-κB in regulating α-Syn levels. These findings highlight the AKT cascade as a potential therapeutic target for synucleinopathies and provide insights into mechanisms that could be utilized to reduce α-Syn toxicity in PD and related disorders, such as multiple system atrophy.

Short-Chain Fatty Acid Aggregates Alpha-Synuclein Accumulation and Neuroinflammation via GPR43-NLRP3 Signaling Pathway in a Model Parkinson's Disease.

Parkinson's disease (PD) is characterized by the aggregation of α-synuclein (α-syn) and the loss of dopaminergic (DA) neurons, with growing evidence suggesting a significant role of gut microbiota and their metabolites in the disease's pathogenesis. This study explores the effects of short-chain fatty acids (SCFAs) on PD progression, focusing on the G protein-coupled receptor 43 (GPR43) and the NLRP3 signaling pathway in both in vitro and in vivo models. Employing the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model and SH-SY5Y cells with SCFAs-treated, this study investigated the impact of SCFAs on α-syn deposition, DA loss, and neuroinflammation. In vitro, supernatant from STC-1 cells was administered to SH-SY5Y cells, and the effects were assessed following the knockdown of NLRP3 or GPR43. In vivo, mice were treated with NLRP3 or GPR43 inhibitors after feeding with SCFAs, and the motor deficits, α-syn pathology, DA neuronal loss, and inflammatory responses were observed. SCFAs were found to exacerbate motor and gastrointestinal dysfunctions in PD models, intensifying α-syn pathology and neuroinflammation. The activation of the NLRP3 inflammasome through GPR43 emerged as a key pathological mechanism, with inhibition of these molecules mitigating the observed effects. Such interventions reduced α-syn accumulation, DA loss, and inflammatory responses, highlighting the pivotal role of the SCFA/GPR43-NLRP3 pathway in PD. The findings from this study elucidate a critical link between gut-derived metabolic changes and neuroinflammatory processes in PD via the SCFA/GPR43-NLRP3 pathway. Targeting this pathway offers a promising therapeutic strategy and enriches our understanding of the gut-brain axis' role in PD progression.

Comparison the Effect of Continuous and Interval Aerobic Training on IL-1 and TNF-α Expression in Cerebellum of Parkinson's Model Rats

Introduction: In Parkinson's disease, the balance between Pro-inflammatory and anti-inflammatory cytokines is disturbed, causing chronic neuroinflammation. The aim of present study was to compare the effects of continuous and interval aerobic training on the expression of interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α) in cerebellum of Parkinson's model rats. Methods: In this experimental study, 28 adult male Wistar rats (weighting 180-250 gr) were randomly divided into four groups (n=7 each): control, Parkinson, Parkinson+ continuous training, and Parkinson+ interval training. Rotenone was utilized to induce Parkinson's in rats. The continuous training lasted between 15 to 40 minutes, while the interval training consisted of two to six sets of running on the treadmill at a speed of 10- 20 meters per minute for six weeks and five sessions per week. At the end of the intervention, the levels of IL-1 and TNF-α in the cerebellum tissue were assessed by Bradford method. The data were analyzed using one-way analysis of variance (ANOVA), followed by post hoc LSD test, utilizing SPSS version 16 software, with a significant level set at P<0.05. Results: The levels of IL-1 and TNF-α in the cerebellar tissue of the control group were significantly lower (P=0.0001) compared to the other groups, and in the Parkinson's group, they were significantly higher than the Parkinson's+ continuous training and Parkinson's+ interval training groups (both; P=0.0001). There was no significant difference in IL-1 levels between the two training groups (P=0.062); nontheless, interval training significantly reduced the level of TNF-α compared to continuous training (P=0.007). Conclusion: Based on these findings, interval aerobic training is a more efficient method in modulating pro-inflammatory cytokines in the cerebellum of Parkinson's model rats compared to continuous training, which can slow down the progression of the disease.

CCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson’s disease models

Parkinson’s disease (PD) is a progressive degenerative disease of the central nervous system associated with neuroinflammation and microglial cell activation. Chemokine signaling regulates neuron-glia communication and triggers a microglial inflammatory profile. Herein, we identified the neuronal chemokine CCL21 as a major cause of microglial cell imbalance through the CCR7 receptor pathway with therapeutic implications for PD. In humans, we found that CCL21 transcript expression was increased in dopaminergic neurons (DANs) of the substantia nigra in PD patients. CCL21 and CCR7 expressions were spatially associated with brain regional vulnerability to synucleinopathies, as well as with the expression of microglial activation, neuroinflammation, and degeneration-related genes. Also, in mouse models of PD, we showed that CCL21 was overexpressed in DANs in vivo and in vitro. Mechanistically, neuronal CCL21 was shown to regulate microglial cell migration, proliferation, and activation in a CCR7-dependent manner through both canonical (PI3K/AKT) and non-canonical (ERK1/2/JNK) signaling pathways. Finally, we demonstrated that navarixin, a clinically relevant chemokine inhibitor with high affinity for the CCR7 receptor, could block CCL21 effects on microglia and prevent neurodegeneration and behavioral deficits in two mouse models of PD induced with either α-synuclein oligomers (αSynO) or 3,4-dihydroxyphenylacetaldehyde (DOPAL). Altogether, our data indicate that navarixin blocks CCL21/CCR7-mediated neuron-microglia communication and could be used as a therapeutic strategy against PD.Graphical

Acute Intermittent Theta-Burst Stimulation Produces Antidepressant-Like Effects by Modulating Neuronal Oscillations and Serotonin Levels of the Medial Prefrontal Cortex in Experimental Parkinson's Disease.

Parkinson's disease (PD)-related depression is associated with aberrant neuronal oscillations and 5-hydroxytryptamine (5-HT) neurotransmission in the medial prefrontal cortex (mPFC). Intermittent theta-burst stimulation (iTBS), an updated pattern of high-frequency repetitive transcranial magnetic stimulation, has possible efficacy in PD-related depression. However, whether iTBS alleviates PD-related depression through modulating neuronal oscillations and 5-HT levels in the mPFC has not been determined. In this study, male Sprague-Dawley rats were used to establish a unilateral 6-hydroxydopamine-induced PD model. Then, acute iTBS was applied to the parkinsonian rats, and behavioral, neurochemical, and electrophysiological experiments were performed. We found that the parkinsonian rats exhibited increased immobility time and decreased sucrose preference accompanied by an increase of δ power and a decrease of θ power in the mPFC compared to sham-operated rats. One block of iTBS (1 block-iTBS, 300 stimuli) alleviated depressive-like behaviors in parkinsonian rats and elevated 5-HT levels in the mPFC compared to sham-iTBS. Additionally, it altered neuronal oscillations in the mPFC in the opposite fashion by suppressing the δ rhythm and enhancing the θ and β rhythms compared to sham-iTBS, suggesting that acute iTBS induces hyperactivity in the mPFC. With this iTBS paradigm, we also observed decreased parvalbumin expression in the mPFC, reflecting reduced cortical inhibition. Finally, correlation analyses showed strong correlation between immobility time and θ power after 1 block-iTBS. These findings suggest that the application of acute iTBS in parkinsonian rats produces antidepressant-like effects, which may be associated with elevated 5-HT levels and normalized neuronal oscillations in the mPFC.

Electrophysiological Alterations in the Progression of Parkinson's Disease and the Therapeutic Effect of Tetrabenazine on Rats With Levodopa-Induced Dyskinesia.

Dopamine replacement therapy is the backbone of Parkinson's disease (PD) treatment. However, long-term levodopa (L-DOPA) administration can lead to the severely disabling motor complication L-DOPA-induced dyskinesia (LID), for which standard, effective therapy is currently lacking. This study was conducted to characterize the distinct neural electrophysiological patterns involved in the progression of PD and to examine the efficacy of tetrabenazine, a vesicular monoamine transporter-2 inhibitor, in alleviating dyskinesia and its underlying electrophysiological mechanism. Electrophysiological analysis was performed to obtain power spectrum density and functional connectivity information from local field potential (LFP) data recorded from the primary motor cortex (M1) and dorsolateral striatum (DLS) during different pathological states in PD model rats. Behavioral tests and abnormal involuntary movements (AIMs) scoring were conducted to confirm PD model establishment and assess LID severity. Increased beta oscillations and abnormally strengthened beta causality in the M1 → DLS direction and exaggerated beta-band M1-DLS functional connectivity were observed in the PD state. L-DOPA administration suppressed beta activity and augmented gamma power in the M1 and DLS, with increased gamma causality in the M1 → DLS direction and beta causality in the DLS → M1 direction, as well as elevated gamma-band M1-DLS functional connectivity. Tetrabenazine strongly ameliorated dyskinetic manifestations. It suppressed gamma power in the M1 and DLS, reduced gamma causality and increased beta causality in the M1 → DLS direction, reduced beta causality in the DLS → M1 direction, and reduced gamma-band M1-DLS functional connectivity. Tetrabenazine abrogated aberrant gamma activity to improve LID symptoms, which provides compelling evidence for its future clinical application in LID therapy.

