Search

(1) Backgrond: Considering the positive effects of citicoline (CIT) in the management of some neurodegenerative diseases, the aim of this work was to develop CIT-Loaded Solid Lipid Nanoparticles (CIT-SLNs) for enhancing the therapeutic use of CIT in parkinsonian syndrome; (2) Methods: CIT-SLNs were prepared by the melt homogenization method using the self-emulsifying lipid Gelucire® 50/13 as lipid matrix. Solid-state features on CIT-SLNs were obtained with FT-IR, thermal analysis (DSC) and X-ray powder diffraction (XRPD) studies. (3) Results: CIT-SLNs showed a mean diameter of 201 nm, −2.20 mV as zeta potential and a high percentage of entrapped CIT. DSC and XRPD analyses evidenced a greater amorphous state of CIT in CIT-SLNs. On confocal microscopy, fluorescent SLNs replacing unlabeled CIT-SLNs released the dye selectively in the cytoplasm. Biological evaluation showed that pre-treatment of SH-SY5Y dopaminergic cells with CIT-SLNs (50 µM) before the addition of 40 µM 6-hydroxydopamine (6-OHDA) to mimic Parkinson's disease's degenerative pathways counteracts the cytotoxic effects induced by the neurotoxin, increasing cell viability with the consistent maintenance of both nuclear and cell morphology. In contrast, pre-treatment with CIT 50 and 60 µM or plain SLNs for 2 h followed by 6-OHDA (40 µM) did not significantly influence cell viability. (4) Conclusions: These data suggest an enhanced protection exerted by CIT-SLNs with respect to free CIT and prompt further investigation of possible molecular mechanisms that underlie this difference. [ABSTRACT FROM AUTHOR]

In this study, we developed an evaluation method using image analysis for reaching tasks. Using this method, we studied forearm function during the reaching task in rats that received a unilateral injection of 6-OHDA into the striatum. The success ratio of the reaching task reduced to 40.5% seven days after the injection. In addition, significant changes were observed in the pronation angle of the forearm, posture control, and targeting (i.e., the distance between all fingertips and the center of the target pellet). Thus, unilateral injection of 6-OHDA reduces dopaminergic function in the brain and causes deterioration of forearm function and posture control in the reaching task. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressively neurodegenerative disease following dopamine neuron loss and motor dysfunction. Selective monoamine oxidase B (MAO-B) inhibitors are regarded as the potential candidates for the treatment of PD. 2-Pyrazoline structure, an important pharmacodynamic parent nucleus of MAO inhibitors, was introduced into the lead compound 2,3-dibromo-4,5-dihydroxylbenzophenone (LM48), thirty-two triphenylpyrazoline ketone chlorophenols were therefore synthesized, and their protective activities against 6-hydroxydopamine damaged SH-SY5Y cells were further evaluated. Seven chlorophenols 9d, 11d, 28d, 29d, 30d, 31d, and 32d exhibited the significant protective activity with the EC50 values in the range of 0.3–1.2 μM, superior to LM48 (EC50 > 20 μM) and Rasagiline (EC50 = 1.1 ± 0.6 μM). Moreover, they could obviously reduce ROS level. Their MAO-A and MAO-B inhibitory activities in vitro were further compared. MAO-A inhibitory activity was not found at 50 μM, but sixteen compounds were discovered showing selective MAO-B inhibitory activity. Of which, compound 6d presented the optimal activity (IC50 = 12.2 ± 2.3 μM). Compared with Rasagiline (an irreversible MAO-B inhibitor), the combination of 6d and MAO-B was reversible displaying the higher selectivity and safety. These findings suggest that triphenylpyrazoline ketone chlorophenols could potentially be promising candidates for the treatment of PD. [ABSTRACT FROM AUTHOR]

Coriandrum sativum L. (coriander), which is an annual herb of the Apiaceae family, has been traditionally used as a remedy. Here we tested whether heated extract of coriander leaf protects nigral dopaminergic neurodegeneration after exposure to 6-hydroxydopamine (6-OHDA). After injection of 6-OHDA into the rat substantia nigra pars compacta (SNpc), dopaminergic degeneration, which was determined by tyrosine hydroxylase immunostaining, was rescued by co-injection of CaEDTA, an extracellular Zn2+ chelator, suggesting that extracellular Zn2+ influx is involved in neurodegeneration. Both intracellular Zn2+ dysregulation determined by ZnAF-2 fluorescence and dopaminergic degeneration in the SNpc induced by 6-OHDA were rescued by co-injection of 0.25% coriander extract, which also reduced reactive oxygen species (ROS) production in the SNpc determined by aminophenyl fluorescein fluorescence. The present study suggests that coriander leaf extract protects nigral dopaminergic neurodegeneration induced by intracellular Zn2+ dysregulation. It is likely that the nutraceutical property of coriander leaf extract contributes to the protection via reducing ROS production. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is an irreversible, progressive disorder that profoundly impacts both motor and non-motor functions, thereby significantly diminishing the individual's quality of life. Dihydrosinularin (DHS), a natural bioactive molecule derived from soft corals, exhibits low cytotoxicity and anti-inflammatory properties. However, the therapeutic effects of DHS on neurotoxins and PD are currently unknown., Objective: This study investigated whether DHS could mitigate 6-hydroxydopamine (6- OHDA)-induced neurotoxicity and explored the role of neuroprotective PI3K downstream signaling pathways, including that of AKT, ERK, JNK, BCL2, and NFκB, in DHS- mediated neuroprotection., Method: We treated the human neuroblastoma cell line, SH-SY5Y, with the neurotoxin 6-OHDA to establish a cellular model of PD. Meanwhile, we assessed the anti-apoptotic and neuroprotective properties of DHS through cell viability, apoptosis, and immunostaining assays. Furthermore, we utilized the PI3K inhibitor LY294002 to validate the therapeutic target of DHS., Results: Based on the physicochemical properties of DHS, it can be inferred that it has promising oral bioavailability and permeability across the blood-brain barrier (BBB). It was demonstrated that DHS upregulates phosphorylated AKT and ERK while downregulating phosphorylated JNK. Consequently, this enhances the expression of BCL2, which exerts a protective effect on neuronal cells by inhibiting caspase activity and preventing cell apoptosis. The inhibition of PI3K significantly reduced the relative protective activity of DHS in 6-OHDA-induced neurotoxicity, suggesting that the neuroprotective effects of DHS are mediated through the activation of PI3K signaling., Conclusion: By investigating the mechanisms involved in 6-OHDA-induced neurotoxicity, we provided evidence concerning the therapeutic potential of DHS in neuroprotection. Further research into DHS and its mechanisms of action holds promise for developing novel therapeutic strategies for PD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.

Parkinson’s disease (PD) is a neurodegenerative disorder caused by oxidative stress-dependent loss of dopaminergic neurons in the substantia nigra and elevated microglial inflammatory responses. Recent studies show that cell loss also occurs in the hypothalamus in PD. However, effective treatments for the disorder are lacking. Thioredoxin is the major protein disulfide reductase in vivo. We previously synthesized an albumin–thioredoxin fusion protein (Alb–Trx), which has a longer plasma half-life than thioredoxin, and reported its effectiveness in the treatment of respiratory and renal diseases. Moreover, we reported that the fusion protein inhibits trace metal-dependent cell death in cerebrovascular dementia. Here, we investigated the effectiveness of Alb–Trx against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. Alb–Trx significantly inhibited 6-OHDA-induced neuronal cell death and the integrated stress response. Alb–Trx also markedly inhibited 6-OHDA-induced reactive oxygen species (ROS) production, at a concentration similar to that inhibiting cell death. Exposure to 6-OHDA perturbed the mitogen-activated protein kinase pathway, with increased phosphorylated Jun N-terminal kinase and decreased phosphorylated extracellular signal-regulated kinase levels. Alb–Trx pretreatment ameliorated these changes. Furthermore, Alb–Trx suppressed 6-OHDA-induced neuroinflammatory responses by inhibiting NF-κB activation. These findings suggest that Alb–Trx reduces neuronal cell death and neuroinflammatory responses by ameliorating ROS-mediated disruptions in intracellular signaling pathways. Thus, Alb–Trx may have potential as a novel therapeutic agent for PD.

