Parkinson's Disease Model Research Articles

Expression variation of long noncoding RNAs in dopaminergic cells-derived from stem cells and their MPP+ induced PD models.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons (DA) which can be caused by environmental and genetic factors. lncRNAs have emerged as an important regulatory layer in neurodegenerative disorders, including PD. In this study, we investigated and validated lncRNAs that may serve as diagnostic or therapeutic targets for PD. Key genes associated with midbrain and DA cells were screened by differential gene expression analysis on GSE213100 dataset and candidate lncRNAs were selected for further examination. P19 cells were differentiated into DA cells and received treatment with MPP+ to induce PD-like cytotoxic events, which were confirmed by light microscopy, RT-qPCR, immunofluorescence and flow cytometry. Then, the cells were used to investigate the changes of lncRNAs Malat1, Norad, Snhg1 and Meg3. Here we found that the neuronal phenotype was mainly observed on the 12th day of differentiation and the number of DA markers significantly decreased in PD model cells compared with the control group. Moreover, the expression levels of Meg3, Norad, and Snhg1 were decreased by MPP+ whereas Malat1 level was noticeably higher in MPP+ cells compared to DA cells and the control group. In conclusion, the expression level of lncRNAs was able to show a significant difference between differentiated dopaminergic cells and their Parkinsonian model, thereby improving our understanding of the molecular pathogenesis of PD.

Network-Based Drug Optimization toward the Treatment of Parkinson's Disease: NRF2, MAO-B, Oxidative Stress, and Chronic Neuroinflammation.

Parkinson's disease (PD), the second most common neurodegenerative disorder, affects around 10 million people worldwide. It is a multifactorial disease marked by dopaminergic neuron loss with oxidative stress (OS) and neuroinflammation as key pathological drivers. Current treatments focus on dopamine replacement and are symptomatic, underscoring the urgent need for disease-modifying therapies. Here, we present a novel class of dual MAO-B inhibitors and NRF2 inducers with neuroprotective properties in in vitro PD models. Through an optimization program, we enhanced their MAO-B inhibitory potency, selectivity, and NRF2 induction capacity while achieving favorable pharmacokinetic profiles. Virtual library screening identified two core derivatives, leading to the development of compound 11, which exhibited potent anti-inflammatory and neuroprotective activity in OS-related in vitro models. Compound 11 also demonstrated high liver microsomal stability and favorable pharmacokinetics in mice, making it a promising candidate for further investigation as a potential PD therapy.

Infiltrating peripheral monocyte TREM-1 mediates dopaminergic neuron injury in substantia nigra of Parkinson’s disease model mice

Neuroinflammation is a key factor in the pathogenesis of Parkinson’s disease (PD). Activated microglia in the central nervous system (CNS) and infiltration of peripheral immune cells contribute to dopaminergic neuron loss. However, the role of peripheral immune responses, particularly triggering receptor expressed on myeloid cells-1 (TREM-1), in PD remains unclear. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD mouse model, we examined TREM-1 expression and monocyte infiltration in the substantia nigra pars compacta (SNpc). We found that MPTP increased peripheral monocytes, and deletion of peripheral monocytes protected against MPTP neurotoxicity in the SNpc. TREM-1 inhibition, both genetically and pharmacologically, reduced monocyte infiltration, alleviated neuroinflammation, and preserved dopaminergic neurons, resulting in improved motor function. Furthermore, adoptive transfer of TREM-1-expressing monocytes from PD model mice to naive mice induced neuronal damage and motor deficits. These results underscore the critical role of peripheral monocytes and TREM-1 in PD progression, suggesting that targeting TREM-1 could be a promising therapeutic approach to prevent dopaminergic neurodegeneration and motor dysfunction in PD.Schematic diagram of monocyte TREM-1-mediated dopaminergic neuron damage. The figure illustrates that in experimental MPTP-induced PD model mice, the number of inflammatory monocytes in the peripheral blood increases, after which the monocytes infiltrate the CNS through the Blood-Brain Barrier(BBB). These infiltrating monocytes increase the release of inflammatory cytokines and eventually cause neuronal injury. TREM-1 gene deletion and pharmacological blockade limit inflammatory monocyte recruitment into the SNpc and ameliorate neuroinflammatory events and the loss of dopaminergic neurons.