Pramipexole decreases allodynia and hyperalgesia via NF-κB in astrocytes in rats with Parkinson's disease.

Pain is one of the principal non-motor symptoms of Parkinson's disease (PD), negatively impacting the patient's quality of life. This study aimed to demonstrate whether an effective dose of pramipexole (PPX) can modulate the NF-κB/p-p65 activation in glial cells (astrocytes and microglia) and diminish the hypersensitivity (allodynia and hyperalgesia) in male Wistar rats with PD. For this, 2μl of 6-hydroxydopamine (6-OHDA, 8μg/μL/0.2μl/min) was administered unilaterally in the Substantia Nigra of the Pars Compacta (SNpc) to establish a PD model rat. Motor behavioral tests were used to validate the PD model, and von Frey filaments were used to evaluate allodynia and hyperalgesia. Immunohistochemical and immunofluorescence were used to analyze the level of tyrosine hydroxylase in SNpc and striatum as well as the expression of GFAP, Iba-1, NF-κB/p-65 in the L4-L6 spinal cord dorsal horn. Unilateral 6-OHDA-lesion reduces motor capacity and produces long-term allodynia and hyperalgesia in both hind paws. L4-L6 spinal cord dorsal horn astrocytes and microglia were active in these 6-OHDA-lesioned rats. Moreover, PPX (1 and 3mg/Kg, i.p./10days, n=10 per group) inhibited the bilateral mechanical hypersensitivity, and PPX (3mg/Kg/i.p./10days) reduced 6-OHDA-induced astrocyte and microglia activation, as well as reduced NF-κB/p-p65 expression only in astrocytes of dorsal horn spinal cord in the L5-L6. These findings suggest that PPX could alleviate pain by decreasing the activation of microglia and astrocytes through the NF-κB/p-p65 pathway in the dorsal horn spinal cord. Therefore, PPX could be considered an optional tool for improving pain hypersensitivity in PD patients.

Challenges and Opportunities in Exploring Non-Motor Symptoms in 6-Hydroxydopamine Models of Parkinson's Disease: A Systematic Review.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic neurons, leading to motor symptoms such as tremors, rigidity, and bradykinesia. Non-motor symptoms, including depression, hyposmia, and sleep disturbances, often emerge in the early stages of PD, but their mechanisms remain poorly understood. The 6-hydroxydopamine (6-OHDA) rodent model is a well-established tool for preclinical research, replicating key motor and non-motor symptoms of PD. In this review, we systematically analyzed 135 studies that used 6-OHDA rodent models of PD to investigate non-motor symptoms. The review process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our analysis highlights the growing use of 6-OHDA PD models for experimental research of non-motor symptoms. It also reveals significant variability in methodologies, including choices of brain target, toxin dosage, lesion verification strategies, and behavioral assessment reporting. Factors that hinder reproducibility and comparability of findings across studies. We highlight the need for standardization in 6-OHDA-based models with particular emphasis on consistent evaluation of lesion extent and reporting of the co-occurrence of non-motor symptoms. By fostering methodological coherence, this framework aims to enhance the reproducibility, reliability, and translational value of 6-OHDA models in PD non-motor symptom research.

Modeling of Parkinson's Disease in Different Models.

Parkinson's Disease (PD) is a progressive disorder worldwide and its etiology remains unidentified. Over the last few decades, animal models of PD have been extensively utilized to explore the development and mechanisms of this neurodegenerative condition. Toxic and transgenic animal models for PD possess unique characteristics and constraints, necessitating careful consideration when selecting the appropriate model for research purposes. Animal models have played a significant role in uncovering the causes and development of PD, including its cellular and molecular processes. These models suggest that the disorder arises from intricate interplays between genetic predispositions and environmental influences. Every model possesses its unique set of strengths and weaknesses. This review provides a critical examination of animal models for PD and compares them with the features observed in the human manifestation of the disease.