Antrodia camphorata (A. camphorata) is an edible fungus containing various bioactive compounds generally used for health benefits. This study aimed to explore the potential neuroprotective activities of solid‐state‐cultured mycelium of A. camphorata (SCMAC) against Parkinson's disease (PD), as well as the underlying mechanism using an in vitro 6‐hydroxydopamine (6‐OHDA)‐induced PC12 cell model. The results showed that SCMAC extracts alleviated cell toxicity induced by 6‐OHDA and the loss of dopaminergic neurons, which was confirmed by the increase of cell viabilities, inhibition of cell apoptosis, the upregulation of tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels and the downregulation of α‐Synuclein level. After purification, 11 compounds were identified by the NMR technique, including a quinone, four phenolic acid derivatives, three ubiquinone derivatives, two alkaloids, and a triterpenoid. The present study suggests that SCMAC could be an attractive candidate for the prevention or treatment of PD. Practical applications: Parkinson's disease seriously affects the lifetime and quality of the elder population for a long history. Long‐term consumption of L‐DOPA will result in side effects, such as developing abnormal involuntary movements called dyskinesia. This study showed that natural SCMAC extracts could be a potential therapeutic agent for the treatment of neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

6-hydroxydopamine (6-OHDA) is used to induce oxidative damage in neuronal cells, which can serve as an experimental model of Parkinson's disease (PD). Jujuboside A and B confer free radical scavenging effects but have never been examined for their neuroprotective effects, especially in PD; therefore, in this study, we aimed to investigate the feasibility of jujubosides as protectors of neurons against 6-OHDA and the underlying mechanisms. 6-OHDA-induced neurotoxicity in the human neuronal cell lines SH-SY5Y and SK-N-SH, was used to evaluate the protective effects of jujubosides. These findings indicated that jujuboside A and B were both capable of rescuing the 6-OHDA-induced loss of cell viability, activation of apoptosis, elevation of reactive oxygen species, and downregulation of the expression levels of superoxide dismutase, catalase, and glutathione peroxidase. In addition, jujuboside A and B can reverse a 6-OHDA-elevated Bax/Bcl-2 ratio, downregulate phosphorylated PI3K and AKT, and activate caspase-3, -7, and -9. These findings showed that jujubosides were capable of protecting both SH-SY5Y and SK-N-SH neuronal cells from 6-OHDA-induced toxicity via the rebalancing of the redox system, together with the resetting of the PI3K/AKT apoptotic signaling cascade. In conclusion, jujuboside may be a potential drug for PD prevention. [ABSTRACT FROM AUTHOR]

Bilateral nucleus tractus solitarii (NTS) lesions, possibly caused by enterovirus 71 infection, cause severe neurogenic hypertension, leading to acute heart failure (HF), pulmonary edema, and death within hours. Alpha-adrenergic blockers attenuate blood pressure and ameliorate HF and pulmonary edema, thereby prolonging survival time. However, the molecular mechanisms of these blockers are not clear. In this study, we investigated these mechanisms in a rat model of 6-hydroxydopamine (6-OHDA)-induced HF. Sprague–Dawley rats were treated with prazosin 10 min after the microinjection of 6-OHDA into the NTS. Immunohistochemistry and dihydroethidium (DHE) staining were used for analysis. In the cardiac tissue of 6-OHDA-induced HF, in situ expression of tumor necrosis factor-alpha (TNF-α), fibroblast growth factor-23 (FGF23), and FGF receptor 1 (FGFR1) increased, but in situ expression of Vitamin D receptor (VDR) decreased. DHE staining revealed several heart cells with high reactive oxygen species production. Prazosin treatment decreased TNF-α, FGF23, and FGFR1 expression in the heart of rats with 6-OHDA-induced HF. It also prevented cardiomyopathy caused by 6-OHDA-induced bilateral NTS lesions by inhibiting the FGF23-FGFR1 pathway and downregulating TNF-α expression. In situ, FGF23, FGFR1, VDR, superoxide, and TNF-α in the heart were found to be involved in acute HF in our rat model of 6-OHDA-induced bilateral NTS lesions. These findings are potentially useful for treating fatal enterovirus 71 infection-induced NTS lesions and HF. [ABSTRACT FROM AUTHOR]

The neurotoxin 6-hydroxydopamine (6-OHDA), following pretreatment with the norepinephrine transport inhibitor desipramine, selectively destroys dopaminergic neurons. When given to rats, neonatal 6-OHDA (n6-OHDA) crosses the blood–brain barrier to destroy 90–99% of dopaminergic nerves in pars compacta substantia nigra (SNpc). The n6-OHDA-lesioned rat is posed as a reasonable animal model for PD: (a) the magnitude of dopaminergic neuronal destruction is expansive, (b) mapping of dopaminergic denervation has been defined, (c) effects on dopamine (DA) receptor alterations have been elucidated (d) as well as changes in receptor sensitivity status, (e) reactive sprouting of serotoninergic innervation (i.e. hyperinnervation) has been mapped, and (f) interplay between serotoninergic and dopaminergic systems is characterized. (g) A broad range of locomotor and stereotyped behaviors has been assessed and (h) large numbers of neurochemical assessments have been attained. (i) n6-OHDA-lesioned rats survive 6-OHDA lesioning and (j) the rat is behaviorally indistinguishable from controls. Dopaminergic destruction in early ontogeny rather in adulthood is a 'treatment liability' of this model, yet other animal models have liability issues of a serious nature—the initial one being use of a neurotoxin to produce the animal model of PD. The n6-OHDA-lesioned rat is proposed as a PD model for its value in associating the SNpc dopaminergic lesion with behavioral outcomes, also for replicability of dopaminergic destruction, and the accompanying neuronal adaptations and interplay between neuronal phenotypes in brain—which provide a means to better define and understand the range of deficits and neuronal adaptations that are likely to occur in human PD. [ABSTRACT FROM AUTHOR]

The aim of the study was to establish an in vitro Parkinson's disease (PD) model and to investigate the cell viability, anti-inflammatory, anti-apoptotic and neuroprotective effects of catechin and EGCG in SK-N-AS and in vitro PD model cells. SK-N-AS human neuroblastoma cells were used. To develop an in vitro PD model, SK-N-AS cells were exposed to 6-hydroxydopamine. Model control was performed after ELISA analysis of dopamine and α-synuclein levels in the culture medium. Catechin and EGCG were administered to SK-N-AS and in vitro PD model cells. Cell viability was measured using MTT assay and trypan blue staining. Anti-inflammatory and anti-apoptotic activities of catechin and EGCG were investigated by indirect immunocytochemistry using anti-TNF-α, anti-IL-1β and anti-caspase-3. After 24 hours of 6-hydroxydopamine administration at 50 μM, higher αlfa-synuclein and lower dopamine levels were found in PD model than SK-N-AS cells. Cell viability was similar between SK-N-AS and in vitro PD model cells. Treatment with both bioactive components increased cell viability of in vitro PD model cells. Caspase-3 immunoreactivity was significantly reduced in SK-N-AS and PD model cells after EGCG administration, while it was decreased only in PD model cells after catechin administration. IL-1β staining intensity weakened after catechin administration in PD model cells, after EGCG administration in SK-N-AS cells. TNF-α staining intensity was similar in both cells. Catechin and EGCG increased cell viability in PD model neuron cells. Both components showed anti-apoptotic and anti-inflammatory effects. Catechin may be more effective in preventing damage to neurons PD. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson’s Disease (PD) associates with changes in sex hormones; however, it remains unknown whether this is either a cause for or a result of the disease. To further evaluate it, we investigated if the development of 6-Hydroxydopamine (6-OHDA)-induced Parkinsonism changes the serum levels of testosterone and prolactin or not. Methods: 6-OHDA was injected into the medial forebrain bundle using stereotaxic surgery. The development of Parkinsonism was evaluated by apomorphine-induced rotational test and the immunofluorescence labeling of Dopaminergic (DA) neurons in substantia nigra. The necessary blood samples were collected before the toxin and in the third and sixth weeks afterward. The hormones levels were determined using Enzyme-Linked Immunosorbent Assay (ELISA) kits. Results: The severity of rotations was different among 6-OHDA-treated rats; accordingly, they were divided into two subgroups of severe and mild parkinsonian rats. The degeneration of DA neurons was observed in both subgroups; however, it was significantly less in the mild group. In the sixth week after the toxin, testosterone level increased but only in the severe subgroup. Prolactin increased in both subgroups in the third week after the toxin but returned to normal in the sixth week. There was no association between the pre-toxin levels of these hormones and the intensity of Parkinsonism. Conclusion: Our findings indicated that the development of 6-OHDA-induced Parkinsonism increases the serum levels of testosterone and prolactin. Increased prolactin occurred earlier and was observed in rats with less DA neuronal loss. Therefore, prolactin levels can predict the death of DA neurons before the clinical signs of PD were revealed.

