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• Uninduced and neuronally-induced DPSCs demonstrate potential for Parkinson's disease therapy. • Uninduced and neuronally-induced DPSCs promote significant recovery in dopaminergic neurons and locomotion. • Neuronally-induced DPSCs prevent GFAP elevation and alter DARPP-32 phosphorylation states. • Uninduced DPSCs reduce JUN levels and mitigate glycosylated DAT elevation. In recent years, dental pulp stromal cells (DPSCs) have emerged as a promising therapeutic approach for Parkinson's disease (PD), owing to their inherent neurogenic potential and the lack of neuroprotective treatments for this condition. However, uncertainties persist regarding the efficacy of these cells in an undifferentiated state versus a neuronally-induced state. This study aims to delineate the distinct therapeutic potential of uninduced and neuronally-induced DPSCs in a rodent model of PD induced by 6-Hydroxydopamine (6-OHDA). DPSCs were isolated from human teeth, characterized as mesenchymal stromal cells, and induced to neuronal differentiation. Neuronal markers were assessed before and after induction. DPSCs were transplanted into the substantia nigra pars compacta (SNpc) of rats 7 days following the 6-OHDA lesion. In vivo tracking of the cells, evaluation of locomotor behavior, dopaminergic neuron survival, and the expression of essential proteins within the dopaminergic system were conducted 7 days postgrafting. Isolated DPSCs exhibited typical characteristics of mesenchymal stromal cells and maintained a normal karyotype. DPSCs consistently expressed neuronal markers, exhibiting elevated expression of βIII-tubulin following neuronal induction. Results from the animal model showed that both DPSC types promoted substantial recovery in dopaminergic neurons, correlating with enhanced locomotion. Additionally, neuronally-induced DPSCs prevented GFAP elevation, while altering DARPP-32 phosphorylation states. Conversely, uninduced DPSCs reduced JUN levels. Both DPSC types mitigated the elevation of glycosylated DAT. Our results suggested that uninduced DPSCs and neuronally-induced DPSCs exhibit potential in reducing dopaminergic neuron loss and improving locomotor behavior, but their underlying mechanisms differ. [ABSTRACT FROM AUTHOR]

In patients with Parkinson's disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients. [ABSTRACT FROM AUTHOR]

There is some evidence that the serotonin receptor subtype 7 (5-HT7) could be new therapeutic target for neuroprotection. The aim of this study was to compare the neuroprotective and neurite outgrowth potential of new 5-HT7 receptor agonists (AH-494, AGH-238, AGH-194) with 5-CT (5-carboxyamidotryptamine) in human neuroblastoma SH-SY5Y cells. The results revealed that 5-HT7 mRNA expression was significantly higher in retinoic acid (RA)-differentiated cells when compared to undifferentiated ones and it was higher in cell cultured in neuroblastoma experimental medium (DMEM) compared to those placed in neuronal (NB) medium. Furthermore, the safety profile of compounds was favorable for all tested compounds at concentration used for neuroprotection evaluation (up to 1 μM), whereas at higher concentrations (above 10 μM) the one of the tested compounds, AGH-194 appeared to be cytotoxic. While we observed relatively modest protective effects of 5-CT and AH-494 in UN-SH-SY5Y cells cultured in DMEM, in UN-SH-SY5Y cells cultured in NB medium we found a significant reduction of H2O2-evoked cell damage by all tested 5-HT7 agonists. However, 5-HT7-mediated neuroprotection was not associated with inhibition of caspase-3 activity and was not observed in RA-SH-SY5Y cells exposed to H2O2. Furthermore, none of the tested 5-HT7 agonists altered the damage induced by 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenylpyridinium ion (MPP +) and doxorubicin (Dox) in UN- and RA-SH-SY5Y cells cultured in NB. Finally we showed a stimulating effect of AH-494 and AGH-194 on neurite outgrowth. The obtained results provide insight into neuroprotective and neurite outgrowth potential of new 5-HT7 agonists. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, which promotes a sustained inflammatory environment in the central nervous system. Regulatory T cells (Tregs) play an important role in the control of inflammation and might play a neuroprotective role. Indeed, a decrease in Treg number and function has been reported in PD. In this context, pramipexole, a dopaminergic receptor agonist used to treat PD symptoms, has been shown to increase peripheral levels of Treg cells and improve their suppressive function. The aim of this work was to determine the effect of pramipexole on immunoregulatory Treg cells and its possible neuroprotective effect on human dopaminergic neurons differentiated from human embryonic stem cells. Methods: Treg cells were sorted from white blood cells of healthy human donors. Assays were performed with CD3/CD28‐activated and non‐activated Treg cells treated with pramipexole at concentrations of 2 or 200 ng/mL. These regulatory cells were co‐cultured with in vitro‐differentiated human dopaminergic neurons in a cytotoxicity assay with 6‐hydroxydopamine (6‐OHDA). The role of interleukin‐10 (IL‐10) was investigated by co‐culturing activated IL‐10‐producing Treg cells with neurons. To further investigate the effect of treatment on Tregs, gene expression in pramipexole‐treated, CD3/CD28‐activated Treg cells was determined by Fluidigm analysis. Results: Pramipexole‐treated CD3/CD28‐activated Treg cells showed significant protective effects on dopaminergic neurons when challenged with 6‐OHDA. Pramipexole‐treated activated Treg cells showed neuroprotective capacity through mechanisms involving IL‐10 release and the activation of genes associated with regulation and neuroprotection. Conclusion: Anti‐CD3/CD28‐activated Treg cells protect dopaminergic neurons against 6‐OHDA‐induced damage. In addition, activated, IL‐10‐producing, pramipexole‐treated Tregs also induced a neuroprotective effect, and the supernatants of these co‐cultures promoted axonal growth. Pramipexole‐treated, activated Tregs altered their gene expression in a concentration‐dependent manner, and enhanced TGFβ‐related dopamine receptor regulation and immune‐related pathways. These findings open new perspectives for the development of immunomodulatory therapies for the treatment of PD. [ABSTRACT FROM AUTHOR]

Studies have shown that dexmedetomidine (DEX, an a2-adrenoceptors agonist) provides a neuroprotective effect and influences blood glucose levels. Here, we evaluated the effect of prolonged treatment with low doses of DEX on the survival rate of dopaminergic (DAergic) neurons in the substantia nigra and also serum glucose levels in 6-hydroxydopamine (6-OHDA) – induced Parkinson's disease (PD) in the rat. The neurotoxin of 6-OHDA was injected into the medial forebrain bundle by stereotaxic surgery. DEX (25 and 50 µg/kg, i.p) and yohimbine, an a2-adrenoceptor antagonist (1 mg/kg, i.p) were administered before the surgery to the 13 weeks afterward. Apomorphine-induced rotational tests and blood sampling were carried out before the surgery and multiple weeks after that. Thirteen weeks after the surgery, the rats' brain was transcardially perfused to assess the survival rate of DAergic neurons using the tyrosine hydroxylase (TH) immunohistochemistry. DEX remarkably attenuated the severity of rotational behavior and reversed the progress of the PD. It also increased the number of TH-labeled neurons by up to 60%. The serum glucose levels in 6-OHDA-received rats did not change in the third and seventh weeks after the surgery but decreased significantly in the thirteenth week. Treatment with DEX prevented this decrement in glucose levels. On the other hand, Treatment with yohimbine did not affect PD symptoms and glucose levels. Our data indicate that DEX through neuroprotective activity attenuates the severity of 6-OHDA-induced PD in rats. DEX might also prevent hypoglycemia during the progress of the PD. [ABSTRACT FROM AUTHOR]