Arsenic-induced mice model of Parkinson's disease: Revealing the neurotoxicity of arsenic through mitochondrial complexes inhibition and dopaminergic neurodegeneration in the substantia nigra region of brain.

The role of environmental contaminants in causing Parkinson's disease (PD) is well known, with rotenone and paraquat being the notable neurotoxins. Traces of the metalloid arsenic are frequently found in drinking water which is considered a threat to the brain's health. Pre-clinical and epidemiological studies have associated arsenic with PD whereby behavioral and neurochemical alterations were observed. However, the impact of arsenic toxicity on the dopaminergic neurons of substantia nigra (SN), the hallmark region which degenerates in PD, has not been shown yet. In the present study, administration of 20 mg/kg b.w., arsenic for 28 days caused significant loss of dopaminergic neurons and their terminals respectively in the SN and striatum regions of mice brain. Moreover, the arsenic-fed rodents exhibited depleted striatal dopamine, prolonged latency to move and correct posture, and reduced exploratory behavior and neurological severity. Further, mitochondrial complexes II and IV were found to be inhibited in the SN, cortex, striatum, and hippocampus of arsenic-fed mice. Additionally, inflammatory marker glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expressed in glial cells and neurons respectively were enhanced in the nigrostriatal pathway of arsenic-fed animals. The present study for the first time reports that arsenic causes Parkinsonism by degenerating nigrostriatal dopaminergic neurons through mitochondrial complex inhibition and inflammatory stress. The study further puts forward validatory evidence for the potential of arsenic in causing PD and the reliability of the arsenic-induced PD model for exploring the disease pathogenesis and treatment.

Ginkgolide B alleviates Parkinson's disease in rats by resisting oxidative stress and inflammatory response and activating PI3K/Akt signaling pathway

This study explored the alleviative effect of ginkgolide B on Parkinson's disease (PD) in rats. PD model was established in 20 rats, which were then randomly divided into model and treatment group, 10 rats in each group. Other 10 rats were selected as control group. The treatment group was treated with ginkgolide B for four weeks. After treatment, compared with model group, in treatment group the behavior test and learning and memory test indexes were improved, the substantia nigra superoxide dismutase and glutathione peroxidase levels were increased, the substantia nigra malondialdehyde and inflammatory factor levels were decreased, and the substantia nigra phosphorylated phosphatidylinositol-3 kinase (p-PI3K)/phosphatidylinositol-3 kinase (PI3K) and phosphorylated serine-threonine protein kinase (p-Akt)/serine-threonine protein kinase (Akt) ratios were increased (all p<0.05). Ginkgolide B can alleviate PD in rats. The action mechanisms may be related to its resisting oxidative stress and inflammatory response and activating PI3K/Akt signaling pathway.

α-Phellandrene: A Promising Natural Remedy for Rotenone-Induced Parkinson's Disease.

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by the pro-gressive loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunction and non-motor symptoms. Current treatments primarily offer symptomatic relief without halt-ing disease progression. This has driven the exploration of natural compounds with neuropro-tective properties. In previous studies, α-phellandrene, a monoterpene present in essential oils of various aromatic plants, has shown promise in mitigating neurodegenerative processes. This study focuses on alpha-phellandrene's therapeutic potential in a rotenone-induced Parkinson's Disease model. Rotenone, a mitochondrial complex I inhibitor, is commonly used to induce PD-like symptoms in experimental models due to its ability to mimic the neurodegenerative processes observed in human PD. Our review explores the neuroprotective effects of alpha-phellandrene, focusing on its antioxidant, anti-inflammatory, and anti-apoptotic properties. Experimental groups of rodents received rotenone to induce PD-like symptoms, followed by alpha-phellandrene treatment. Biochemical analyses were performed to measure oxidative stress markers, inflammatory cytokines, and apoptotic signals in brain tissues. Results indi-cated that alpha-phellandrene administration significantly improved motor function and re-duced rotenone-induced oxidative stress, inflammation, and apoptosis in dopaminergic neu-rons. Histopathological examinations revealed a notable preservation of neuronal integrity in alpha-phellandrene-treated groups compared to controls. In conclusion, alpha-phellandrene demonstrates considerable neuroprotective effects in a rotenone-induced Parkinson's dmodel. These findings suggest that alpha-phellandrene could be a promising natural therapeutic agent for PD, warranting further investigation into its mechanisms of action and potential clinical applications. Specifically, our review indicates that alpha-phellandrene may exert neuropro-tective effects by various mechanisms, such as reducing oxidative stress, modulating neuro-transmitter levels, or inhibiting neuroinflammation. These mechanisms highlight its potential to alleviate PD symptoms and slow disease progression, underscoring the need for in-depth studies to validate these therapeutic effects in clinical settings.