Targeting the glymphatic system to promote α-synuclein clearance: a novel therapeutic strategy for Parkinson's disease.

The excessive buildup of neurotoxic α-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease, highlighting the urgent need for innovative therapeutic strategies to promote α-synuclein clearance, particularly given the current lack of disease-modifying treatments. The glymphatic system, a recently identified perivascular fluid transport network, is crucial for clearing neurotoxic proteins. This review aims to synthesize current knowledge on the role of the glymphatic system in α-synuclein clearance and its implications for the pathology of Parkinson's disease while emphasizing potential therapeutic strategies and areas for future research. The review begins with an overview of the glymphatic system and details its anatomical structure and physiological functions that facilitate cerebrospinal fluid circulation and waste clearance. It summarizes emerging evidence from neuroimaging and experimental studies that highlight the close correlation between the glymphatic system and clinical symptom severity in patients with Parkinson's disease, as well as the effect of glymphatic dysfunction on α-synuclein accumulation in Parkinson's disease models. Subsequently, the review summarizes the mechanisms of glymphatic system impairment in Parkinson's disease, including sleep disturbances, aquaporin-4 impairment, and mitochondrial dysfunction, all of which diminish glymphatic system efficiency. This creates a vicious cycle that exacerbates α-synuclein accumulation and worsens Parkinson's disease. The therapeutic perspectives section outlines strategies for enhancing glymphatic activity, such as improving sleep quality and pharmacologically targeting aquaporin-4 or its subcellular localization. Promising interventions include deep brain stimulation, melatonin supplementation, γ-aminobutyric acid modulation, and non-invasive methods (such as exercise and bright-light therapy), multisensory γ stimulation, and ultrasound therapy. Moreover, identifying neuroimaging biomarkers to assess glymphatic flow as an indicator of α-synuclein burden could refine Parkinson's disease diagnosis and track disease progression. In conclusion, the review highlights the critical role of the glymphatic system in α-synuclein clearance and its potential as a therapeutic target in Parkinson's disease. It advocates for further research to elucidate the specific mechanisms by which the glymphatic system clears misfolded α-synuclein and the development of imaging biomarkers to monitor glymphatic activity in patients with Parkinson's disease. Findings from this review suggest that enhancing glymphatic clearance is a promising strategy for reducing α-synuclein deposits and mitigating the progression of Parkinson's disease.

HDAC4/5 Inhibitor, LMK-235 Improves Animal Voluntary Movement in MPTP-Induced Parkinson's Disease Model.

Oxidation of dopamine can cause various side effects, which ultimately leads to cell death and contributes to Parkinson's disease (PD). To counteract dopamine oxidation, newly synthesized dopamine is quickly transported into vesicles via vesicular monoamine transporter 2 (VMAT2) for storage. VMAT2 expression is reduced in patients with PD, and studies have shown increased accumulation of dopamine oxidation byproducts and α-synuclein in animals with low VMAT2 expression. Conversely, animals that overexpress VMAT2 show better protection for dopamine neurons. Based on these findings, this study used histone deacetylase inhibitors (HDACi) to increase VMAT2 expression, reduce dopamine-induced oxidative stress, and evaluate the resulting behavioral improvements in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. LMK-235 not only increased VMAT2 expression at various concentrations in the SH-SY5Y cell line differentiated into dopaminergic cells but also demonstrated effective cytoprotective properties in several toxicity assays. It significantly raised VMAT2 expression in both the striatum and the ventral tegmental area of an MPTP-induced PD model, supporting its role in reversing behavioral abnormalities linked to PD. In addition to these results, coadministration of LMK-235 with L-DOPA, a standard therapy for PD, restored typical behavioral patterns, highlighting the potential of HDACi in alleviating PD symptoms. The expression of VMAT2 induced by LMK-235, an inhibitor of Class IIa histone deacetylases primarily found in the nervous system, aids in sequestering dopamine into vesicles, potentially enhancing cell survival by inhibiting dopamine oxidation. Additionally, upregulation of VMAT2 has been shown to offer effective protection against MPTP-induced toxicity and significantly improve behavioral abnormalities associated with PD. Coadministration with L-DOPA produced the most notable improvement in behavioral outcomes. Altogether, these findings suggest that the overexpression of VMAT2 may offer a promising strategy for developing treatments for PD by mitigating dopaminergic neuron death resulting from dopamine oxidation.