Introduction. Animal modelling of Parkinsons disease is an essential step in studying disease pathogenesis and searching for effective treatment methods. An accurate assessment of the resulting model is critical. The aim of the study was to identify the correlation between the location of a lesion in the striatal dopaminergic innervation when the neurotoxin 6-hydroxydopamine (6-OHDA) was administered to rodents and the resulting behavior. Materials and methods. The study was carried out on 75 male Wistar rats that received intranigral injection of 3 l of 6-OHDA at a dose of 4 g/l. The animals were examined in the open field test and narrowing beam walking test 33 days after administration, after which some of the animals were decapitated (n = 25) for immunohistochemical analysis. Results. The inactive animal group was statistically significantly different from the active animal group, with more pronounced damage to the dopamine endings in the dorsomedial (p = 0.0235) and ventral (p = 0.091) striatum. In contrast, in the active animals, the lesion was primarily in the dorsolateral striatum. In the inactive animal group, the mean distance travelled in the open field test was significantly shorter (p 0.001), while freezing time (p 0.0168) and the average score on the neuroticism scale (p 0.001) were higher compared to the active animals. Spearman's correlation results showed a significant negative correlation (rS = 0.762; p 0.0001) between tyrosine hydroxylase staining intensity in the dorsolateral striatum and freezing time in the open field test. No correlation was found between freezing time and damage to other striatal areas. Conclusion. Damage to the dorsomedial and dorsolateral striatum causes less severe motor and emotional disturbances than damage to the ventral striatum. The narrowing beam walking test can be used to assess the presence and severity of striatal damage reliably. This evaluation is critical in studies of subsequent treatment efficacy to reduce Parkinsonian syndrome.

We previously demonstrated that JM-20, a molecule with neuroactive functions, protects rats against rotenone and 6-hydroxydopamine (6-OHDA) neurotoxicity. In addition, we demonstrated that JM-20 inhibits the aggregation and cytotoxicity of alpha-synuclein in vitro. In this study, we performed correlation studies between morphological and molecular variables, as well as the motor behavior of parkinsonian rats (6-OHDA and rotenone lesion) treated with JM-20 at different doses (oral with gavage). Our results showed that higher asymmetry evaluated in the cylinder test correlated with greater redox alterations, death of dopaminergic neurons and increased astrogliosis. In the rotenone model, our results showed that a lower number of vertical rearing was correlated with greater redox alterations and increased mitochondrial dysfunction. In both models (6-OHDA and rotenone), parkinsonian animals treated with the highest doses of JM-20 (20 and 40 mg/kg) showed reduced behavioral impairments (lower asymmetry value and higher amount of vertical rearing). Also, a reduced loss of mesencephalic dopaminergic neurons, a smaller number of astrocyte cells in this region, less redox alterations and less mitochondrial dysfunction was observed. In total, our results demonstrate a correlation between behavioral and biochemical variables evaluated in the preclinical models of parkinsonism induced by 6-OHDA and rotenone. [Display omitted] [ABSTRACT FROM AUTHOR]

Carotenoids, fat-soluble pigments found ubiquitously in plants and fruits, have been reported to exert significant neuroprotective effects against free radicals. However, the neuroprotective effects of total mixed carotenes complex (TMC) derived from virgin crude palm oil have not been studied extensively. Therefore, the present study was designed to establish the neuroprotective role of TMC on differentiated human neural cells against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. The human neural cells were differentiated using retinoic acid for six days. Then, the differentiated neural cells were pre-treated for 24 hr with TMC before exposure to 6-OHDA. TMC pre-treated neurons showed significant alleviation of 6-OHDA-induced cytotoxicity as evidenced by enhanced activity of the superoxide dismutase (SOD) and catalase (CAT) enzymes. Furthermore, TMC elevated the levels of intra-neuronal dopamine and tyrosine hydroxylase (TH) in differentiated neural cells. The 6-OHDA induced overexpression of α-synuclein was significantly hindered in neural cells pre-treated with TMC. In proteomic analysis, TMC altered the expression of ribosomal proteins, α/β isotypes of tubulins, protein disulphide isomerases (PDI) and heat shock proteins (HSP) in differentiated human neural cells. The natural palm phytonutrient TMC is a potent antioxidant with significant neuroprotective effects against free radical-induced oxidative stress.

Our previous in vivo study found that resveratrol (Res), which is a phytoalexin, attenuated 6-hydroxydopamine (6-OHDA)-induced motor dysfunction by activating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway in rats. Therefore, we further explored the protective effect of Res on 6-OHDA-induced damage to PC12 cells in vitro with respect to the PI3K/Akt signaling pathway.

Neurotoxins have been extensively investigated, particularly in the field of neuroscience. They induce toxic damage, oxidative stress, and inflammation on neurons, triggering neuronal dysfunction and neurodegenerative diseases. Here we demonstrate the neuroprotective effect of a silicon (Si)-based hydrogen-producing agent (Si-based agent) in a juvenile neurotoxic mouse model induced by 6-hydroxydopamine (6-OHDA). The Si-based agent produces hydrogen in bowels and functions as an antioxidant and anti-inflammatory agent. However, the effects of the Si-based agent on neural degeneration in areas other than the lesion and behavioral alterations caused by it are largely unknown. Moreover, the neuroprotective effects of Si-based agent in the context of lactation and use during infancy have not been explored in prior studies. In this study, we show the neuroprotective effect of the Si-based agent on 6-OHDA during lactation period and infancy using the mouse model. The Si-based agent safeguards against the degradation and neuronal cell death of dopaminergic neurons and loss of dopaminergic fibers in the striatum (STR) and ventral tegmental area (VTA) caused by 6-OHDA. Furthermore, the Si-based agent exhibits a neuroprotective effect on the length of axon initial segment (AIS) in the layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC). As a result, the Si-based agent mitigates hyperactive behavior in a juvenile neurotoxic mouse model induced by 6-OHDA. These results suggest that the Si-based agent serves as an effective neuroprotectant and antioxidant against neurotoxic effects in the brain, offering the possibility of the Si-based agent as a neuroprotectant for nervous system diseases. • Si-based agent has a neuroprotective effect against neurotoxicity. • Si-based agent acts as neuroprotectant in areas other than the lesion. • Si-based agent mitigates behavioral alterations caused by neurotoxin. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a range of motor symptoms. Treatments are focused on dopamine replacement therapy or deep brain stimulation (DBS). The subthalamic nucleus (STN) is a common target for DBS treatment of PD. However, the function of the STN in normal conditions and pathology is poorly understood. Here, we show in rats that optogenetic modulation of STN neuronal activity exerts bidirectional control of motor function, where inhibition of the STN increases movement and STN activation decreases movement. We also examined the effect of bidirectional optogenetic manipulation STN neuronal activity under dopamine depleted condition using the bilateral rodent 6-hydroxydopamine (6-OHDA) model of Parkinson's disease. Optogenetic inhibition of the STN in the absence of dopamine had no impact on motor control yet STN excitation led to pronounced abnormal involuntary movement. Administration of levodopa rescued the abnormal involuntary movements induced by STN excitation. Although dopamine and STN dysfunction are well established in PD pathology, here we demonstrate simultaneous STN over activity and loss of dopamine lead to motor deficits. Moreover, we show the dysfunction of the STN is dependent on dopamine. This study provides evidence that the loss of dopamine and the over activity of the STN are key features of PD motor deficits. These results provide insight into the STN pathology in PD and therapeutic mechanism of targeting the STN for the treatment for PD. [ABSTRACT FROM AUTHOR]

Intermittent administration of L -dopa in Parkinson's disease is associated with L -dopa-induced dyskinesia (LID). Long-acting dopamine agonists may reduce the risk of LID by continuous dopaminergic stimulation. We examined the LID-like behavior, preprodynorphin messenger ribonucleic acid (mRNA) expression in the striatum (a neurochemical LID hallmark), and the volume of the entopeduncular nucleus (a pathological LID hallmark) in Parkinson's disease rat models that were treated with L -dopa and cabergoline. Cabergoline co-treatment with L -dopa reduced LID, striatal preprodynorphin mRNA expression, and hypertrophy of the entopeduncular nucleus, indicating that cabergoline has an anti-LID effect independent of the L -dopa-sparing effect. • Cabergoline is a long-acting dopamine agonist. • Cabergoline co-treatment with L -dopa reduced L -dopa-induced dyskinesia in model rats. • Cabergoline co-treatment decreased striatal preprodynorphin mRNA expression. • Cabergoline co-treatment suppressed hypertrophy of the entopeduncular nucleus. • Cabergoline has an anti-dyskinesia effect independent of the L -dopa-sparing effect. [ABSTRACT FROM AUTHOR]