Ginkgolide B regulates apoptosis, oxidative stress, and mitochondrial dysfunction in MPP+-induced SK-N-SH cells by targeting HDAC4/JNK pathway.

Ginkgolide B (GB) is a bioactive constituent found in Ginkgo biloba leaves that has been long recognized as a protective agent against many neurological disorders. Our study aimed to examine the effect of GB in an in vitro Parkinson's disease (PD) model and to investigate its neuroprotective mechanism as a primary objective. SK-N-SH cells were challenged with 1-methyl-4-phenylpyridinium (MPP+) to act as a PD-like model of neuronal damage. CCK-8 method, flow cytometry assay, and fluorescent probe JC-1 respectively measured cell viability, apoptosis, and mitochondrial membrane potential (MMP). Oxidative stress parameters were examined with assay kits. Nicotinamide adenine dinucleotide phosphate level and adenosine triphosphate (ATP) synthesis were also appraised. RT-qPCR examined mitochondrial DNA (mtDNA) release. Western blotting analyzed the proteins implicated in apoptosis and the histone deacetylase 4 (HDAC4)/Jun N-terminal kinase (JNK) pathway. GB concentration-dependently alleviated MPP+-stimulated viability loss, apoptosis, oxidative stress, and mitochondrial dysfunction in SK-N-SH cells. GB docked with HDAC4 and downregulated the HDAC4/JNK pathway. HDAC4 overexpression further reduced the viability and aggravated apoptosis, oxidative stress, and mitochondrial dysfunction in GB-treated SK-N-SH cells challenged with MPP+. Altogether, GB might inactivate the HDAC4/JNK pathway to protect against MPP+-triggered neuronal damage in PD.

Adeno-associated viral vectors for modeling Parkinson's disease in non-human primates.

The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor, but extremely challenging. Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials. While these failures have many possible explanations, it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate. In other words, the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials. However, this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes. Although still facing several limitations, these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy, delineating a more optimistic scenario for the near future.

The 6-OHDA Parkinson's Disease Mouse Model Shows Deficits in Sensory Behavior.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta, leading to dopamine depletion in the striatum and the hallmark motor symptoms of the disease. However, non-motor deficits, particularly sensory symptoms, often precede motor manifestations, offering a potential early diagnostic window. The impact of non-motor deficits on sensation behavior and the underlying mechanisms remain poorly understood. In this study, we examined changes in tactile sensation within a parkinsonian state by employing a mouse model of PD induced by 6-hydroxydopamine (6-OHDA) to deplete striatal DA. Leveraging the conserved mouse whisker system as a model for tactile-sensory stimulation, we conducted psychophysical experiments to assess sensory-driven behavioral performance during a tactile detection task in both the healthy and PD-like state. Our findings reveal a range of deficits across subjects following 6-OHDA lesion, including DA loss, motor asymmetry, weight loss, and varying levels of altered tactile sensation behavior. Behavioral changes ranged from no impairments in minor cases to isolated sensory-behavioral deficits in moderate cases and severe motor dysfunction in advanced stages. These results underscore the complex relationship between DA imbalance and sensory-motor processing, emphasizing the need for precise and multifaceted behavioral measurements to accurately capture the diverse manifestations of PD.

2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione protects against MPP+-induced neurotoxicity by ameliorating oxidative stress, apoptosis and autophagy in SH-SY5Y cells.