Ginkgolide B ameliorates MPTP-induced neuroinflammation and neurodegeneration by improving mitochondrial electron transport chain complex I

Although the pathology and clinical symptoms of Parkinson's disease (PD) are well-defined, the cellular and molecular mechanisms underlying the selective degeneration of dopaminergic neurons remain unclear. Mitochondrial dysfunction and neuroinflammation are increasingly recognized as central contributors to the pathogenesis of PD. The leaf extract of Ginkgolide, Ginkgo biloba, is known for its neuroprotective properties in several neurodegenerative diseases. In the present study, we sought to investigate the neuroprotective mechanism of Ginkgolide B (BN52021), a terpene lactone derived from the leaf of Ginkgo biloba, in an animal model of PD. Adult C57BL/6 mice treated with MPTP (30 mg/ kg b.wt.) exhibited significant motor deficits, ameliorated by cotreatment with BN52021 (20 mg/ Kg b.wt.), as evidenced by improved motor behaviors. MPTP administration resulted in a marked reduction in the mitochondrial complex I activity and antioxidant enzymes, specifically in the substantia nigra, whereas the striatum remained unaffected. Notably, BN52021 cotreatment restored the complex I function and antioxidant enzymes in the substantia nigra, highlighting its region-specific neuroprotective properties. Additionally, MPTP exposure significantly increased myeloperoxidase activity, a marker of oxidative stress and inflammation mitigated by BN52021. Moreover, the inflammatory markers NLRP3, MCP-1, and IL-1β were significantly upregulated following MPTP administration, indicating the activation of the inflammasome pathway. However, coadministration of MPTP with BN52021 effectively suppressed the upregulation of these inflammatory markers, suggesting a strong anti-inflammatory effect. These findings underscore the therapeutic potential of Ginkgolide in PD, primarily through its ability to enhance mitochondrial electron transport complex I activity, restore antioxidant defense, and suppress neuroinflammation.

Peripherally administered TNF inhibitor is not protective against α-synuclein-induced dopaminergic neuronal death in rats.

The underlying cause of neuronal loss in Parkinson's disease (PD) remains unknown, but evidence implicates neuroinflammation in PD pathobiology. The pro-inflammatory cytokine soluble tumor necrosis factor (TNF) seems to play an important role and thus has been proposed as a therapeutic target for modulation of the neuroinflammatory processes in PD. In this regard, dominant-negative TNF (DN-TNF) agents are promising antagonists that selectively inhibit soluble TNF signaling, while preserving the beneficial effects of transmembrane TNF. Previous studies have tested the protective potential of DN-TNF-based therapy in toxin-based PD models. Here we test for the first time the protective potential of a DN-TNF therapeutic against α-synuclein-driven neurodegeneration in the viral vector-based PD female rat model. To do so, we administered the DN-TNF agent XPro1595 subcutaneously for a period of 12 weeks. In contrast to previous studies using different PD models, neuroprotection was not achieved by systemic XPro1595 treatment. α-synuclein-induced loss of nigrostriatal neurons, accumulation of pathological inclusions and microgliosis was detected in both XPro1595- and saline-treated animals. XPro1595 treatment increased the percentage of the hypertrophic/ameboid Iba1+ cells in SN and reduced the striatal MHCII+ expression in the α-synuclein-overexpressing animals. However, the treatment did not prevent the MHCII upregulation seen in the SN of the model, nor the increase of CD68+ phagocytic cells. Therefore, despite an apparently immunomodulatory effect, this did not suffice to protect against viral vector-derived α-synuclein-induced neurotoxicity. Further studies are warranted to better elucidate the therapeutic potential of soluble TNF inhibitors in PD.