• The HDAC5 inhibitor MC1568 prevents 6-OHDA-induced neurite length decreases in dopamine neurons. • MC1568 prevents 6-OHDA-induced HDAC5 nuclear accumulation in cultured dopamine neurons. • MC1568 i.p. injection protects motor symptoms and nigrostriatal neurons in 6-OHDA-lesioned rats. • MC1568 prevents microglial activation and HDAC5 nuclear accumulation in 6-OHDA-lesioned rats. • HDAC5 inhibition is a promising neuroprotective therapeutic avenue for Parkinson's disease. Parkinson's disease (PD) is a neurodegenerative disorder characterised by nigrostriatal dopaminergic (DA) neurodegeneration. There is a critical need for neuroprotective therapies, particularly those that do not require direct intracranial administration. Small molecule inhibitors of histone deacetylases (HDIs) are neuroprotective in in vitro and in vivo models of PD, however it is unknown whether Class IIa-specific HDIs are neuroprotective when administered peripherally. Here we show that 6-hydroxydopamine (6-OHDA) treatment induces protein kinase C (PKC)-dependent nuclear accumulation of the Class IIa histone deacetylase (HDAC)5 in SH-SY5Y cells and cultured DA neurons in vitro. Treatment of these cultures with the Class IIa-specific HDI, MC1568, partially protected against 6-OHDA-induced cell death. In the intrastriatal 6-OHDA lesion in vivo rat model of PD, MC1568 treatment (0.5 mg/kg i.p.) for 7 days reduced forelimb akinesia and partially protected DA neurons in the substantia nigra and their striatal terminals from 6-OHDA-induced neurodegeneration. MC1568 treatment prevented 6-OHDA-induced increases in microglial activation in the striatum and substantia nigra. Furthermore, MC1568 treatment decreased 6-OHDA-induced increases in nuclear HDAC5 in nigral DA neurons. These data suggest that peripheral administration of Class IIa-specific HDIs may be a potential therapy for neuroprotective in PD. [ABSTRACT FROM AUTHOR]

Copyright of Anatolian Clinic Journal of Medical Sciences is the property of Hayat Saglik ve Sosyal Hizmetler Vakfi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Intracellular iron accumulation in dopaminergic neurons contributes to neuronal cell death in progressive neurodegenerative disorders such as Parkinson's disease. However, the mechanisms of iron homeostasis in this context remain incompletely understood. In the present study, we assessed the role of the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) in cellular iron homeostasis. We identified that PPARδ inhibited 6-hydroxydopamine (6-OHDA)-triggered neurotoxicity in SH-SY5Y neuroblastoma cells. PPARδ activation with GW501516, a specific PPARδ agonist, mitigated 6-OHDA-induced neuronal damage. Further, PPARδ activation also suppressed iron accumulation, which contributes to 6-OHDA-induced neuronal damage. PPARδ activation attenuated 6-OHDA-induced neuronal damage in a similar manner to that of the iron chelator deferoxamine. We further elucidated that PPARδ modulated cellular iron homeostasis by regulating expression of divalent metal transporter 1, ferroportin 1, and ferritin, but not transferrin receptor 1, through iron regulatory protein 1 in 6-OHDA-treated cells. Interestingly, PPARδ activation suppressed 6-OHDA-triggered generation of reactive oxygen species and lipid peroxides. The effects of GW501516 were abrogated by shRNA knockdown of PPARδ, indicating that the effects of GW501516 were PPARδ-dependent. Taken together, these findings suggest that PPARδ attenuates 6-OHDA-induced neurotoxicity by preventing intracellular iron accumulation, thereby suppressing iron overload-associated generation of reactive oxygen species and lipid peroxides, key mediators of ferroptotic cell death. [ABSTRACT FROM AUTHOR]

Background: L-DOPA, the predominant therapy for Parkinson's disease (PD) is associated with motor deficits after prolonged use. The nigrostriatal tract, a primary target of neurodegeneration in PD, contains abundant Vitamin-D receptors, suggesting a potential role for VD in the disease. Therefore, we tested the impact of Vitamin D3 (VD3) in a mouse model of PD. Methods: PD was induced in adult male C57BL6 mice by a single intrastriatal injection of 6-hydroxydopamine. Two weeks post lesion, these mice received injections of a vehicle, VD3, L-DOPA, or a combination of VD3/L-DOPA and compared with sham controls. Treatment lasted three weeks, during which motor-cognitive neurobehaviour was assessed. Five weeks post lesion, brains were collected and striatal levels of the following proteins assessed: tyrosine hydroxylase (TH), dopamine decarboxylase (DDC), monoamine oxidase (MAO-B), Catechol-O-methyl transferase (COMT), dopamine transporter (DAT), brain-derived neurotrophic factor (BDNF), microglia marker (CD11b), inflammation (IL-1β), apoptotic signaling (BAX) and oxidative stress (p47phox). Results: Treatment with VD3 attenuated behavioural deficits induced by 6-OHDA, protein associated with dopamine metabolism and biomarkers of oxidative stress. VD3 significantly increased contralateral wall touches, exploratory motor and cognitive activities. VD3 significantly enhanced the expression of TH, DAT, BDNF, while significantly reducing expression of MAO-B, CD11b, IL-I β and p47phox. Conclusion: VD3 reversed some of the 6-OHDA induced changes in proteins involved in modulating the dopamine system, behavioural deficits and oxidative stress biomarkers. The data suggests that VD3 might be beneficial in reducing L-DOPA dosage, thereby reducing problems associated with dosage and prolonged use of L-DOPA in PD management. [ABSTRACT FROM AUTHOR]

The development, at the experimental level, of therapeutic strategies based on natural products to attenuate neurological alterations in degenerative disorders has gained attention. Antioxidant molecules exhibit both anti-inflammatory and neuroprotective properties. Alpha-mangostin (α-Man) is a natural xanthonoid isolated from the mangosteen tree with demonstrated antioxidant and cytoprotective properties. In this study, we investigated the antioxidant and protective properties of α-Man, both ex vivo and in vivo. We assessed the mitochondrial reductant capacity and oxidative damage to lipids in rat cortical slices, and several endpoints characteristic of physiological stress in the nematode, Caenorhabditis elegans (C. elegans), upon exposure to the parkinsonian neurotoxin, 6-hydroxydopamine (6-OHDA). In rat cortical slices, α-Man (25 and 50 µM) reduced the 6-OHDA (100 µM)-induced oxidative damage to lipid levels, but failed to reverse loss in cell viability. In wild-type (N2) C. elegans, α-Man (5–100 µM) protected against 6-OHDA (25 mM)-induced decrease in survival when administered either as pre- or post-treatment. Protective effects of α-Man were also observed on survival in the VC1772 strain (skn-1 KO−) exposed to 6-OHDA, though the extent of the protection was lesser than in the wild-type N2 strain. However, α-Man (5–50 µM) failed to attenuate the 6-OHDA-induced motor alterations in the N2 strain. The loss of lifespan induced by 6-OHDA in the N2 strain was fully reversed by high concentrations of α-Man. In addition, while 6-OHDA decreased the expression of glutathione S-transferase in the CL2166 C. elegans strain, α-Man preserved and stimulated the expression of this protein. α-Man (25 µM) also prevented 6-OHDA-induced dopaminergic neurodegeneration in the BZ555 C. elegans strain. Altogether, our novel results suggest that α-Man affords partial protection against several, but not all, short-term toxic effects induced by 6-OHDA in cortical slices and in a skn-1-dependent manner in C. elegans. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is one of the most common neurodegenerative disorders which is characterized by progressive loss of dopaminergic neurons in substantia nigra. Therefore, drugs or natural agents that have suppressive effects on dopaminergic cell death may reduce the progression of such disorder. Here, the effect of natural product alpha-pinene was evaluated on 6-hydroxydopamine (6-OHDA)-induced damage in SH-SY5Y human dopaminergic cell line as an in vitro model of PD. Methods: The cells were incubated by 150 μM 6-OHDA alone or accompanied with different concentration of alpha-pinene (10–180 μM). Cell viability was determined by MTT assay. The amount of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were measured by fluorescence spectrophotometry. In addition, the components of molecular apoptotic pathway such as cytochrome c release, Bax, Bcl-2, and caspase-3 levels were measured by immunoblotting. Gamma-aminobutyric acid (GABA) antagonist, bicuculline, was used to find the role of GABA Type A (GABAA) receptors in the signaling of alpha-pinene. Results: The data showed that 6-OHDA produced cell damage, decreased mitochondrial membrane potential, increased intracellular ROS and cytochrome c release, as well as increased Bax/Bcl-2 ratio and caspase-3 activity. Moreover, alpha-pinene (70 μM) significantly inhibited cellular and molecular abnormalities. Blockage of GABAA receptor significantly suppressed the protective effect of alpha-pinene. Conclusion: The results suggest that alpha-pinene has a protective effect against dopaminergic toxicity, and at least in part, its antioxidant and antiapoptotic properties are probably involved in such protection. [ABSTRACT FROM AUTHOR]