2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) is a cyclohexanedione compound extracted from the roots of Averrhoa carambola L. Several studies have documented its beneficial effects on diabetes, Alzheimer's disease, and cancer. However, its potential neuroprotective effects on Parkinson's disease (PD) have not yet been explored. The present study aimed to investigate the protective effects and underlying mechanisms of DMDD in a cellular model of PD. In this study, SH-SY5Y cells were incubated with or without DMDD following intoxication with the parkinsonian neurotoxin 1-methyl-4-phenylpyridine (MPP+). Cell viability and apoptosis were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and Hoechst 33,342 staining, respectively. The mitochondrial membrane potential (Δψm) was assessed through the JC-10 assay. The activities of superoxide dismutase (SOD) and the levels of reactive oxygen species (ROS) were measured using WST-8 and DCFH-DA assays. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore significant biological processes and pathways influenced by DMDD. Molecular docking was employed to predict the domains of potential protein targets interacting with DMDD. Western blotting was subsequently conducted to determine the protein expression levels of TH, Nrf2, Bax, Bcl-2, Caspase-3, Beclin-1, PARP, LC3-II, LC3-I, p-PI3K, PI3K, p-mTOR and mTOR. Our study showed that DMDD treatment significantly increased cell viability and reduced apoptosis in MPP+-treated SH-SY5Y cells. In addition, DMDD treatment reversed the loss of TH expression and Δψm in MPP+-exposed SH-SY5Y cells. Moreover, DMDD treatment reduced MPP+-induced ROS production by promoting SOD activity. Additionally, compared with those in the MPP+ group, the protein expression levels of Beclin-1, Caspase-3, and PARP and the LC3II/I ratio were significantly decreased, whereas the protein expression levels of Nrf2 and the Bcl-2/Bax, p-PI3K/PI3K, and p-mTOR/mTOR ratios were significantly increased in the DMDD-treated group. In conclusion, DMDD protects against MPP+-induced cytotoxicity by mitigating oxidative stress, apoptosis, and autophagy. PI3K/mTOR signaling at least partly mediates the cytoprotective effect of DMDD.

Steady Moderate Exercise Confers Resilience Against Neurodegeneration and Neuroinflammation in a Mouse Model of Parkinson’s Disease

Intensive aerobic exercise slows the progression of movement disorders in Parkinson's disease (PD) and is therefore recommended as an important component of treatment for PD patients. Studies in animal models of PD have shown that vigorous exercise has neuroprotective effects, and emerging evidence suggests that it may be a disease-modifying treatment in humans. However, many people with PD may not be able to participate in vigorous exercise because of multiple medical conditions that severely limit their physical activity. In this study, we have shown that chronic MPTP treatment in sedentary mice resulted in loss of dopaminergic neurons in the SNpc, decreased levels of neurotrophins, BDNF and GDNF, and increased levels of inflammatory markers and pro-inflammatory changes in immunocompetent cells. Moderate exercise, initiated both before and after chronic MPTP treatment, significantly attenuated the loss of dopaminergic neurons and increased BDNF and GDNF levels even above those in sedentary control mice. No signs of inflammation were observed in MPTP-treated mice, either when training began before or after MPTP treatment. Training induced beneficial changes in the dopaminergic system, increased levels of neurotrophins and suppression of inflammation were similar for both steady moderate (present data) and intense training (our previously published data). This suggests that there is a kind of saturation when the percentage of rescued dopaminergic neurons reaches the highest possible value, and therefore further increases in exercise intensity do not enhance neuroprotection. In conclusion, our present results compared with the previous data show that increasing exercise intensity beyond the level used in this study does not increase the neuroprotective effect of aerobic training in a mouse model of Parkinson's disease.

Gentiopicroside alleviates neuroinflammation in Parkinson's disease by mediating microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway.

The study aimed to evaluate the therapeutic potential of gentiopicroside (GPS) in Parkinson's disease (PD) through both in vitro and in vivo experiments, focusing on elucidating the underlying mechanisms of its action. To achieve this, a PD model was established in C57BL6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by assessment of behavioral changes, pathological alterations, microglial activation, and neuroinflammation. Simultaneously, a cellular PD model was developed in the BV-2 mouse microglia cell line by exposing them to 1-methyl-4-phenyl-pyridinium (MPP+). The expression of pro-inflammatory molecules was quantified using enzyme-linked immunosorbent assay (ELISA), while pyroptosis was analyzed by flow cytometry with caspase-1/PI double staining. The expression of key factors in the nuclear factor-kappa B (NF-κB)/NOD-like receptor thermal protein domain-associated protein 3 (NLRP3)/gasdermin D (GSDMD) signaling pathway was determined by immunoblotting. The findings revealed that GPS effectively mitigated motor deficits, neurological impairments, microglial activation, and neuroinflammation in the MPTP-induced mouse model of PD. Additionally, GPS protected BV-2 cells from MPP+-induced inflammatory cytokine production and pyroptosis. Mechanistic studies indicated that GPS may exert its neuroprotective effects by inactivating the NF-κB/NLRP3/GSDMD-mediated pyroptotic pathway in both in vivo and in vitro settings. GPS exhibits neuroprotective effects in PD by suppressing microglia-mediated neuroinflammation and pyroptosis, suggesting its potential as a favorable therapeutic agent for PD treatment.