High Selectivity Fluorescence and Electrochemical Dual-Mode Detection of Glutathione in the Serum of Parkinson's Disease Model Mice and Humans.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of alpha-synuclein. Glutathione (GSH), a key antioxidant, is significantly depleted in PD patients. This study presents a dual-mode detection strategy for selectively determining GSH using a single probe. A series of "turn-on" electrochemical and fluorescent probes were developed, with resorufin (Re) serving as the reporting unit and featuring specific GSH recognition sites. Among these, the 7-(3,5-dinitrophenoxy)-3H-phenoxazin-3-one (Re-DNP) probe was selected for its high selectivity as both a fluorescent and electrochemical probe. Its response to GSH was superior in comparison to that observed for hydrogen sulfide (H2S) and cysteine (Cys). For electrochemical detection using screen-printed carbon electrode (SPCE)/carbon nanotube (CNT) modified electrodes, the detection limit for GSH was 5 μM, with a linear range of 25-500 μM. In fluorescence detection, the probe produced a 78-fold increase in emission at 630 nm in the presence of GSH, with a strong linear correlation between fluorescence intensity and GSH concentration in the range of 10-700 μM, and a detection limit of 2 μM. When applied to real clinical serum samples, the probe demonstrated significantly lower GSH levels in both PD mice and human patients compared to healthy controls. This dual-mode detection method provides a sensitive and accurate tool for GSH detection, with potential applications in understanding GSH's role in PD and related neurodegenerative diseases.

Loureirin C inhibits ferroptosis and apoptosis in 6-OHDA-induced Parkinson's model.

Parkinson's disease (PD) is a type of chronic neurodegenerative disorder. There is an ongoing need for the development of new medications to address this illness. Loureirin C is known to have a protective impact on neurological disorders. Nonetheless, its specific function in Parkinson's Disease (PD) has yet to be fully understood. In this study, we examined the effects of Loureirin C in a cellular model of PD. The PD cell model was established by treating PC-12 cells with 6-hydroxydopamine (6-OHDA). We revealed that Loureirin C promoted the growth of 6-OHDA-treated PC-12 cells. In addition, Loureirin C suppressed the apoptosis of 6-OHDA-treated PC-12 cells and alleviated ferroptosis. Further, Loureirin C improved mitochondrial membrane potential in 6-OHDA-treated PC-12 cells. Mechanically, Loureirin C mediated Nrf2 pathway. Accordingly, Loureirin C not only inhibits ferroptosis but also apoptosis in the 6-OHDA-induced PD cell model, leading us to consider the potential value of Loureirin C in the treatment of PD.

Novel Nose-to-brain delivery of carbenoxolone via mucoadhesive solid lipid nanoparticles for Parkinson's symptoms management: In vitro and in vivo evaluation in a rotenone-induced rat model.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by motor and non-motor symptoms, with limited effective treatment options. This study proposes a novel approach utilizing intranasal delivery of carbenoxolone (CBX) via chitosan-coated solid lipid nanoparticles (CS-coated SLNs) to manage PD symptoms by enhancing CBX delivery and brain targeting. Formulated CS-coated SLNs exhibited favorable quality attributes including particle size (164 ± 0.12 nm), surface charge (18 ± 0.89 mV), high entrapment efficiency (97.98 ± 0.98 %), and sustained drug release profile. In vivo evaluations in a rotenone-induced rat model of PD involved intranasal administration of CBX suspension and CBX-loaded CS-coated SLN (equivalent to 20 mg/kg/day) over four weeks. The CBX nano-formulation group showed significant improvements in motor function, coordination, and balance, as well as modulation of neurotransmitter levels, with increased dopamine and decreased α-synuclein levels compared to the control group. Moreover, the CBX nano-formulation exhibited superior efficacy in reducing neuroinflammation, oxidative stress, and apoptosis markers. Histological examination revealed restored neuronal architecture, suggesting potential neuroprotective effects. In conclusion, mucoadhesive chitosan-coated SLNs offer a promising nasal delivery system overcoming brain drug delivery obstacles facing CBX therapy in PD, paving the way to the development of novel treatments and improved quality of life for PD patients.