The neuroprotective capacity of newly synthesized amantadine derivative tyrosinyl-amantadine (Tyr-Am) with expected antiparkinsonian properties was evaluated in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease. Male Wistar rats were divided into the following groups: sham-operated (SO), striatal 6-OHDA-lesioned control group, 6-OHDA-lesioned rats pretreated for 6 days with Tyr-Am (16 mg/kg administered intraperitoneally, i.p.), and 6-OHDA-lesioned rats pretreated for 6 days with amantadine (40 mg/kg i.p.), used as a referent. On the first, second and third week post-lesion, the animals were subjected to some behavioral tests (apomorphine-induced rotation, rotarod, and passive avoidance test). The acetylcholinesterase (AChE) activity and key oxidative stress parameters including lipid peroxidation levels (LPO) and superoxide dismutase (SOD) were measured in brain homogenates. The results showed that the neuroprotective effect of Tyr-Am was comparable to that of amantadine, improving neuromuscular coordination and learning and memory performance even at a 2.5-fold lower dose. Tyr-Am demonstrated significant antioxidant properties via decreased LPO levels but had no effect on AChE activity. We can conclude that the newly synthesized amantadine derivative Tyr-Am demonstrated significant antiparkinsonian activity in a 6-OHDA experimental model. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common progressive neurodegenerative disease, after Alzheimer's disease. In our previous study, we found that amber—a fossilized plant resin—can protect cells from apoptosis by decreasing the generation of reactive oxygen species (ROS). In this study, we focused on the effect of amber on 6-hydroxydopamine-induced cell apoptosis in the human neuroblastoma cell line SHSY5Y (one model for PD). Initially, we determined the protective effect of amber on the PD model. We found that amber extract has a protective effect against 6-hydroxydopamine-induced cell apoptosis. The decrease in ROS, cleaved caspase-3, pERK, and extracellular signal-regulated kinase (ERK) protein levels confirmed that amber extract decreases apoptosis via the ROS-mediated ERK signaling pathway. Furthermore, we determined the effects of amber extract on autophagy. The results showed that amber extract increased the levels of LC3II and Beclin-1, suggesting that amber extract can protect neuronal cells against 6-hydroxydopamine-induced cell apoptosis by promoting autophagy. [ABSTRACT FROM AUTHOR]

With the increase in life expectancy and consequent aging of the world's population, the prevalence of many neurodegenerative diseases is increasing, without concomitant improvement in diagnostics and therapeutics. These diseases share neuropathological hallmarks, including mitochondrial dysfunction. In fact, as mitochondrial alterations appear prior to neuronal cell death at an early phase of a disease's onset, the study and modulation of mitochondrial alterations have emerged as promising strategies to predict and prevent neurotoxicity and neuronal cell death before the onset of cell viability alterations. In this work, differentiated SH-SY5Y cells were treated with the mitochondrial-targeted neurotoxicants 6-hydroxydopamine and rotenone. These compounds were used at different concentrations and for different time points to understand the similarities and differences in their mechanisms of action. To accomplish this, data on mitochondrial parameters were acquired and analyzed using unsupervised (hierarchical clustering) and supervised (decision tree) machine learning methods. Both biochemical and computational analyses resulted in an evident distinction between the neurotoxic effects of 6-hydroxydopamine and rotenone, specifically for the highest concentrations of both compounds. [ABSTRACT FROM AUTHOR]

Luteolin is one of the most common flavonoids present in edible plants and its potential benefits to the central nervous system include decrease of microglia activation, neuronal damage and high antioxidant properties. The aim of this research was to evaluate the neuroprotective, antioxidant and anti-inflammatory activities of luteolin-7-O-glucoside (Lut7). Undifferentiated and retinoic acid (RA)-differentiated SH-SY5Y cells were pretreated with Lut7 and incubated with 6-hydroxydopamine (6-OHDA). Cytotoxic and neuroprotective effects were determined by MTT assay. Antioxidant capacity was determined by DPPH, FRAP, and ORAC assays. ROS production, mitochondrial membrane potential (ΔΨm), Caspase–3 activity, acetylcholinesterase inhibition (AChEI) and nuclear damage were also determined in SH-SY5Y cells. TNF-α, IL-6 and IL-10 release were evaluated in LPS-induced RAW264.7 cells by ELISA. In undifferentiated SH-SY5Y cells, Lut7 increased cell viability after 24 h, while in RA-differentiated SH-SY5Y cells, Lut7 increased cell viability after 24 and 48 h. Lut7 showed a high antioxidant activity when compared with synthetic antioxidants. In undifferentiated cells, Lut7 prevented mitochondrial membrane depolarization induced by 6-OHDA treatment, decreased Caspase-3 and AChE activity, and inhibited nuclear condensation and fragmentation. In LPS-stimulated RAW264.7 cells, Lut7 treatment reduced TNF-α levels and increased IL-10 levels after 3 and 24 h, respectively. In summary, the results suggest that Lut7 has neuroprotective effects, thus, further studies should be considered to validate its pharmacological potential in more complex models, aiming the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Introduction: Parkinsonchr('39')s disease (PD) presentations comprise frequent movement disorders in the elderly with various symptoms consisting of motor and non-motor complications. Paeonol is a phenolic chemical agent that has shown antioxidant and anti-inflammatory effects in different disorders and promising effects on metabotropic glutamate receptors (mGluR)- and GABAA-mediated neurotransmission. In this research, we tried to show the neuroprotective potential of paeonol in rat PD model induced by intrastriatal 6-hydroxydopamine (6-OHDA). Methods: Rats with intrastriatal 6-OHDA lesioning received with paeonol at a dosage of 100 mg/kg/d for one week. In the end, some biomarkers of oxidative stress, apoptosis, and astrogliosis in nigral and striatal tissues were evaluated in addition to behavioral and Tyrosine Hydroxylase (TH) immunohistochemical analysis. Results: The obtained data showed that paeonol alleviates apomorphine-induced rotations and reduces the delay time to initiate and the total time in the narrow beam test. However, its beneficial behavioral effect vanished after intracerebroventricular administration of mGluR III or GABAA receptor antagonists. Moreover, paeonol significantly restored striatal malondialdehyde, tissue levels of reactive oxygen species, the activity of the protective and vital enzymes consisting of superoxide dismutase and catalase, Glial Fibrillary Acidic Protein (GFAP), DNA fragmentation, phosphor apoptosis signal-regulating kinase 1, and nigral aquaporin 4 with no significant and proper change of nitrite, interleukin-1β, inducible nitric oxide synthase, and angiotensin II. Additionally, paeonol prevented injury and reduced tyrosine hydroxylase-containing neurons in the midbrain nigral tissue. Conclusion: These obtained findings evidently designate neuroprotective property of paeonol in 6-OHDA murine model of PD that is exerted via easing of oxidative stress, apoptosis, astrogliosis, and its advantageous effect is to some extent mediated via mGluR III/GABAA pathway.