Synaptic phosphoproteome modifications and cortical circuit dysfunction are linked to the early-stage progression of alpha-synuclein aggregation.

Cortical dysfunction is increasingly recognized as a major contributor to the non-motor symptoms associated with Parkinson's disease (PD) and other synucleinopathies. Although functional alterations in cortical circuits have been observed in preclinical PD models, the underlying molecular mechanisms are unclear. To bridge this knowledge gap, we investigated tissue-level changes in the cortices of rats and mice treated with alpha-synuclein (aSyn) seeds using a multi-omics approach. Our study revealed significant phosphoproteomic changes, but not global proteomic or lipid profiling changes, in the rat sensorimotor cortex 3 months after intra-striatal injection with aSyn preformed fibrils (PFFs). Gene ontology analysis of the phosphoproteomic data indicated that PFF administration impacted pathways related to synaptic transmission and cytoskeletal organization. Similar phosphoproteomic perturbations were observed in the sensorimotor cortex of mice injected intrastriatally or intracortically with aSyn PFFs. Functional analyses demonstrated increased neuronal firing rates and enhanced spike-spike coherence in the sensorimotor cortices of PFF-treated mice, indicating seed-dependent cortical circuit dysfunction. Bioinformatic analysis of the altered phosphosites suggested the involvement of several kinases, including casein kinase-2 (CK2), which has been previously implicated in PD pathology. Collectively, these findings highlight the importance of phosphorylation-mediated signaling pathways in the cortical response to aSyn pathology spread in PD and related synucleinopathies, setting the stage for developing new therapeutic strategies.

Estrogen deficiency promotes neurodegeneration in female hemi-parkinsonian mice: The role of regulatory T cells.

Circulating levels of the female hormone estrogen has been associated with the development of Parkinson's disease (PD), although the underlying mechanism remains unclear. Immune homeostasis mediated by peripheral regulatory T cells (Treg) is a crucial factor in PD. The aim of this study was to explore the effects of estrogen deficiency on neuroinflammation and neurodegeneration in a rodent model of PD, with particular reference to Treg. Estrogen deficiency was established in a mouse model by bilateral ovariectomy (OVX). PD was modeled by the injection of LPS into the striatum. Motor performance was assessed in each experimental group. Dopaminergic degeneration was evaluated using tyrosine-hydroxylase (Th) immunohistochemical staining of the substantia nigra (SN) and striatum. Dopamine and dopamine metabolite levels in the striatum were also evaluated, together with the infiltration of CD4 T cells into the SN. Neuroinflammation was assessed by evaluating the mRNA level of microglial and M1/M2 phenotype markers, as well as the abundance of pro-inflammatory cytokines in the midbrain. The frequency of peripheral Treg cells was evaluated using flow cytometry. OVX prior to LPS injection markedly aggravated neurodegeneration, neuroinflammation, motor performance, and CD4 T cell infiltration compared to the LPS-only group. Estradiol treatment or activation of the G protein-coupled estrogen receptor (GPER) in OVX mice prior to LPS injection induced functional improvement and reduced the levels of neurodegeneration, neuroinflammation, and CD4 T cell infiltration. OVX prior to LPS injection also led to a decreased frequency of Treg compared to the LPS-only group. Moreover, estradiol treatment or GPER activation of OVX mice prior to LPS injection significantly increased the Treg frequency. Antibody-mediated depletion of Treg after GPER activation counteracted the ability of GPER to alleviate neurodegeneration, CD4 T cell infiltration, the release of pro-inflammatory cytokines, and motor performance in the PD model. Estrogen deficiency can disrupt Treg-mediated immune homeostasis and thus further aggravate microglial inflammation and dopaminergic degeneration in PD model. The effects of estrogen on Treg may be partially mediated by GPER signaling, and thus GPER is a promising target for PD, especially in estrogen-deficient women.