Curcumin prevents neurodegeneration by blocking HDAC6-NLRP3 pathway-dependent neuroinflammation in Parkinson's disease.

Curcumin is a hydrophobic polyphenolic compound with potent anti-inflammatory properties. However, whether it can achieve therapeutic effects by alleviating neuroinflammation in patients with Parkinson's disease (PD) and its potential mechanism are still unknown. This study explored the effects of curcumin on neuroinflammation in dopaminergic neurons and deciphered its direct target in the histone deacetylase 6 (HDAC6)-Nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) pathway, revealing the potential role of curcumin in the treatment of Parkinson's disease. Here, we show that curcumin alleviated the degeneration of neurons in a PD model by mitigating the activation of the NLRP3-mediated inflammatory response both in vivo and in vitro. Furthermore, we discovered that curcumin prevented neuroinflammation by blocking the HDAC6-NLRP3 pathway in a PD model. Moreover, overexpression of HDAC6 could eliminate the effect of curcumin on the neuroinflammatory response mediated by NLRP3. Curcumin and the HDAC6 inhibitor WT161 could alleviate neurodegeneration. In addition, activated HDAC6 directly deacetylated NLRP3 at lysine 84 to maintain its stability, which increased the inflammatory response and promoted neurodegeneration. These findings show that curcumin, a neuroinflammation inhibitor, blocks neurodegeneration via the HDAC6-NLRP3 pathway and represents a potentially practical pharmacological approach for treating neuroinflammation-driven neurodegenerative diseases. For the first time, HDAC6 was shown to directly regulate the acetylation of NLRP3.

Hormonal mechanisms in the paraventricular nuclei associated with hyperalgesia in Parkinson's disease model rats.

Pain is a major non-motor symptom of Parkinson's disease (PD). The relationship between hyperalgesia and neuropeptides originating from paraventricular nucleus (PVN) in 6-hydroxydopamine (6-OHDA) rats has already been investigated for oxytocin (OXT), but not yet for arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH). The present study aimed to investigate the alterations in these neuropeptides following nociceptive stimulation in PD model rats and to examine the mechanisms of hyperalgesia. Dopaminergic nigrostriatal lesions were induced by injecting 6-OHDA into the medial forebrain bundle. Subcutaneous formalin injection into the vibrissa pad was performed in rats as a nociceptive stimulus in the orofacial region. Dopamine depletion's effect on nociception was assessed by counting the p-ERK-immunoreactive (-IR) cells in the trigeminal spinal subnucleus caudalis (Vc). The PD model rats induced by 6-OHDA injection (6-OHDA rats) showed a significantly higher number of p-ERK-IR cells in the Vc than the sham rats, confirming hyperalgesia in 6-OHDA rats. Then, we investigated the immunohistochemical responses to OXT, AVP, and CRH cells in the PVN and examined the changes in blood levels of these neuropeptides. As a result, formalin injection increased neuronal activity and blood levels of OXT and CRH in sham rats, but these were suppressed in the 6-OHDA rats. Contrarily, neuronal activity and blood level of AVP were unaffected by nociceptive stimuli and were significantly lower in 6-OHDA rats than in sham rats. Our findings suggest that OXT and CRH suppression is linked to hyperalgesia in PD, whereas AVP does not directly influence the observed hyperalgesia.

Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's Disease

Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopaminergic neurons and the presence of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-Syn) fibrils. Compelling evidence supports that, in PD brains, synapses are the sites where neurodegeneration initiates several years before the manifestation of motor symptoms. Furthermore, the amount of α-Syn deposited at synaptic terminals is several orders greater than that constituting LB. This hints that pathological synaptic α-Syn aggregates may be the main trigger for the retrograde synapse-to-cell body degeneration pattern characterizing early prodromal phases of PD. Identifying reliable biomarkers of synaptopathy is therefore crucial for early diagnosis. Here, we studied the alterations of key dopaminergic and non-dopaminergic striatal synaptic markers during the initial phases of axonal and cell body degeneration in mice subjected to 3 or 10 administrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine + probenecid (MPTPp), a model for early prodromal PD. We found that MPTPp administration resulted in progressive deposition of α-Syn, advancing from synaptic terminals to axons and dopaminergic neuron cell bodies. This was accompanied by marked co-accumulation of Synapsin III (Syn III), a synaptic protein previously identified as a component of α-Syn fibrils in post-mortem PD brains and as a main stabilizer of α-Syn aggregates, as well as very early and severe reduction of vesicular monoamine transporter 2 (VMAT2), dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunoreactivity in nigrostriatal neurons. Results also showed that striatal α-Syn accumulation and VMAT2 decrease, unlike other markers, did not recover following washout from 10 MPTPp administrations, supporting that these changes were precocious and severe. Finally, we found that early changes in striatal α-Syn, Syn III, VMAT2 and DAT observed following 3 MPTPp administrations, correlated with nigrostriatal neuron loss after 10 MPTPp administrations. These findings indicate that α-Syn/Syn III co-deposition characterizes very early stages of striatal dopaminergic dysfunction in the MPTPp model and highlight that VMAT2 and Syn III could be two reliable molecular imaging biomarkers to predict dopamine neuron denervation and estimate α-Syn-related synaptopathy in prodromal and early symptomatic phases of PD.

G6PD deficiency triggers dopamine loss and the initiation of Parkinson's disease pathogenesis.

Loss of dopaminergic neurons in Parkinson's disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels, resulting in DA oxidation and decreased total DA levels. We find that α-syn anchors the PPP enzyme G6PD to synaptic vesicles via the α-syn C terminus and that this interaction is lost in PD. Furthermore, G6PD clinical mutations are associated with PD diagnosis, and G6PD deletion phenocopies PD pathology. Finally, we show that restoring NADPH or GSH levels through genetic and pharmacological intervention blocks DA oxidation and rescues steady-state DA levels, identifying G6PD as a pharmacological target against PD.

Cytoprotective effect of melatonin against MPP+ toxicity in SH-SY5Y cells: Role sharing of two types of antioxidative activities of melatonin

Melatonin is a neurohormone that is not only a regulator of circadian cycles, but also a potent antioxidant. Parkinson’s disease (PD) is a major neurodegenerative disease that may result from oxidative stress as a part of its pathogenic cascade. Therefore, antioxidants, including melatonin, have attracted attention as potential candidates for neuroprotection against PD-related neurotoxicity. In this study, we report that melatonin has 2 types of antioxidant mechanisms of neuroprotection in an experimental cellular PD model using 1-Methyl-4-phenylpyridinium ion (MPP+) in human neuroblastoma SH-SY5Y cells. The first mechanism is a classical antioxidative mechanism through the direct action of melatonin, which reduces lipid hydroperoxide and 8-OHdG. The second mechanism is an indirect antioxidative effect via the melatonin receptor (Mel-R)/PI3K/Akt/Nrf2 cascade. Melatonin and Mel-R agonist activated PI3K/Akt signaling and Nrf2. Both Mel-R antagonist and the PI3K inhibitor blocked transcription induced by Nrf2 and the cytoprotective effect of melatonin. Interestingly, the antioxidative effect due to the Nrf2-related mechanism contributed mainly to a decrease of protein carbonyl, but not to lipid hydroperoxide and 8-OHdG. Mel-R agonist also showed a similar effect. Our results elucidate the mechanism of melatonin's powerful antioxidative effect and suggest the application of melatonin therapy to PD-related cytotoxicity.