To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson's disease. It was recently observed in a rodent model of Alzheimer's disease that the interaction between the a7 subtype of nicotinic acetylcholine receptor (a7-nAChR) and sigma-1 receptor (s1-R) could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson's disease. In this context, the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide (PHA) 543613 as an a7-nAChR agonist and 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate (PRE)-084 as a s1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson's disease. The animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 post-lesion. Although no effect was noticed in the amphetamine-induced rotation test, our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons (15–20%), assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia nigra. Furthermore, this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion, i.e, the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum, and the CD11b and glial fibrillary acidic protein staining in the substantia nigra. Hence, this study reports for the first time that concomitant activation of a7-nAChR and s1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial activation. The study was approved by the Regional Ethics Committee (CEEA Val de Loire n°19) validated this protocol (Authorization N°00434.02) on May 15, 2014.

Accumulating evidence has already indicated that traditional Chinese medicine (TCM) possesses tremendous potential for treating neurodegenerative diseases. Astragalus, also named Huangqi, is a famous traditional medical herb that can be applied to treat cerebral ischemia and prevent neuronal degeneration. Nevertheless, the underlying mechanisms remain largely unexplored. In the present study, Astragalus-containing serum (ASMES) was prepared and added into the culture medium of PC12 cells to explore its neuroprotective effect on 6-hydroxydopamine (6-OHDA)-caused neuronal toxicity. Our data showed that ASMES significantly ameliorated the cellular viability of cultured PC12 cells against the neurotoxicity induced by 6-OHDA (P < 0.05). Moreover, ASMES significantly decreased the cell apoptosis triggered by 6-OHDA (P < 0.01). Furthermore, 2′,7′-dichlorofluorescin diacetate assay was performed to detect the changes in oxidative stress, and we showed that 6-OHDA elevated the production of reactive oxygen species (ROS), whereas ASMES significantly reversed these changes (P < 0.01). Besides, mitochondrial membrane potential (MMP) assay showed that ASMES could restore 6-OHDA-damaged MMP in cultured PC12 cells (P < 0.05). In conclusion, Astragalus could protect PC12 cells from 6-OHDA-caused neuronal toxicity, and possibly, the ROS-mediated apoptotic pathway participated in this process. Collectively, our findings provided valuable insights into the potential in treatment of neurodegenerative diseases.

Dysfunctional autophagy often occurs during the development of neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. The purinergic P2X4 receptor is an ATP-gated ion channel that is widely expressed in the microglia, astrocytes, and neurons of the central and peripheral nervous systems. P2X4R is involved in the regulation of cellular excitability, synaptic transmission, and neuroinflammation. However, the role played by P2X4R in Parkinson's disease remains poorly understood. Rat models of Parkinson's disease were established by injecting 6-hydroxydopamine into the substantia nigra pars compacta. P2X4R-targeted small interfering RNA (siRNA) was injected into the same area 1 week before injury induction to inhibit the expression of the P2X4 receptor. The results showed that the inhibition of P2X4 receptor expression in Parkinson's disease model rats reduced the rotation behavior induced by apomorphine treatment, increased the latency on the rotarod test, and upregulated the expression of tyrosine hydroxylase, brain-derived neurotrophic factor, LC3-II/LC3-I, Beclin-1, and phosphorylated tropomyosin receptor kinase B (TrkB) in brain tissue, while simultaneously reducing p62 levels. These findings suggest that P2X4 receptor activation might inhibit neuronal autophagy through the regulation of the brain-derived neurotrophic factor/TrkB signaling pathway, leading to dopaminergic neuron damage in the substantia nigra and the further inhibition of P2X4 receptor-mediated autophagy. These results indicate that P2X4 receptor might serve as a potential novel target for the treatment of Parkinson's disease. This study was approved by the Animal Ethics Committee of Affiliated Hospital of Qingdao University (approval No. QYFYWZLL26119) on April 12, 2016.

In this work investigated the neuroprotective activity of analogues of substituted glyproline GZK-111 at the N-terminus in vitro. Oxidative stress caused by H2O2 (1.5 mM) led to significant decrease in the hippocampal cells HT-22 viability. The ethyl ester N-phenypropionyl-glycyl-proline (GZK-45) was effective at the concentrations up to 10–6 M in both experimental schemes. The compounds with N-acethyl (GZK-49) and N-capronoyl (GZK-46) fragments did not protective effect in both experimental schemes. GZK-45 also had protective effect in the 6-hydroxydopamine induced damage of SH-SY5Y neuroblastoma cells.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a range of motor symptoms. Treatments are focused on dopamine replacement therapy or deep brain stimulation (DBS). The subthalamic nucleus (STN) is a common target for DBS treatment of PD. However, the function of the STN in normal conditions and pathology is poorly understood. Here, we show in rats that optogenetic modulation of STN neuronal activity exerts bidirectional control of motor function, where inhibition of the STN increases movement and STN activation decreases movement. We also examined the effect of bidirectional optogenetic manipulation STN neuronal activity under dopamine depleted condition using the bilateral rodent 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease. Optogenetic inhibition of the STN in the absence of dopamine had no impact on motor control yet STN excitation led to pronounced abnormal involuntary movement. Administration of levodopa rescued the abnormal involuntary movements induced by STN excitation. Although dopamine and STN dysfunction are well established in PD pathology, here we demonstrate simultaneous STN over activity and loss of dopamine lead to motor deficits. Moreover, we show the dysfunction of the STN is dependent on dopamine. This study provides evidence that the loss of dopamine and the over activity of the STN are key features of PD motor deficits. These results provide insight into the STN pathology in PD and therapeutic mechanism of targeting the STN for the treatment for PD.

Background We assessed whether ICT can alleviate 6-OHDA-induced cell damage via inhibition of oxidative stress by evaluating the protective effect of icaritin (ICT) against 6-hydroxydopamine (6-OHDA)-induced MN9D cell damage and further determined the mechanism by which ICT reduces oxidative stress. Methods MN9D cells were treated with 6-OHDA, to study the mechanism underlying the neuroprotective effect of ICT. MN9D cell damage was assessed by the CCK-8 assay, flow cytometry was performed to measure the content of reactive oxygen species (ROS) in cells, a superoxide dismutase (SOD) kit was used to evaluate SOD activity, and Western blotting was used to measure the expression of α-synuclein (α-Syn), Tyrosine hydroxylase (TH), nuclear factor erythroid-2 related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Results ICT reduced damage to MN9D cells induced by 6-OHDA. ICT increased SOD activity and TH expression and reduced ROS production and α-Syn expression. ICT promoted the translocation of Nrf2 from the cytoplasm to the nucleus and further increased the protein expression of HO-1. Conclusions ICT protects against 6-OHDA-induced dopaminergic neuronal cell injury by attenuating oxidative stress, and the mechanism is related to modulate the activities of Nrf2, HO-1 protein, and SOD.

Background: Parkinson's disease (PD) is a multifactorial movement disorder with the progressive degeneration of the nigrostriatal system that impairs patients' movement ability. Oxidative stress has been found to affect the etiology and pathogenesis of PD. Thymol, a monoterpenic phenol, is one of the most important dietary constituents in thyme species. It has been used in traditional medicine and possesses some properties including antioxidant, free radical scavenging, anti-inflammatory. In this study, in vitro and in vivo experiments were performed with the thymol in order to investigate its potential neuroprotective effects in models of PD. Methods: The present study aimed to evaluate the therapeutic potential of thymol in 6-hydroxydopamine (6-OHDA)-induced cellular and animal models of PD. Results: Post-treatment with thymol in vitro was found to protect PC12 cells from toxicity induced by 6-OHDA administration in a dose-dependent manner by (1) increasing cell viability and (2) reduction in intracellular reactive oxygen species, intracellular lipid peroxidation, and annexin-positive cells. In vivo, post-treatment with thymol was protective against neurodegenerative phenotypes associated with systemic administration of 6-OHDA. Results indicated that thymol improved the locomotor activity, catalepsy, akinesia, bradykinesia, and motor coordination and reduced the apomorphine-caused rotation in 6-OHDA-stimulated rats. Increased level of reduced glutathione content and a decreased level of MDA (malondialdehyde) in striatum were observed in the 6-OHDA rats post-treated with thymol. Conclusions: Collectively, our findings suggest that thymol exerts protective effects, possibly related to an anti-oxidation mechanism, in these in vitro and in vivo models of Parkinson's disease. [ABSTRACT FROM AUTHOR]