[Display omitted] • Unilateral PD model reveals bilateral gray matter atrophy and PD progression. • Decreased gray matter in cortical areas associated with motor impairment. • Atlas-based volumetric analysis revealed more affected brain regions in PD. • Basal ganglia-thalamocortical circuit alterations reflected in volumetric changes. • Innovative Machine Learning models classify PD without prior disease knowledge. Magnetic resonance imaging (MRI) based brain morphometric changes in unilateral 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD) model can be elucidated using voxel-based morphometry (VBM), study of alterations in gray matter volume and Machine Learning (ML) based analyses. We investigated gray matter atrophy in 6-OHDA induced PD model as compared to sham control using statistical and ML based analysis. VBM and atlas-based volumetric analysis was carried out at regional level. Support vector machine (SVM)-based algorithms wherein features (volume) extracted from (a) each of the 150 brain regions (b) statistically significant features (only) and (c) volumes of each cluster identified after application of VBM (VBM_Vol) were used for training the decision model. The lesion of the 6-OHDA model was validated by estimating the net contralateral rotational behaviour by the injection of apomorphine drug and motor impairment was assessed by rotarod and open field test. In PD, gray matter volume (GMV) atrophy was noted in bilateral cortical and subcortical brain regions, especially in the internal capsule, substantia nigra, midbrain, primary motor cortex and basal ganglia-thalamocortical circuits in comparison with sham control. Behavioural results revealed an impairment in motor performance. SVM analysis showed 100% classification accuracy, sensitivity and specificity at both 3 and 7 weeks using VBM_Vol. Unilateral 6-OHDA induced GMV changes in both hemispheres at 7th week may be associated with progression of the disease in the PD model. SVM based approaches provide an increased classification accuracy to elucidate GMV atrophy. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, and is due to the degeneration of dopaminergic neurons. It is multifactorial, caused by genetic and environmental factors and currently has no definitive cure. We have investigated the protective effects of parthenolide (PTN), a compound with known anti-inflammatory and antioxidant properties, in an in vitro model of PD, that is induced by 6-OHDA, and that causes neurotoxicity in SH-SY5Y human neuroblastoma cells. Methods and results: SH-SY5Y cells were pretreated with PTN to assess its protective effects in 6-OHDA-induced cellular damage. Cell viability was measured using Alamar blue. Apoptosis was evaluated using an Annexin V-FITC/PI kit. Reactive oxygen species (ROS) levels were quantified, and expression levels of apoptotic markers (Bax, Bcl-2, p53) and NF-κB were analyzed via Western blotting and Quantitative real-time- (qRT-) PCR. We found that 6-OHDA reduced cell viability, that was inhibited significantly by pre-treatment with PTN (p < 0.05). Flow cytometry revealed that PTN reduced apoptosis induced by 6-OHDA. PTN also reduced the ROS levels raised by 6-OHDA (p < 0.05). Moreover, PTN decreased the expression of Bax, p53, NF-κB, and p-NF-κB that were increased by treatment with 6-OHDA. Conclusion: These findings indicate the potential beneficial effects of PTN in an in vitro model of PD via mitigating oxidative stress and inflammation, suggested PTN as a promising agent to be used for PD therapy, warranting further investigation in preclinical and clinical studies. [ABSTRACT FROM AUTHOR]

Among the symptoms of Parkinson's disease (PD), apathy comprises a set of behavioral, affective, and cognitive features that can be classified into several subtypes. However, the pathophysiology and brain regions that are involved in these different apathy subtypes are still poorly characterized. We examined which subtype of apathy is elicited in a mouse model of PD with 6-hydroxydopamine (6-OHDA) lesions and the behavioral symptoms that are exhibited. Male C57/BL6J mice were allocated to sham (n = 8) and 6-OHDA (n = 13) groups and locally injected with saline or 4 µg 6-OHDA bilaterally in the dorsal striatum. We then conducted motor performance tests and apathy-related behavioral experiments. We then pathologically evaluated tyrosine hydroxylase (TH) immunostaining. The 6-OHDA group exhibited significant impairments in motor function. In the behavioral tests of apathy, significant differences were observed between the sham and 6-OHDA groups in the hole-board test and novelty-suppressed feeding test. The 6-OHDA group exhibited impairments in inanimate novel object preference, whereas social preference was maintained in the three-chamber test. The number of TH+ pixels in the caudate putamen and substantia nigra compacta was significantly reduced in the 6-OHDA group. The present mouse model of PD predominantly showed dorsal striatum dopaminergic neuronal loss and a decrease in novelty seeking as a symptom that is related to the cognitive apathy component. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson's disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients' quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety. Methods: This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation. Results: No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze. Conclusions: These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD. [ABSTRACT FROM AUTHOR]

In this study, we collected seven prevalent Taiwanese Desmodium plants, including three species with synonymous characteristics, in order to assess their antioxidant phytoconstituents and radical scavenging capacities. Additionally, we compared their inhibitory activities on monoamine oxidase (MAO) and 6-hydroxydopamine (6-OHDA) auto-oxidation. Subsequently, we evaluated the neuroprotective potential of D. pulchellum on 6-OHDA-induced nerve damage in SH-SY5Y cells and delved into the underlying neuroprotective mechanisms. Among the seven Desmodium species, D. pulchellum exhibited the most robust ABTS radical scavenging capacity and relative reducing power; correspondingly, it had the highest total phenolic and phenylpropanoid contents. Meanwhile, D. motorium showcased the best hydrogen peroxide scavenging capacity and, notably, D. sequax demonstrated remarkable prowess in DPPH radical and superoxide scavenging capacity, along with selective inhibitory activity against MAO-B. Of the aforementioned species, D. pulchellum emerged as the frontrunner in inhibiting 6-OHDA auto-oxidation and conferring neuroprotection against 6-OHDA-induced neuronal damage in the SH-SY5Y cells. Furthermore, D. pulchellum effectively mitigated the increase in intracellular ROS and MDA levels through restoring the activities of the intracellular antioxidant defense system. Therefore, we suggest that D. pulchellum possesses neuroprotective effects against 6-OHDA-induced neurotoxicity due to the radical scavenging capacity of its antioxidant phytoconstituents and its ability to restore intracellular antioxidant activities. [ABSTRACT FROM AUTHOR]

Epidemiological studies report an elevated risk of Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors. With an objective to characterize clinically translatable doses of DPP-4 inhibitors (gliptins) in a well-characterized PD rodent model, sitagliptin, PF-00734,200 or vehicle were orally administered to rats initiated either 7-days before or 7-days after unilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) lesioning. Measures of dopaminergic cell viability, dopamine content, neuroinflammation and neurogenesis were evaluated thereafter in ipsi- and contralateral brain. Plasma and brain incretin and DPP-4 activity levels were quantified. Furthermore, brain incretin receptor levels were age-dependently evaluated in rodents, in 6-OHDA challenged animals and human subjects with/without PD. Cellular studies evaluated neurotrophic/neuroprotective actions of combined incretin administration. Pre-treatment with oral sitagliptin or PF-00734,200 reduced methamphetamine (meth)-induced rotation post-lesioning and dopaminergic degeneration in lesioned substantia nigra pars compacta (SNc) and striatum. Direct intracerebroventricular gliptin administration lacked neuroprotective actions, indicating that systemic incretin-mediated mechanisms underpin gliptin-induced favorable brain effects. Post-treatment with a threefold higher oral gliptin dose, likewise, mitigated meth-induced rotation, dopaminergic neurodegeneration and neuroinflammation, and augmented neurogenesis. These gliptin-induced actions associated with 70–80% plasma and 20–30% brain DPP-4 inhibition, and elevated plasma and brain incretin levels. Brain incretin receptor protein levels were age-dependently maintained in rodents, preserved in rats challenged with 6-OHDA, and in humans with PD. Combined GLP-1 and GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone. In conclusion, these studies support further evaluation of the repurposing of clinically approved gliptins as a treatment strategy for PD. [ABSTRACT FROM AUTHOR]