Effects on neuroprotection and α-synuclein expression of a Canna coccinea rhizome extract.

Parkinson's disease (PD) is the second most common neurodegenerative disorder in the elderly, currently with no cure. Its mechanisms are not well understood, however α-synuclein protein aggregation plays a central role in the pathogenesis of PD, leading to neurodegeneration. We demonstrated that in a PD model dietary in Caenorhabditis elegans treatment with an extract from the rhizome of Canna coccinea decreased the accumulation of α-synuclein. The extract showed low toxicity to neuro 2a cells and protected them from oxidative damage with H2O2 as a model for neurodegeneration. We studied the chemical profile of the extract using liquid chromatography couple to Mass Spectrometry. In order to characterize the herbal extract, we quantified rosmarinic acid as a marker compound and measured its antioxidant activity in vitro. Altogether, apart from its potential as a functional food, Canna coccinea may be an interesting source of secondary metabolites in the development of potential novel anti-neurodegenerative drugs.

Luteolin Exhibits Anxiolytic and Antidepressant Potential in Parkinson's Disease Rat: Antioxidant and Anti-Inflammatory Effects.

Parkinson's disease (PD) is accompanied by a complex array of nonmotor and motor manifestations. The exploration of anti-inflammatory and antioxidant active ingredient as potential therapeutic interventions in PD-associated mood alterations has gained significant attention. This study aimed to assess the antidepressant and anxiolytic properties of luteolin (LTN), a potent antioxidant and anti-inflammatory component, using a 6-hydroxydopamine (6-OHDA)-induced animal model of PD. Rats were administered LTN (10, 25, and 50 mg/kg, per oral) and fluoxetine (10 mg/kg/per oral) over a 28-day period. Behavioral tests were employed to estimate the depression- and anxiety-like behaviors. Rats treated with LTN exhibited significant improvement in 6-OHDA-induced mood alterations, as per behavioral tests. Additionally, LTN treatment led to increased hippocampal levels of catalase and superoxide dismutase, and a reduction in malondialdehyde. LTN downregulated the gene expression of nuclear factor kappa B (NF-κB)/nod-like receptor (NLR) pyrin domain-containing 3 (NLRP3) axis components, including NF-κB, NLRP3, ASC, and Caspase1 and reduced the protein level of pro-inflammatory cytokines, including interleukin (IL)-6, interleukin (IL)-1β, and tumor necrosis factor alpha (TNF-α), in addition to augmenting the protein levels of TNF-α, IL-1β, and IL-6. Furthermore, LTN exhibited an upregulatory effect on the anti-inflammatory cytokine IL-10 within the hippocampus of 6-OHDA-induced PD rats. Also, molecular docking showed higher affinity between LTN and NF-κB/NLRP3 axis components. These findings highlight the potential anxiolytic and antidepressant impacts of LTN through its antioxidant and anti-inflammatory mechanisms against 6-OHDA-induced alterations in a rat PD model.

OTUD5 Protects Dopaminergic Neurons by Promoting the Degradation of α-Synuclein in Parkinson's Disease Model.