[Display omitted] Oxidative stress is a critical factor that triggers a "domino" cascade of events leading to the degeneration of dopaminergic neurons in Parkinson disease. Tocotrienols (T3) have antioxidant effects and can protect neuronal cells against oxidative damage. In the present study, we investigated the neuroprotective effects of different forms of T3 (alpha, delta, gamma) or tocotrienol-rich fraction (TRF) against 6-hydroxydopamine (6-OHDA)-induced oxidative damage in differentiated SH-SY5Y human neural cells. Differentiating the SH-SY5Y cells with retinoic acid and a low-serum culture medium for 6 days allowed development of human dopamine-like neural cells. Subsequently, the differentiated SH-SY5Y neural cells were pretreated with different forms of T3 for 24 hours before these cells were exposed to 6-OHDA. The T3 analogues and TRF displayed neuroprotective effects (P <.05) via restoration of cell viability and activation of antioxidant enzymes (e.g., superoxide dismutase, catalase). Notably, TRF was highly efficient in scavenging reactive oxygen species and upregulating dopamine and tyrosine hydroxylase levels in the differentiated SH-SY5Y cells. Gamma-T3 exhibited the most potent effects in attenuating apoptosis, whereas alpha-T3 was most effective in preventing 6-OHDA-induced leakage of α-Synuclein. Delta-T3 displayed a noticeable effect in upregulating the dopamine receptor D2 gene expression compared with controls. These findings suggest T3 isoforms and TRF demonstrate significant neuroprotective effects in protecting differentiated neural cells against 6-OHDA-mediated oxidative stress. [ABSTRACT FROM AUTHOR]

Low-intensity pulsed ultrasound (LIPUS) is a promising non-invasive neuromodulation tool for deep brain stimulation. Here, we investigated the impact of LIPUS, including neuroprotective effects, on the pathology of Parkinson's disease (PD) in an animal model. Sprague-Dawley rats were injected with 6-hydroxydopamine (6-OHDA) at two sites in the right striatum. LIPUS (1 MHz, 5% duty cycle, 1-Hz pulse repetition frequency, 15 min/d) stimulation was then applied to some of the rats (the 6-OHDA + LIPUS group) beginning 2 wk after the 6-OHDA administration, while the remaining rats (the 6-OHDA group) received no LIPUS stimulation. The 6-OHDA-induced inflammatory responses and expressions of neurotrophic factors were quantified with immunofluorescence activity. The safety of LIPUS was assessed using hematoxylin and eosin and Nissl staining. LIPUS treatment significantly inhibited 6-OHDA-induced glial activation and the phosphorylation of nuclear factor-κB p65 in the substantia nigra pars compacta. Further study revealed that LIPUS effectively preserved the levels of neurotrophic factors, dopamine transporter and tight junction proteins of the blood-brain barrier in the 6-OHDA + LIPUS group compared with the 6-OHDA group. These results indicate that LIPUS acts via multiple neuroprotective mechanisms in the PD rat model and suggest that LIPUS can be viewed as a potential treatment for PD. [ABSTRACT FROM AUTHOR]

Astrocytes and astrocyte-related proteins play important roles in maintaining normal brain function, and also regulate pathological processes in brain diseases and injury. However, the role of astrocytes in the dopamine-depleted striatum remains unclear. A rat model of Parkinson’s disease was therefore established by injecting 10 μL 6-hydroxydopamine (2.5 μg/μL) into the right medial forebrain bundle. Immunohistochemical staining was used to detect the immunoreactivity of glial fibrillary acidic protein (GFAP), calcium-binding protein B (S100B), and signal transducer and activator of transcription 3 (STAT3) in the striatum, and to investigate the co-expression of GFAP with S100B and STAT3. Western blot assay was used to measure the protein expression of GFAP, S100B, and STAT3 in the striatum. Results demonstrated that striatal GFAP-immunoreactive cells had an astrocytic appearance under normal conditions, but that dopamine depletion induced a reactive phenotype with obvious morphological changes. The normal striatum also contained S100B and STAT3 expression. S100B-immunoreactive cells were uniform in the striatum, with round bodies and sparse, thin processes. STAT3-immunoreactive cells presented round cell bodies with sparse processes, or were darkly stained with a large cell body. Dopamine deprivation induced by 6-hydroxydopamine significantly enhanced the immunohistochemical positive reaction of S100B and STAT3. Normal striatal astrocytes expressed both S100B and STAT3. Striatal dopamine deprivation increased the number of GFAP/S100B and GFAP/STAT3 double-labeled cells, and increased the protein levels of GFAP, S100B, and STAT3. The present results suggest that morphological changes in astrocytes and changes in expression levels of astrocyte-related proteins are involved in the pathological process of striatal dopamine depletion. The study was approved by Animal Care and Use Committee of Sun Yat-sen University, China (Zhongshan Medical Ethics 2014 No. 23) on September 22, 2014.

Introduction: Parkinson’s Disease (PD) is a prevalent neurodegenerative condition among the elderly. Considering the limited symptomatic improvement associated with PD treatments, introducing more effective agents is necessary. Citrus aurantium flower extract (CAE) is recognized as a neuroprotective and hepatoprotective agent with bioactive compounds, such as flavonoids, phenolics, and vitamins. Considering the mitigating role of CAE against oxidative damage, the present study examined the neuroprotective effects of CAE in a PD model. Methods: Overall, 60 male rats were classified into 6 groups, as follows: sham (SH); control (C); lesion (L); and CAE-treated lesion (200, 400, and 600 mg/mL CAE+L). For the hemi-PD model, 6-hydroxydopamine (12.5 g/L of saline ascorbate) was injected intrastriatally. Intraperitoneal pretreatment with hydroalcoholic CAE (200, 400, and 600 mg/kg) was applied in the E+SH and E+L groups at one week pre-surgery. At two weeks post-surgery, rotational behaviors were examined by apomorphine hydrochloride. Moreover, stained neurons were measured in the Substantia Nigra pars compacta (SNc). Results: In comparison with the C group, significant contralateral turning was reported due to apomorphine, in the L group at two weeks post-surgery (P

Cognitive deficit is a frequent non-motor symptom in Parkinson’s disease (PD) with an unclear pathogenesis. Recent research indicates possible involvement of insulin resistance and glutamate excitotoxicity in PD development. We investigated cognitive performance and the brain glutamate and insulin signaling in a rat model of PD induced by bilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA). Cognitive functions were assessed with Passive Avoidance (PA) and Morris Water Maze (MWM) tests. The expression of tyrosine hydroxylase (TH) and proteins involved in insulin (insulin receptor - IR, phosphoinositide 3 kinase - pI3K, extracellular signal-regulated kinases-ERK) and glutamate receptor (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptos-AMPAR, N-methyl-D-aspartate receptor - NMDAR) signaling was assessed in the hippocampus (HPC), hypothalamus (HPT) and striatum (S) by immunofluorescence, Western blot and enzyme-linked immunosorbent assay (ELISA). Three months after 6-OHDA treatment, cognitive deficit was accompanied by decreased AMPAR activity and TH levels (HPC, S), while levels of the proteins involved in insulin signaling remained largely unchanged. Spearman’s rank correlation revealed a strong positive correlation for pAMPAR-PA (S), pNMDAR-pI3K (HPC) and pNMDAR-IR (all regions). Additionally, a positive correlation was found for TH-ERK and TH-pI3K, and a negative one for TH-MWM/errors and pI3K-MWM/time (S). These results suggest a possible association between brain glutamate (but not insulin) signaling dysfunction and cognitive deficit in a rat PD model, detected three months after 6-OHDA treatment.

Abstract Background Parkinson’s disease (PD) is characterised by dopaminergic cell loss within the substantia nigra pars compacta (SNc) that leads to reduced striatal dopamine content and resulting motor deficits. Identifying new strategies to protect these cells from degeneration and retain striatal dopaminergic innervation is therefore of great importance. Chondroitin sulphate proteoglycans (CSPGs) are recognised contributors to the inhibitory extracellular milieu known to hinder tissue recovery following CNS damage. Digestion of these molecules by the bacterial lyase chondroitinase ABC (ChABC) has been shown to promote functional recovery in animal models of neurological injury. Although ChABC has been shown to promote sprouting of dopaminergic axons following transection of the nigrostriatal pathway, its ability to protect against nigrostriatal degeneration in a toxin-based module with better construct validity for PD has yet to be explored. Here we examined the neuroprotective efficacy of ChABC treatment in the full and partial 6-hydroxydopamine (6-OHDA) lesion mouse models of PD. Results In mice bearing a full 6-OHDA lesion, ChABC treatment failed to protect against the loss of either nigral cells or striatal terminals. In contrast, in mice bearing a partial 6-OHDA lesion, ChABC treatment significantly protected cells of the rostral SNc, which remained at more than double the numbers seen in vehicle-treated animals. In the partial lesion model, ChABC treatment also significantly preserved dopaminergic fibres of the rostral dorsal striatum which increased from 15.3 ± 3.5% of the intact hemisphere in saline-treated animals to 36.3 ± 6.5% in the ChABC-treated group. These protective effects of ChABC treatment were not accompanied by improvements in either the cylinder or amphetamine-induced rotations tests of motor function. Conclusions ChABC treatment provided significant protection against a partial 6-OHDA lesion of the nigrostriatal tract although the degree of protection was not sufficient to improve motor outcomes. These results support further investigations into the benefits of ChABC treatment for providing neuroprotection in PD.