Aerobic exercise has been shown to have established benefits on motor function in Parkinson's disease (PD). However, the impact of exercise on depressive symptoms in PD remains unclear. This study aimed to investigate the effects of regular exercise, specifically using a forced running wheel, on both motor performance and the prevalence of depression in a unilateral 6-OHDA-lesioned rat model of PD. The behavioral outcomes of exercise were assessed through the rotarod test (RT), forelimb adjusting step test (FAST), sucrose consumption test (SCT), and novelty sucrose splash test (NSST). Our data revealed evident depressive symptoms in the PD animals, characterized by reduced sucrose consumption in the SCT and diminished exploratory activity in the NSST compared to the naïve control group. Specifically, after 11 weeks of exercise, the PD exercise group demonstrated the most significant improvements in sucrose consumption in the SCT. Additionally, this group exhibited reduced immobility and increased exploratory behavior compared to the PD control group in the NSST. Furthermore, the PD exercise group displayed the greatest improvement in correcting forelimb stepping bias. Our results suggested that a regimen of running wheel exercise enhances motor abilities and mitigates the occurrence of depressive behaviors caused by 6-OHDA dopamine depletion in the PD rat model.

Parkinson's disease resultant in the degeneration of Dopaminergic neurons and accumulation of α-synuclein in the substantia nigra pars compacta. The synthetic therapeutics for Parkinson's disease have moderate symptomatic benefits but cannot prevent or delay disease progression. In this study, nicotine was employed by using transgenic Caenorhabditis elegans Parkinson's disease models to minimize the Parkinson's disease symptoms. The results showed that the nicotine at 100, 150, and 200 µM doses reduced degeneration of Dopaminergic neurons caused by 6-hydroxydopamine (14, 33, and 40%), lowered the aggregative toxicity of α-synuclein by 53, 56, and 78%, respectively. The reduction in food-sensing behavioral disabilities of BZ555 was observed to be 18, 49, and 86%, respectively, with nicotine concentrations of 100 µM, 150 µM, and 200 µM. Additionally, nicotine was found to enhance Daf-16 nuclear translocation by 14, 31, and 49%, and dose-dependently increased SOD-3 expression by 10, 19, and 23%. In summary, the nicotine might a promising therapy option for Parkinson's disease. [ABSTRACT FROM AUTHOR]

Introduction: Deep brain stimulation (DBS) is a highly effective treatment option in Parkinson's disease. However, the underlying mechanisms of action, particularly effects on neuronal plasticity, remain enigmatic. Adult neurogenesis in the subventricular zone-olfactory bulb (SVZ-OB) axis and in the dentate gyrus (DG) has been linked to various non-motor symptoms in PD, e.g., memory deficits and olfactory dysfunction. Since DBS affects several of these non-motor symptoms, we analyzed the effects of DBS in the subthalamic nucleus (STN) and the entopeduncular nucleus (EPN) on neurogenesis in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. Methods: In our study, we applied five weeks of continuous bilateral STN-DBS or EPN-DBS in 6-OHDA-lesioned rats with stable dopaminergic deficits compared to 6-OHDA-lesioned rats with corresponding sham stimulation. We injected two thymidine analogs to quantify newborn neurons early after DBS onset and three weeks later. Immunohistochemistry identified newborn cells co-labeled with NeuN, TH and GABA within the OB and DG. As a putative mechanism, we simulated the electric field distribution depending on the stimulation site to analyze direct electric effects on neural stem cell proliferation. Results: STN-DBS persistently increased the number of newborn dopaminergic and GABAergic neurons in the OB but not in the DG, while EPN-DBS does not impact neurogenesis. These effects do not seem to be mediated via direct electric stimulation of neural stem/progenitor cells within the neurogenic niches. Discussion: Our data support target-specific effects of STN-DBS on adult neurogenesis, a putative modulator of non-motor symptoms in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD) appears to possess some neuroprotective properties, but experimental data are still inconsistent. Therefore, this in vitro study aimed to compare the effects of CBD in a wide range of concentrations on oxidative stress and excitotoxic-related cell damage. Results showed that low concentrations of CBD ameliorated the H2O2-evoked cell damage of primary cortical neuronal cell culture. However, higher concentrations of CBD alone (5–25 μM) decreased the viability of cortical neurons in a concentration-dependent manner and aggravated the toxic effects of hydrogen peroxide (H2O2). Neuroprotection mediated by CBD in primary neurons against H2O2 was not associated with a direct influence on ROS production nor inhibition of caspase-3, but we found protective effects of CBD at the level of mitochondrial membrane potential and DNA fragmentation. However, CBD had no protective effect on the glutamate-induced cell damage of cortical neurons, and in higher concentrations, it enhanced the toxic effects of this cell-damaging factor. Likewise, CBD, depending on its concentration, at least did not affect or even enhance cortical cellular damage exposed to oxygen–glucose deprivation (OGD). Finally, we showed that CBD in submicromolar or low micromolar concentrations significantly protected human neuronal-like SH-SY5Y cells against H2O2- and 6-hydroxydopamine (6-OHDA)-induced cell damage. Our data indicate that CBD has a dual effect on oxidative stress-induced neuronal death-in low concentrations, it is neuroprotective, but in higher ones, it may display neurotoxic activity. On the other hand, in excitotoxic-related models, CBD was ineffective or enhanced cell damage. Our data support the notion that the neuroprotective effects of CBD strongly depend on its concentration and experimental model of neuronal death. [ABSTRACT FROM AUTHOR]