Defective clearance and accumulation of α-synuclein (α-Syn) is the key pathogenic factor in Parkinson's disease (PD). Recent studies emphasize the importance of E3 ligases in regulating the degradation of α-Syn. However, the molecular mechanisms by which deubiquitinases regulate α-Syn degradation are scarcely studied. In this study, it is found that the protein levels of α-Syn are negatively regulated by ovarian tumor protease deubiquitinase 5 (OTUD5) which protects dopaminergic (DA) neurons in the PD model. Mechanistically, OTUD5 promotes K63-linked polyubiquitination of α-Syn independent of its deubiquitinating enzyme activity and mediates its endolysosomal degradation by recruiting the E3 ligase neural precursor cell expressed developmentally downregulated 4 (NEDD4). Furthermore, OTUD5 conditional knockoutin DA neurons results in more severe α-Syn related pathology and dyskinesia after injection of α-Syn preformed fibrils (PFF). Overall, the data unveil a novel mechanism to regulate the degradation of α-Syn and provide a new therapeutic strategy to alleviate DA neurodegeneration.

Leflunomide exerts neuroprotective effects in an MPTP‑treated mouse model of Parkinsonism.

Neuroinflammation and the immune response are recognized as significant mechanisms contributing to the progression and pathophysiology of Parkinson's disease (PD). Consequently, extensive research is being conducted on drugs targeting inflammation and immune response. Leflunomide, known for its anti‑inflammatory and immunomodulatory properties, is currently used as a disease‑modifying agent for the treatment of rheumatoid arthritis. The objective of this study was to investigate the effect of leflunomide on PD. The PD model was established by administering 18 mg/kg of 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP) intraperitoneally for 5 consecutive days. Leflunomide was administered intraperitoneally at doses of 1, 5, and 10 mg/kg for 14 days. Motor and behavioral deficits were assessed using the rotarod test, locomotor activity assessment, hanging wire test, and pole test. MPTP administration impaired motor function and locomotor activity, and caused muscle weakness and bradykinesia. Leflunomide at a dose of 10 mg/kg mitigated the severity of motor deficits and muscle weakness. Furthermore, leflunomide at a dose of 10 mg/kg suppressed the MPTP‑induced elevation of interleukin‑2, interleukin‑6, and tumor necrosis factor‑alpha levels in the brain tissue. Similarly, leflunomide attenuated the increased expression of nuclear factor kappa B and inducible nitric oxide synthase caused by MPTP treatment. Moreover, leflunomide at a dose of 10 mg/kg preserved neuronal integrity and prevented the loss of tyrosine hydroxylase expression induced by MPTP administration. Based on our findings, leflunomide exhibited a beneficial effect on the MPTP‑induced PD model, potentially through modulation of anti‑inflammatory mechanisms.

In vivo self-assembled siRNAs within small extracellular vesicles attenuate LRRK2-induced neurodegeneration in Parkinson's disease models.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene play an important role in Parkinson's disease (PD) pathogenesis, and downregulation of LRRK2 has become a promising therapy for PD. Here, we developed a synthetic biology strategy for the self-assembly and delivery of small interfering RNAs (siRNAs) of LRRK2 into the substantia nigra via small extracellular vesicles (sEVs) using a genetic circuit (in the form of naked DNA plasmid) to attenuate PD-like phenotypes in mouse model. We generated the genetic circuit encoding both a neuron-targeting rabies virus glycoprotein (RVG) tag and a LRRK2 siRNA under the control of a cytomegalovirus (CMV) promoter, and assessed its therapeutic effects using LRRK2R1441G mouse models of PD. After intravenous injection, the genetic circuit was taken up by the host liver to reprogram liver cells to produce and self-assemble LRRK2 siRNAs into sEVs, and then the sEV-enclosed LRRK2 siRNAs were further transferred by the endogenous circulating system of sEVs and guided by the RVG tag to the substantia nigra. Intravenous injection of this genetic circuit reduced total and phosphorylated LRRK2 levels in the substantia nigra, and attenuated PD-like phenotypes in two mouse models by rescuing LRRK2R1441G-induced dopaminergic neurodegeneration and reducing microgliosis. This study provides an efficient therapeutic strategy to attenuate LRRK2-induced neurodegeneration and neuroinflammation in PD mouse models, and may open a new avenue to safely deliver siRNA into brain after peripheral intravenous injection and facilitate PD treatment.