This focus of our research is to investigate the protective effect of Baicalin on apoptosis and mTOR/AKT/GSK-3β pathway in substantia nigra neurons in a rat model for Parkinson's disease, induced by 6-Hydroxydopamine. Thirty healthy female Sprague-Dawley rats were randomly divided into control group, model group, and Baicalin group. The Parkinson model was established by injecting 6-Hydroxydopamine into the right substantia nigra of rats in model and Baicalin group. The rats in Baicalin group were intragastrically administered with Baicalin (25 mg/kg/day) for four weeks. At the same time, the rats in control and model groups were intragastrically administered with equivalent solvents. We observed the rat turns, rotation speed and left forelimb usage. The protein expression levels of α-SYN, mTOR, AKT, and GSK-3β in substantia nigra were detected by immunohistochemistry and Western blotting. Compared with model group, Baicalin significantly reduced the number of rotation speeds and neuron apoptosis (P < 0.001, respectively). However, the left forelimb use rate was notably increased after treatment with Baicalin (P < 0.001, respectively). Also, Baicalin decreased the expression levels of α-SYN, mTOR, AKT, and GSK-3β in rats when compared with those in model group (P < 0.001, respectively).

This systematic review was carried out with the aim of evaluating the use of medicinal Cannabis for the treatment of Parkinson's disease in experimental models. Furthermore, we sought to understand the main intracellular mechanisms capable of promoting the effects of phytocannabinoids on motor disorders, neurodegeneration, neuroinflammation and oxidative stress. The experimental models were developed in mice, rats and marmosets. There was a predominance of using only males in relation to females; in three studies, the authors evaluated treatments in males and females. Drugs were used as inducers of Parkinson's disease: 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), lipopolysaccharide (LPS), and rotenone. Substances capable of promoting catalepsy in animals were also used: haloperidol, L-nitro-N-arginine (L-NOARG), WIN55,212-2, and reserpine. The inducing agent was injected stereotaxically or intraperitoneally. The most commonly used treatments were cannabidiol (CBD), Delta-9-tetrahydrocannabinol (Δ-9 THC) and Delta-9-tetrahydrocannabivarin (Δ-9 THCV), administered intraperitoneally, orally, subcutaneously and intramuscularly. The use of phytocannabinoids improved locomotor activity and involuntary movement and reduced catalepsy. There was an improvement in the evaluation of dopaminergic neurons, while in relation to dopamine content, the treatment had no effect. Inflammation, microglial/astrocyte activation and oxidative stress were reduced after treatment with phytocannabinoids, the same was observed in the results of tests for allodynia and hyperalgesia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oxidative stress and gut dysbiosis have been known to precede Parkinson’s disease (PD). An antioxidant-rich product, mangosteen pericarp (MP), has the ability to counterbalance excessive free radicals and the imbalanced gut microbiota composition, suggesting the MP’s capacity to delay PD progression. In this study, we explored the effects of two doses of MP extract in a unilateral 6-hydroxydopamine (6-OHDA)-induced PD rat model. We revealed that the 8-week supplementation of a low dose (LMP) and a high dose of the MP extract (HMP) improved motor function, as observed in decreased contralateral rotation, improved time spent on rod, and higher dopamine binding transporter (DAT) in the substantia nigra pars compacta (SNc). The MP extract, especially the HMP, also increased antioxidant-related gene expressions, restored muscle mitochondrial function, and remodeled fecal microbiota composition, which were followed by reduced reactive oxygen species levels in brain and inflammation in plasma. Importantly, bacterial genera Sutterella, Rothia, and Aggregatibacter, which were negatively correlated with antioxidant gene expressions, decreased in the HMP group. It is imperative to note that in addition to directly acting as an antioxidant to reduce excessive free radicals, MP extract might also increase antioxidant state by rebuilding gut microbiota, thereby enhanced anti-inflammatory capacity and restored mitochondrial function to attenuate motor deficit in 6-OHDA-induced PD-like condition. All in all, MP extract is a potential candidate for auxiliary therapy for PD.

Fucoxanthin is the most abundant carotenoid found in marine brown algae that exhibits several healthy properties. Dietary fucoxanthin is metabolized in the intestine, plasma, and other tissues to various metabolites, including fucoxanthinol. In this regard, the contribution of fucoxanthinol to the healthy properties of its precursor, fucoxanthin, against pathogenetic events associated with neurodegenerative diseases remains unexplored. Here, we evaluated and compared the antioxidant and neuroprotective effects of the carotenoids fucoxanthin and fucoxanthinol in in vitro models of Alzheimer's (AD) and Parkinson's (PD) disease. Neuronal SH-SY5Y cells were used to evaluate the antioxidant properties of the carotenoids against ABTS radical in the membrane and cytoplasm and oxidative stress elicited by tert -butyl hydroperoxide using the 2',7'-dichlorodihydrofluorescein diacetate probe. We also assessed the ability of the carotenoids to increase the glutathione (GSH) and activate the Nrf2/Keap1/ARE pathway using the monochlorobimane probe and western blotting method, respectively. The neuroprotective effects of the carotenoids against the neurotoxicity generated by oligomers of Beta-Amyloid (1-42) peptide (OAβ) and 6-hydroxydopamine (6-OHDA), which are neurotoxins of AD and PD, respectively, were finally evaluated in the same neuronal cells using the thiazolyl blue tetrazolium bromide assay. Both carotenoids could reach the cytoplasm, which explains the mainly free radical scavenging activity at this level. Notably, fucoxanthinol had higher and lower antioxidant activity than fucoxanthin at extracellular and cellular levels. Although studied carotenoids exerted the ability to activate the Nrf2/Keap1/ARE pathway, leading to an increase of intracellular GSH, our results suggested that the antioxidant activity of the carotenoids could be mainly attributed to their radical scavenging activity in neuronal membrane and cytoplasm, where they accumulate. Fucoxanthinol also shared similar neuroprotective effects as fucoxanthin against the neurotoxicity generated by OAβ and 6-OHDA, suggesting a potential neuroprotective contribution to the action of fucoxanthin administered as a food supplement in in vivo experimental models. These results encourage further research to evaluate the bioavailability of fucoxanthinol and other metabolites of fucoxanthin at the brain level to elucidate the dietary neuroprotective potential of fucoxanthin.

The cholinergic anti-inflammatory pathway (CAIP) has been proposed to regulate gastrointestinal inflammation via acetylcholine released from the vagus nerve activating α7 nicotinic receptor (α7nAChR) on macrophages. Parkinson's disease (PD) patients and PD rats with substantia nigra (SN) lesions exhibit gastroparesis and a decayed vagal pathway. To investigate whether activating α7nAChR could ameliorate inflammation and gastric dysmotility in PD rats, ELISA, western blot analysis, and real-time PCR were used to detect gastric inflammation. In vitro and in vivo gastric motility was investigated. Proinflammatory mediator levels and macrophage numbers were increased in the gastric muscularis of PD rats. α7nAChR was located on the gastric muscular macrophages of PD rats. The α7nAChR agonists PNU-282987 and GTS-21 decreased nuclear factor κB (NF-κB) activation and monocyte chemotactic protein-1 mRNA expression in the ex vivo gastric muscularis of PD rats, and these effects were abolished by an α7nAChR antagonist. After treatment with PNU-282987 in vivo, the PD rats showed decreased NF-κB activation, inflammatory mediator production, and contractile protein expression and improved gastric motility. The present study reveals that α7nAChR is involved in the development of gastroparesis in PD rats and provides novel insight for the treatment of gastric dysmotility in PD patients. [ABSTRACT FROM AUTHOR]