Naturally occurring peptides, such as rubiscolins derived from spinach leaves, have been shown to possess some interesting activities. They exerted central effects, such as antinociception, memory consolidation and anxiolytic-like activity. The fact that rubiscolins are potent even when given orally makes them very promising drug candidates. The present work tested whether rubiscolin-6 (R-6, Tyr-Pro-Leu-Asp-Leu-Phe) analogs have neuroprotective and anti-inflammatory effects. These hypotheses were tested in the 6-hydroxydopamine (6-OHDA) injury model of human neuroblastoma SH-SY5Y and lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The determination of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), Caspase-3 activity, lipid peroxidation and nitric oxide (NO) production allowed us to determine the effects of peptides on hallmarks related to Parkinson's Disease (PD) and inflammation. Additionally, we investigated the impact of R-6 analogs on serine-threonine kinase (also known as protein kinase B, AKT) and mammalian target of rapamycin (mTOR) activation. The treatment with analogs 3 (Tyr-Inp-Leu-Asp-Leu-Phe-OH), 5 (Dmt-Inp-Leu-Asp-Leu-Phe-OH) and 7 (Tyr-Inp-Leu-Asp-Leu-Phe-NH2) most effectively prevented neuronal death via attenuation of ROS, mitochondrial dysfunction and Caspase-3 activity. Peptides 5 and 7 significantly increased the protein expression of the phosphorylated-AKT (p-AKT) and phosphorylated-mTOR (p-mTOR). Additionally, selected analogs could also ameliorate LPS-mediated inflammation in macrophages via inhibition of intracellular generation of ROS and NO production. Our findings suggest that R-6 analogs exert protective effects, possibly related to an anti-oxidation mechanism in in vitro model of PD. The data shows that the most potent peptides can inhibit 6-OHDA injury by activating the PI3-K/AKT/mTOR pathway, thus playing a neuroprotective role and may provide a rational and robust approach in the design of new therapeutics or even functional foods. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic brain damage (HIBD) can have long-term implications on patients' physical and mental health, yet the available treatment options are limited. Recent research has shown that low-intensity pulsed ultrasound (LIPUS) holds promise for treating neurodegenerative diseases and traumatic brain injuries. Our objective was to explore the therapeutic potential of LIPUS for HIBD. Due to the lack of a suitable animal model for neonatal HIBD, we will initially simulate the therapeutic effects of LIPUS on neuronal cells under oxidative stress and neuroinflammation using cell experiments. Previous studies have investigated the biologic responses following intracranial injection of 6-hydroxydopamine (6-OHDA). In this experiment, we will focus on the biologic effects produced by LIPUS treatment on neuronal cells (specifically, SH-SY5Y cells) without the presence of other neuroglial cell assistance after stimulation with 6-OHDA. We found that (i) pulsed ultrasound exposure, specifically three-intermittent sonication at intensities ranging from 0.1 to 0.5 W/cm², did not lead to a significant decrease in viability among SH-SY5Y cells; (ii) LIPUS treatment exhibited a positive effect on cell viability, accompanied by an increase in glial cell-derived neurotrophic factor (GDNF) levels and a decrease in caspase three levels; (iii) the administration of 6-OHDA had a significant impact on cell viability, resulting in a decrease in both brain cell-derived neurotrophic factor (BDNF) and GDNF levels, while concurrently elevating caspase three and matrix metalloproteinase-9 (MMP-9) levels; and (iv) LIPUS treatment demonstrated its potential to alleviate the changes induced by 6-OHDA, particularly in the levels of BDNF, GDNF, and tyrosine hydroxylase (TH). LIPUS treatment may possess partial therapeutic capabilities for SH-SY5Y cells damaged by 6-OHDA neurotoxicity. Our findings enhance our understanding of the effects of LIPUS treatment on cell viability and its modulation of key factors involved in the pathophysiology of HIBD and show the promising potential of LIPUS as an alternative therapeutic approach for neonates with HIBD. [ABSTRACT FROM AUTHOR]

Abstract Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease, with a progressive loss of dopaminergic cells and fibers. The purpose of this study was to use different doses of 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB) of mice to mimic the different stages of the disease and to characterize in detail their motor and non-motor behavior, as well as neuropathological features in the nigrostriatal pathway. MFB were injected with 0.5 μg, 1 μg, 2 μg of 6-OHDA using a brain stereotaxic technique. 6-OHDA induced mitochondrial damage dose-dependently, as well as substantia nigra pars compacta (SNpc) tyrosine hydroxylase-positive (TH+) cell loss and striatal TH fiber loss. Activation of astrocytes and microglia in the SNpc and striatum were consistently observed at 7 weeks, suggesting a long-term glial response in the nigrostriatal system. Even with a partial or complete denervation of the nigrostriatal pathway, 6-OHDA did not cause anxiety, although depression-like behavior appeared. Certain gait disturbances were observed in 0.5 μg 6-OHDA lesioned mice, and more extensive in 1 μg group. Despite the loss of more neurons from 2 μg 6-OHDA, there was no further impairment in behaviors compared to 1 μg 6-OHDA. Our data have implications that 1 μg 6-OHDA was necessary and sufficient to induce motor and non-motor symptoms in mice, thus a valuable mouse tool to explore disease progression and new treatment in PD.

The positive effect of levodopa in the treatment of Parkinson’s disease, although it is limited in time and has severe side effects, has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons. Successful preclinical studies with coenzyme Q10, mitoquinone, isradipine, nilotinib, TCH346, neurturin, zonisamide, deferiprone, prasinezumab, and cinpanemab prompted clinical trials. However, these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease, despite its severe side effects after 4–6 years of chronic treatment. The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big problem. In our opinion, the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine, that induce a very fast, massive and expansive neurodegenerative process, which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons. The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to (i) a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron, (ii) a neurotoxic event that is not expansive and (iii) the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons. The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome, since it (i) is generated within neuromelanin-containing dopaminergic neurons, (ii) does not cause an expansive neurotoxic effect and (iii) triggers all the mechanisms involved in the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s disease. In conclusion, based on the hypothesis that the neurodegenerative process of idiopathic Parkinson’s disease corresponds to a single-neuron neurodegeneration model, we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2. It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease, with a progressive loss of dopaminergic cells and fibers. The purpose of this study was to use different doses of 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB) of mice to mimic the different stages of the disease and to characterize in detail their motor and non-motor behavior, as well as neuropathological features in the nigrostriatal pathway. MFB were injected with 0.5 μg, 1 μg, 2 μg of 6-OHDA using a brain stereotaxic technique. 6-OHDA induced mitochondrial damage dose-dependently, as well as substantia nigra pars compacta (SNpc) tyrosine hydroxylase-positive (TH+) cell loss and striatal TH fiber loss. Activation of astrocytes and microglia in the SNpc and striatum were consistently observed at 7 weeks, suggesting a long-term glial response in the nigrostriatal system. Even with a partial or complete denervation of the nigrostriatal pathway, 6-OHDA did not cause anxiety, although depression-like behavior appeared. Certain gait disturbances were observed in 0.5 μg 6-OHDA lesioned mice, and more extensive in 1 μg group. Despite the loss of more neurons from 2 μg 6-OHDA, there was no further impairment in behaviors compared to 1 μg 6-OHDA. Our data have implications that 1 μg 6-OHDA was necessary and sufficient to induce motor and non-motor symptoms in mice, thus a valuable mouse tool to explore disease progression and new treatment in PD. [ABSTRACT FROM AUTHOR]

The existent pre‐clinical models of Parkinson's disease do not simultaneously recapitulate severe degeneration of dopamine neurons and the occurrence of alpha‐synuclein (aSyn) aggregation in one study system. In this study, we injected aSyn pre‐formed fibrils (PFF) and 6‐hydroxydopamine (6‐OHDA) unilaterally into the striatum of C57BL/6 wild‐type male mice at an interval of 2 weeks to induce aggregation of aSyn protein and trigger the loss of dopamine neurons simultaneously in one model and studied the behavioural effects of the combination in these mice. 6‐OHDA was tested at three different doses, and 2 μg of 6‐OHDA combined with PFF‐induced aSyn aggregation was found to produce the most optimal disease phenotype. At 14 weeks timepoint, mice injected with a combination of PFF and 6‐OHDA sustained significant damage to the nigrostriatal pathway and exhibited aSyn‐positive aggregation. Our data suggest that the neurons that formed large aSyn aggregates were particularly vulnerable to 6‐OHDA‐induced degeneration. We also demonstrate the manifestation of a relatively aggressive pathology in 2‐ to 4‐month‐old mice, as compared to younger 7‐ to 9‐week‐old ones. Furthermore, cerebral dopamine neurotrophic factor (CDNF) administered intrastriatally rescued dopamine neurons and motor behaviour of the animals to some extent from 6‐OHDA toxicity. However, no such effect could be seen in the novel 6‐OHDA + PFFs combination model. For the first time, we demonstrate the combined effect of PFF and 6‐OHDA simultaneously in one model. We further discuss the scope for further optimizing this combination model to develop it as a promising pre‐clinical platform for drug screening and development. [ABSTRACT FROM AUTHOR]

IntroductionDeep brain stimulation (DBS) is a highly effective treatment option in Parkinson’s disease. However, the underlying mechanisms of action, particularly effects on neuronal plasticity, remain enigmatic. Adult neurogenesis in the subventricular zone-olfactory bulb (SVZ-OB) axis and in the dentate gyrus (DG) has been linked to various non-motor symptoms in PD, e.g., memory deficits and olfactory dysfunction. Since DBS affects several of these non-motor symptoms, we analyzed the effects of DBS in the subthalamic nucleus (STN) and the entopeduncular nucleus (EPN) on neurogenesis in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats.MethodsIn our study, we applied five weeks of continuous bilateral STN-DBS or EPN-DBS in 6-OHDA-lesioned rats with stable dopaminergic deficits compared to 6-OHDA-lesioned rats with corresponding sham stimulation. We injected two thymidine analogs to quantify newborn neurons early after DBS onset and three weeks later. Immunohistochemistry identified newborn cells co-labeled with NeuN, TH and GABA within the OB and DG. As a putative mechanism, we simulated the electric field distribution depending on the stimulation site to analyze direct electric effects on neural stem cell proliferation.ResultsSTN-DBS persistently increased the number of newborn dopaminergic and GABAergic neurons in the OB but not in the DG, while EPN-DBS does not impact neurogenesis. These effects do not seem to be mediated via direct electric stimulation of neural stem/progenitor cells within the neurogenic niches.DiscussionOur data support target-specific effects of STN-DBS on adult neurogenesis, a putative modulator of non-motor symptoms in Parkinson’s disease.

ABSTRACTDopamine (DA) plays a significant role in regulating hippocampal function, particularly in modulating synaptic plasticity. Despite this, a comprehensive understanding of the molecular mechanisms involved in neuroplasticity-related signaling influenced by DA remains incomplete. This study aimed to elucidate the changes in the expression of key molecules related to hippocampal neuroplasticity following DA depletion in rats. To induce DA depletion, unilateral striatal infusions of 6-hydroxydopamine (6-OHDA) were administered to adult Sprague-Dawley rats. The subsequent loss of nigrostriatal DAergic signaling in these 6-OHDA-lesioned rats was confirmed using an apomorphine-induced rotation test at 4 weeks post-infusion and by assessing the expression levels of tyrosine hydroxylase (TH) through immunohistochemistry and western blotting at 7 weeks post-infusion. A decrease in DAergic signaling, evidenced by reduced TH-positive immunoreactivity, was also noted in the ipsilateral hippocampus of the lesioned rats. Interestingly, 6-OHDA infusion led to increased phosphorylation of pivotal hippocampal plasticity-related proteins, including extracellular signal-regulated kinase (ERK), protein kinase B (Akt), glycogen synthase kinase 3β (GSK3β), and cAMP response element-binding protein (CREB), in the ipsilateral hippocampus 7 weeks following the infusion. To extend these findings, in vitro experiments were conducted on primary hippocampal neurons exposed to DA and/or the active D1/D2 DA receptor antagonist, flupentixol (Flux). DA inhibited the constitutive phosphorylation of ERK, Akt, GSK3, and CREB, while Flux restored these phosphorylation levels. Taken together, these findings indicate that DA depletion triggers an increase in plasticity-related signaling in the hippocampus, suggesting a possible compensatory mechanism that promotes activity-independent neuroplasticity following DA depletion.

Among the symptoms of Parkinson’s disease (PD), apathy comprises a set of behavioral, affective, and cognitive features that can be classified into several subtypes. However, the pathophysiology and brain regions that are involved in these different apathy subtypes are still poorly characterized. We examined which subtype of apathy is elicited in a mouse model of PD with 6-hydroxydopamine (6-OHDA) lesions and the behavioral symptoms that are exhibited. Male C57/BL6J mice were allocated to sham (n = 8) and 6-OHDA (n = 13) groups and locally injected with saline or 4 µg 6-OHDA bilaterally in the dorsal striatum. We then conducted motor performance tests and apathy-related behavioral experiments. We then pathologically evaluated tyrosine hydroxylase (TH) immunostaining. The 6-OHDA group exhibited significant impairments in motor function. In the behavioral tests of apathy, significant differences were observed between the sham and 6-OHDA groups in the hole-board test and novelty-suppressed feeding test. The 6-OHDA group exhibited impairments in inanimate novel object preference, whereas social preference was maintained in the three-chamber test. The number of TH+ pixels in the caudate putamen and substantia nigra compacta was significantly reduced in the 6-OHDA group. The present mouse model of PD predominantly showed dorsal striatum dopaminergic neuronal loss and a decrease in novelty seeking as a symptom that is related to the cognitive apathy component.

Parkinson's disease (PD) is the second most common neurodegenerative illness worldwide. It is an age-related sickness. An illness treatment plan is urgently required. Such secondary metabolites from plants may undoubtedly be the source of the medications with less adverse effects. 6-Hydroxydopamine (6-OHDA) is used experimentally to mimic Parkinson's disease in adult zebrafish. In the realm of medicine, there are no ideal cures for ailments. For the past few decades, a number of plant secondary chemicals have been tested in preclinical settings to cure this illness. Many references have been made to cyclotide's neuroprotective, anti-inflammatory, and antioxidant properties. Furthermore, it has recently been demonstrated that amantadine (AMA), an aminoadamantane well-known for its mild antiparkinsonian action, counteracts central nervous system dysfunction. Apart from oxidative stress and mitochondrial damage, 6-OHDA may also cause decreased cytosolic levels of Tyrosine Hydroxylase (TH). Since this is primarily thought to be in charge of dopamine production in the central nervous system, an antagonist of TH may be the best medication option when treating Parkinson's disease. Since Amantadine (AMA) is the conventional medication, the current study compares the potential of Cyclotide as Tyrosine Hydroxylase Inhibitors to examine the molecular anti-TH interactions in 6-OHDA-induced adult zebrafishes. [ABSTRACT FROM AUTHOR]

Deep-brain subthalamic nucleus stimulation (DBS-STN) has become a well-established therapeutic option for advanced Parkinson's disease (PD). While the motor benefits of DBS-STN are widely acknowledged, the neuropsychiatric effects are still being investigated. Beyond its immediate effects on neuronal circuits, emerging research suggests that DBS-STN might also modulate the peripheral inflammation and neuroinflammation. In this work, we assessed the effects of DBS-STN on food-related motivation, food intake pattern, and the level of anxiety and compared them with markers of cellular and immune activation in nigrostriatal and mesolimbic areas in rats with the 6-OHDA model of early PD. To evaluate the potential mechanism of observed effects, we also measured corticosterone concentration in plasma and leukocyte distribution in peripheral blood. We found that DBS-STN applied during neurodegeneration has beneficial effects on food intake pattern and motivation and reduces anxiety. These behavioral effects occur with reduced percentages of IL-6-labeled cells in the ventral tegmental area and substantia nigra pars compacta in the stimulated brain hemisphere. At the same brain structures, the cFos cell activations were confirmed. Simultaneously, the corticosterone plasma concentration was elevated, and the peripheral blood lymphocytes were reduced after DBS-STN. We believe that comprehending the relationship between the effects of DBS-STN on inflammation and its therapeutic results is essential for optimizing DBS therapy in PD. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurodevelopmental illness that often emerges in early childhood. The incidence of ASD has shown a notable rise in recent years. ASD is defined by deficits in social communication, and presence of rigid and repetitive behaviors and interests. The underlying mechanisms of ASD remain elusive. Multiple studies have documented the presence of neuroinflammation and increased levels of inflammatory cytokines, specifically, IL-6, TNF, and NF-κB, in various brain regions, including the prefrontal cortex (PFC) and hippocampus in individuals with ASD. Noradrenergic neurons play a crucial role in brain development and the regulation of motor, behavioral, and memory functions. This study sought to examine the impact of intracerebroventricular (icv.) injection of the neurotoxin, 6-hydroxydopamine (6-OHDA), in the caudal dorsal vagal complex A2 neurons on various neuroinflammatory pathways at the hippocampus and PFC in valproic acid (VPA) autistic animal model. This was done in conjunction with an intraperitoneal (i.p.) injection of Lipopolysaccharides (LPS) in animal models with VPA-induced autism. We specifically examined the impact of the caudal fourth ventricle 6-OHDA icv. injection and LPS (i.p.) injection on self-grooming behavior. We measured the mRNA expression of IL-6, TNF-a, and NF-κB using qRT-PCR, and the protein expression of COX-2, GPX-1, p-AMPK, and AMPK using western blot analysis. The self-grooming activity was considerably higher in the combined treatment group (6-OHDA icv. + LPS i.p.) compared to the control group. A substantial increase observed in the expression of IL-6, TNF-α, and NF-κB genes in the PFC of the treatment group that received icv. Administration of 6-OHDA, compared to the control group. The VPA-autism rats that received the combo treatment exhibited a slight increase in the expression level of NF-κB gene in the hippocampus, compared to the control group. At the PFC, we noticed a substantial drop in the expression of the antioxidant protein GPX-1 in the group that received the combo treatment compared to the control group. Our data investigates a novel aspect that the 6-OHDA-induced inhibition of hindbrain A2 neurons could be influencing the neuroinflammatory pathways in the PFC and hippocampus of autistic animal models.

Full treatment of the second most common neurodegenerative disorder, Parkinson’s disease (PD), is still considered an unmet need. As the psychostimulants, amphetamine (AMPH) and methylphenidate (MPH), were shown to be neuroprotective against stroke and other neuronal injury diseases, this study aimed to evaluate their neuroprotective potential against two dopaminergic neurotoxicants, 6-hydroxydopamine (6-OHDA) and paraquat (PQ), in differentiated human dopaminergic SH-SY5Y cells.Neither cytotoxicity nor mitochondrial membrane potential changes were seen following a 24-hour exposure to either therapeutic concentration of AMPH or MPH (0.001–10 μM). On the other hand, a 24-hour exposure to 6-OHDA (31.25–500 μM) or PQ (100–5000 μM) induced concentration-dependent mitochondrial dysfunction, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and lysosomal damage, evaluated by the neutral red uptake assay. The lethal concentrations 25 and 50 retrieved from the concentration-toxicity curves in the MTT assay were 99.9 µM and 133.6 µM for 6-OHDA, or 422 µM and 585.8 µM for PQ. Both toxicants caused mitochondrial membrane potential depolarization, but only 6-OHDA increased reactive oxygen species (ROS). Most importantly, PQ-induced toxicity was partially prevented by 1 μM of AMPH or MPH. Nonetheless, neither AMPH nor MPH could prevent 6-OHDA toxicity in this experimental model.According to these findings, AMPH and MPH may provide some neuroprotection against PQ-induced neurotoxicity, but further investigation is required to determine the exact mechanism underlying this protection.

There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis. Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids, such as docosahexaenoic acid, and exercise in Parkinson’s disease, we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway. First, mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation. Four weeks after lesion, animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks. During this period, the animals had access to a running wheel, which they could use or not. Docosahexaenoic acid treatment, voluntary exercise, or the combination of both had no effect on (i) distance traveled in the open field test, (ii) the percentage of contraversive rotations in the apomorphine-induction test or (iii) the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta. However, the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum. Compared to docosahexaenoic acid treatment or exercise alone, the combination of docosahexaenoic acid and exercise (i) improved forelimb balance in the stepping test, (ii) decreased the striatal DOPAC/dopamine ratio and (iii) led to increased dopamine transporter levels in the lesioned striatum. The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.

In this study, we collected seven prevalent Taiwanese Desmodium plants, including three species with synonymous characteristics, in order to assess their antioxidant phytoconstituents and radical scavenging capacities. Additionally, we compared their inhibitory activities on monoamine oxidase (MAO) and 6-hydroxydopamine (6-OHDA) auto-oxidation. Subsequently, we evaluated the neuroprotective potential of D. pulchellum on 6-OHDA-induced nerve damage in SH-SY5Y cells and delved into the underlying neuroprotective mechanisms. Among the seven Desmodium species, D. pulchellum exhibited the most robust ABTS radical scavenging capacity and relative reducing power; correspondingly, it had the highest total phenolic and phenylpropanoid contents. Meanwhile, D. motorium showcased the best hydrogen peroxide scavenging capacity and, notably, D. sequax demonstrated remarkable prowess in DPPH radical and superoxide scavenging capacity, along with selective inhibitory activity against MAO-B. Of the aforementioned species, D. pulchellum emerged as the frontrunner in inhibiting 6-OHDA auto-oxidation and conferring neuroprotection against 6-OHDA-induced neuronal damage in the SH-SY5Y cells. Furthermore, D. pulchellum effectively mitigated the increase in intracellular ROS and MDA levels through restoring the activities of the intracellular antioxidant defense system. Therefore, we suggest that D. pulchellum possesses neuroprotective effects against 6-OHDA-induced neurotoxicity due to the radical scavenging capacity of its antioxidant phytoconstituents and its ability to restore intracellular antioxidant activities.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson’s disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients’ quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety. Methods: This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation. Results: No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze. Conclusions: These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD.

Objective: Parkinson’s disease (PD) is a neurodegenerative disorder described by the dynamic decline of dopaminergicneurons in the substantia nigra pars compacta (SNpc). Stem cell transplantation is a new therapeutic strategy in thetreatment of PD. The objective of the study was to assess the impact of intravenous infusion of adipose-derivedmesenchymal stem cells (AD-MSCs) on memory disorder in Parkinsonian rats.Materials and Methods: In this experimental study, male Wistar rats were randomly divided to four groups containingsham, cell treatment, control, and lesion. The cell treatment group received intravenous injection of AD-MSCs 12 daysafter PD induction by bilateral injection of 6-hydroxydopamine. Four weeks after lesion formation, spatial memorywas examined using the Morris water maze (MWM) assessment. The rats’ brains were removed and assessed bybromodeoxyuridine (BrdU), tyrosine hydroxylase (TH), and glial fibrillary acidic protein (Gfap) immunostaining.Results: Statistical analyses revealed a significant addition and reduction in time spent and escape latency in the targetquadrant, respectively, in the cell group as compared to the lesion group. Also, BrdU-labeled cells were present in thesubstantia nigra (SN). The density of TH-positive cells was significantly increased in the AD-MSCs transplantation groupas compared to the lesion group, and the density of astrocytes significantly diminished in the AD-MSCs transplantationgroup as compared to the lesion group.Conclusion: It appears that AD-MSCs treatment for Parkinson’s could decrease the density of astrocytes and promotethe density of TH-positive neurons. It appears that AD-MSCs could improve spatial memory impairment in PD.

Objective: Hesperetin (Hst) has shown several pharmacological effects. The efficacy of Hst is highly restricted in vivo due mainly to poor bioavailability. This investigation was intended to compare the influence of Hst and nano-Hst treatment on 6-hydroxydopamine (6-OHDA)-induced behavioral deficits and oxidative stress in rats.Materials and Methods: Forty-two Wistar male rats were equally assigned to 6 groups: control, 6-OHDA, Hst5, Hst10, nano-Hst5, and nano-Hst10. Treatment with Hst and nano-Hst was initiated 1 day after the intrastriatal injection of 6-OHDA and continued for 28 days. Behavioral deficits were evaluated using apomorphine-induced rotation test (AIRT), narrow beam test (NBT) and novel object recognition test (NORT), and the hippocampus and striatum were used to evaluate oxidative stress-related parameters.Results: The rats injected only with 6-OHDA showed learning and memory deficits but Hst and nano-Hst treatments improved it (p

Background: 6-Hydroxydopamine (6-OHDA) is widely used to induce neurotoxicity and investigate the mechanisms of Parkinson disease. 6-OHDA causes cell injury through various mechanisms including oxidative stress, inflammation and apoptosis. The selective Rho-kinase inhibitor, fasudil displays neuroprotective effects in several neurodegenerative disorders. The aim of this study was to assess the protective effect of fasudil in PC12 cytotoxicity induced by 6-OHDA. Methods: PC12 cells were exposed to 5, 10, 25, and 50 µM of fasudil concentrations. After 24 h, the IC50 value of 6-OHDA (150 µM) was added. Twenty-four hours later, the viability of cells was evaluated via MTT assay and the formation of reactive oxygen species (ROS) was measured by the fluorimetric method. At the 50 µM concentration of fasudil, with or without 6-OHDA, the changes of protein levels including STAT3, P-STAT3, JAK2, P-JAK2, and caspase-3 were determined via western blotting. Results: Our results showed that 6-OHDA increased the intracellular level of ROS, reduced cell viability, upregulated p-STAT3/STAT3 and p-JAK2/JAK2 ratios and significantly raised cleaved caspase-3 in comparison to control group. Furthermore, pretreatment of cells with fasudil (50 µM) for 24 h could reverse all changes induced by 6-OHDA. Conclusion: 6-OHDA caused cytotoxicity in PC12 cells through inducing oxidative stress and activating JAK/STAT and apoptosis pathways, while pretreatment with fasudil exhibited protective effect on 6-OHDA-induced neurotoxicity via the inhibition of oxidative stress and prevention of these pathways.

Despite its established neuroprotective effect on dopaminergic neurons and encouraging phase I results, intraputaminal GDNF administration failed to demonstrate significant clinical benefits in Parkinson’s disease patients. Different human GDNF doses were delivered in the striatum of rats with a progressive 6-hydroxydopamine lesion using a sensitive doxycycline-regulated AAV vector. GDNF treatment was applied either continuously or intermittently (2 weeks on/2 weeks off) during 17 weeks. Stable reduction of motor impairments as well as increased number of dopaminergic neurons and striatal innervation were obtained with a GDNF dose equivalent to 3- and 10-fold the rat endogenous level. In contrast, a 20-fold increased GDNF level only temporarily provided motor benefits and neurons were not spared. Strikingly, oxidized DNA in the substantia nigra increased by 50% with 20-fold, but not 3-fold GDNF treatment. In addition, only low-dose GDNF allowed to preserve dopaminergic neuron cell size. Finally, aberrant dopaminergic fiber sprouting was observed with 20-fold GDNF but not at lower doses. Intermittent 20-fold GDNF treatment allowed to avoid toxicity and spare dopaminergic neurons but did not restore their cell size. Our data suggest that maintaining GDNF concentration under a threshold generating oxidative stress is a pre-requisite to obtain significant symptomatic relief and neuroprotection.

Using a model of Parkinson's disease (PD) induced by the bilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA) into rat brain substantia nigra (SN), we showed uridine to exert a protective effect associated with activation of the mitochondrial ATP-dependent potassium (mitoK-ATP) channel. Injection of 4 µg neurotoxin evoked a 70% decrease in the time the experimental animal spent on the rod in the RotaRod test, an increase in the amount of lipid peroxides in blood serum and cerebral-cortex mitochondria and the rate of reactive oxygen species formation, and a decrease in Ca2+ retention in mitochondria. Herewith, lymphocytes featured an increase in the activity of lactate dehydrogenase, a cytosolic enzyme of glycolysis, without changes in succinate-dehydrogenase activity. Structural changes occurring in the SN and striatum manifested themselves in the destruction of mitochondria, degeneration of neurons and synapses, and stratification of myelin sheaths in them. Subcutaneous injections of 30 µg/kg uridine for 22 days restored the neurotoxin-induced changes in these parameters to levels close to the control. 5-Hydroxydecanoate (5 mg/kg), a specific mitoK-ATP channel inhibitor, eliminated the beneficial effect of uridine for almost all characteristics tested, indicating the involvement of the mitoK-ATP channel in the protective effect of uridine. The mechanism of the protective effect of uridine and its therapeutic applications for the prevention and treatment of PD are discussed. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that the gut–brain axis plays a crucial role in Parkinson's disease (PD). The abnormal accumulation of aggregated alpha-synuclein (aSyn) in the brain is a key pathological feature of PD. Intracerebral 6-hydroxydopamine (6-OHDA) is a widely used dopaminergic lesion model of PD. It exerts no aSyn pathology in the brain, but changes in the gut have not been assessed. Here, 6-OHDA was administered unilaterally either to the rat medial forebrain bundle (MFB) or striatum. Increased levels of glial fibrillary acidic protein in the ileum and colon were detected at 5 weeks postlesion. 6-OHDA decreased the Zonula occludens protein 1 barrier integrity score, suggesting increased colonic permeability. The total aSyn and Ser129 phosphorylated aSyn levels were elevated in the colon after the MFB lesion. Both lesions generally increased the total aSyn, pS129 aSyn, and ionized calcium-binding adapter molecule 1 (Iba1) levels in the lesioned striatum. In conclusion, 6-OHDA-induced nigrostriatal dopaminergic damage leads to increased aSyn levels and glial cell activation particularly in the colon, suggesting that the gut–brain axis interactions in PD are bidirectional and the detrimental process may start in the brain. [ABSTRACT FROM AUTHOR]

The degeneration of dopamine (DA) neurons is known to be associated with defects in mitochondrial biogenesis caused by aging, environmental factors, or mutations in genes, leading to Parkinson's disease (PD). As PD has not yet been successfully cured, the strategy of using small molecule drugs to protect and restore mitochondrial biogenesis is a promising direction. This study evaluated the efficacy of synthetic chiisanoside (CSS) identified in the leaves of Acanthopanax sessiliflorus to prevent PD symptoms. The results show that in the 6-hydroxydopamine (6-OHDA) model, CSS pretreatment can effectively alleviate the reactive oxygen species generation and apoptosis of SH-SY5Y cells, thereby lessening the defects in the C. elegans model including DA neuron degeneration, dopamine-mediated food sensitivity behavioral disorders, and shortened lifespan. Mechanistically, we found that CSS could restore the expression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α), a key molecule in mitochondrial biogenesis, and its downstream related genes inhibited by 6-OHDA. We further confirmed that this is due to the enhanced activity of parkin leading to the ubiquitination and degradation of PGC-1α inhibitor protein Zinc finger protein 746 (ZNF746). Parkin siRNA treatment abolished this effect of CSS. Furthermore, we found that CSS inhibited 6-OHDA-induced expression of miR-181a, which targets parkin. The CSS's ability to reverse the 6-OHDA-induced reduction in mitochondrial biogenesis and activation of apoptosis was abolished after the transfection of anti-miR-181a and miR-181a mimics. Therefore, the neuroprotective effect of CSS mainly promotes mitochondrial biogenesis by regulating the miR-181a/Parkin/ZNF746/PGC-1α axis. CSS potentially has the opportunity to be developed into PD prevention agents. [ABSTRACT FROM AUTHOR]

Parkinson's-disease (PD) is an incurable, age-related neurodegenerative disease, and its global prevalence of disability and death has increased exponentially. Although motor symptoms are the characteristic manifestations of PD, the clinical spectrum also contains a wide variety of non-motor symptoms, which are the main cause of disability and determinants of the decrease in a patient's quality of life. Noteworthy in this regard is the stress on the cardiac system that is often observed in the course of PD; however, its effects have not yet been adequately researched. Here, an untargeted metabolomics approach was used to assess changes in cardiac metabolism in the 6-hydroxydopamine model of PD. Beta-sitosterol, campesterol, cholesterol, monoacylglycerol, α-tocopherol, stearic acid, beta-glycerophosphoric acid, o-phosphoethanolamine, myo-inositol-1-phosphate, alanine, valine and allothreonine are the metabolites that significantly discriminate parkinsonian rats from sham counterparts. Upon analysis of the metabolic pathways with the aim of uncovering the main biological pathways involved in concentration patterns of cardiac metabolites, the biosynthesis of both phosphatidylethanolamine and phosphatidylcholine, the glucose-alanine cycle, glutathione metabolism and plasmalogen synthesis most adequately differentiated sham and parkinsonian rats. Our results reveal that both lipid and energy metabolism are particularly involved in changes in cardiac metabolism in PD. These results provide insight into cardiac metabolic signatures in PD and indicate potential targets for further investigation. [ABSTRACT FROM AUTHOR]

Parkinson's disease (P.D.) is the second most progressive neurodegenerative disorder in the elderly. Degeneration of dopaminergic (DA) neurons and α‐synuclein (α‐Syn) accumulated toxicity is the major contributor to this disease. At present, the disease has no effective treatment. Many recent studies focus on identifying novel therapeutics that provide benefits to stop the disease progression in P.D. patients. Screening novel and effective drugs in P.D. animal models is time‐ and cost‐consuming. Rose Essential Oil (REO) extracted from Rosa Rugosa species (R. Setate × R. Rugosa). REO contains Citronellol, Geraniol, and Octadiene that possess anti‐Aβ, anti‐oxidative, and anti‐depression‐like properties, but no reports have defined the REO effect on P.D. yet. The present study examines the REO neuroprotective potential in transgenic Caenorhabditis elegans P.D. models. We observed that REO reduced α‐Syn aggregations and diminished DA neuron degenerations induced by 6‐OHDA, reduced food‐sensing behavioural disabilities, and prolonged the lifespan of the nematode. Moreover, REO augmented the chymotrypsin‐like proteasome and SOD‐3 activities. Further, we observed the anti‐oxidative role of REO by reducing internal cells ROS. Together, these findings supported REO as an anti‐PD drug and may exert its effects by lowering oxidative stress via the anti‐oxidative pathway. [ABSTRACT FROM AUTHOR]

Background: Bladder dysfunction is a common non-motor disorder in Parkinson's disease (PD). This study attempted to determine the bladder dysfunction with disease progression in the PD rat model produced from unilateral/bilateral injections of 6-hydroxydopamine (6-OHDA). Methods: Cystometrographic (CMG) and external urethral sphincter electromyographic (EUS-EMG) measurements were scheduled in a time-course manner to determine the disease timing, onset, and severity. Animals were allotted into normal control, unilateral, bilateral 6-OHDA injected groups and subjected to scheduled CMG, EUS-EMG analyses at weeks 1, 2, and 4. Results: The urodynamic results concluded that voiding efficiency (VE) was reduced in both unilateral and bilateral PD rats at all-time points. VE had decreased from 57 ± 11% to 31 ± 7% in unilateral PD rats and in bilateral PD rats, a decreased VE of 20 ± 6% was observed compared to control and unilateral PD rats. The EMG results in unilateral PD rats indicated declines in bursting period (BP) (3.78–2.94 s), active period (AP) (93.38–88.75 ms), and silent period (SP) (161.62–114.30 ms). A sudden reduction was noticed in BP (3.62–2.82 s), AP (92.21–86.01 ms), and SP (128.61–60.16 ms) of bilateral PD rats than in control and unilateral PD rats. Histological evidence exhibited a progressive dopaminergic neurons (DA) depletion in the substantia nigra (SN) region in 6-OHDA lesioned rats. Conclusion: The experimental outcomes strongly implied that significant variations in bladder function and VE decline were due to the depletion of DA neurons in the SN region of the brain.

Previous studies have found that deficiency in nuclear receptor-related factor 1 (Nurr1), which participates in the development, differentiation, survival, and degeneration of dopaminergic neurons, is associated with Parkinson’s disease, but the mechanism of action is perplexing. Here, we first ascertained the repercussion of knocking down Nurr1 by performing liquid chromatography coupled with tandem mass spectrometry. We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency, 14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis. To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms, we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model. The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes, the preponderance of which encode components of the major histocompatibility II complex. Cd74, H2-Ab1, H2-Aa, H2-Eb1, Lyz2, Mrc1, Slc6a3, Slc47a1, Ms4a4b, and Ptprc2 were the top 10 differentially expressed genes. Immunofluorescence staining showed that, after Nurr1 knockdown, the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased. In addition, Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine. Taken together, our results suggest that Nurr1 deficiency results in an increase in Cd74 expression, thereby leading to the destruction of dopaminergic neurons. These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.

Abstract Parkinson’s disease (PD) is the second-most common neurodegenerative disease worldwide. Several studies have investigated PD for decades; however, the exact mechanism of disease development remains unknown. To study PD, SH-SY5Y cells are often treated with 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP+) to induce PD. To understand the mechanism of PD pathogenesis, we confirmed protein changes between 6-OHDA- and MPP+-treated SH-SY5Y cells via proteomics analysis using liquid chromatography coupled with tandem mass spectrometry. 6-OHDA-treated SH-SY5Y cells showed increased expression of electron transporter-related proteins compared to that in the control group, along with decreased expression in MPP+-treated SH-SY5Y cells. However, both down- and upregulation of electron transporter-related proteins increased mitochondrial dysfunction and apoptosis. These proteins were confirmed via protein–protein interaction network analysis using IPA and STRING to induce mitochondrial dysfunction and apoptosis. Cell-based experiments using flow cytometry verified that apoptosis and mitochondrial membrane potential were increased in both 6-OHDA- and MPP+-treated SH-SY5Y cells. Our results provide new insights into PD pathogenesis, thereby contributing to the understanding of the mechanisms of PD development.

Skin-derived precursor Schwann cells have been reported to play a protective role in the central nervous system. The neuroprotective effects of skin-derived precursor Schwann cells may be attributable to the release of growth factors that nourish host cells. In this study, we first established a cellular model of Parkinson’s disease using 6-hydroxydopamine. When SH-SY5Y cells were pretreated with conditioned medium from skin-derived precursor Schwann cells, their activity was greatly increased. The addition of insulin-like growth factor-2 neutralizing antibody markedly attenuated the neuroprotective effects of skin-derived precursor Schwann cells. We also found that insulin-like growth factor-2 levels in the peripheral blood were greatly increased in patients with Parkinson’s disease and in a mouse model of Parkinson’s disease. Next, we pretreated cell models of Parkinson’s disease with insulin-like growth factor-2 and administered insulin-like growth factor-2 intranasally to a mouse model of Parkinson’s disease induced by 6-hydroxydopamine and found that the level of tyrosine hydroxylase, a marker of dopamine neurons, was markedly restored, α-synuclein aggregation decreased, and insulin-like growth factor-2 receptor down-regulation was alleviated. Finally, in vitro experiments showed that insulin-like growth factor-2 activated the phosphatidylinositol 3 kinase (PI3K)/AKT pathway. These findings suggest that the neuroprotective effects of skin-derived precursor Schwann cells on the central nervous system were achieved through insulin-like growth factor-2, and that insulin-like growth factor-2 may play a neuroprotective role through the insulin-like growth factor-2 receptor/PI3K/AKT pathway. Therefore, insulin-like growth factor-2 may be an useful target for Parkinson’s disease treatment.