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Parkinson's disease (PD) is the second-most prevalent neurodegenerative disease worldwide, which worsens with advancing age. It is a common movement disorder and is often associated with several vascular diseases with decreased stroke frequency. Circulating platelets substantially regulate vascular complications, including stroke, and share striking similarities with PD neurons. Although structural alterations in platelets are well-documented in PD, their functional parameters remain unclear. This study aimed to investigate the functional abnormalities in platelets associated with PD by evaluating key functional aspects such as adhesion, activation, secretion, aggregation, and clot retraction. To achieve this, we treated human blood platelets with 6-hydroxydopamine or 6-OHDA, that selectively destroys dopaminergic neurons, thereby creating an in vitro experimental model that closely resembles the pathogenic environment in PD, and examine its impact on platelet functions. In our study, platelet adhesion was assessed and further evaluated by a microplate reader, activation and secretion by a flow cytometer, aggregation by aggregometer, and clot retraction by Sonoclot. Phase-contrast and confocal microscopic studies further verified the results from the above experiments. Our findings showed that 6-OHDA treatment significantly inhibited thrombin (a platelet agonist)-induced functions, including adhesion, activation, aggregation, secretion, and clot retraction in human-washed platelets. In summary, this research provides pioneering evidence that 6-OHDA induces abnormal platelet functions, shedding light on the previously unexplored processes by which 6-OHDA affects platelet activity., 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 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a successful treatment option in Parkinson's disease (PD) for different motor and non-motor symptoms, but has been linked to postoperative cognitive impairment., Aim: Since both dopaminergic and norepinephrinergic neurotransmissions play important roles in symptom development, we analysed STN-DBS effects on dopamine and norepinephrine availability in different brain regions and morphological alterations of catecholaminergic neurons in the 6-hydroxydopamine PD rat model., Methods: We applied one week of continuous unilateral STN-DBS or sham stimulation, respectively, in groups of healthy and 6-hydroxydopamine-lesioned rats to quantify dopamine and norepinephrine contents in the striatum, olfactory bulb and dentate gyrus. In addition, we analysed dopaminergic cell counts in the substantia nigra pars compacta and area tegmentalis ventralis and norepinephrinergic neurons in the locus coeruleus after one and six weeks of STN-DBS., Results: In 6-hydroxydopamine-lesioned animals, one week of STN-DBS did not alter dopamine levels, while striatal norepinephrine levels were decreased. However, neither one nor six weeks of STN-DBS altered dopaminergic neuron numbers in the midbrain or norepinephrinergic neuron counts in the locus coeruleus. Dopaminergic fibre density in the dorsal and ventral striatum also remained unchanged after six weeks of STN-DBS. In healthy animals, one week of STN-DBS resulted in increased dopamine levels in the olfactory bulb and decreased contents in the dentate gyrus, but had no effects on norepinephrine availability., Conclusions: STN-DBS modulates striatal norepinephrinergic neurotransmission in a PD rat model. Additional behavioural studies are required to investigate the functional impact of this finding., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

The effects of trehalose, an autophagy-inducing disaccharide with neuroprotective properties, on the neurotoxicity of parkinsonian mimetics 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpiridinium (MPP + ) are poorly understood. In our study, trehalose suppressed 6-OHDA-induced caspase-3/PARP1 cleavage (detected by immunoblotting), apoptotic DNA fragmentation/phosphatidylserine externalization, oxidative stress, mitochondrial depolarization (flow cytometry), and mitochondrial damage (electron microscopy) in SH-SY5Y neuroblastoma cells. The protection was not mediated by autophagy, autophagic receptor p62, or antioxidant enzymes superoxide dismutase and catalase. Trehalose suppressed 6-OHDA-induced activation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and AMP-activated protein kinase (AMPK), as revealed by immunoblotting. Pharmacological/genetic inhibition of JNK, p38 MAPK, or AMPK mimicked the trehalose-mediated cytoprotection. Trehalose did not affect the extracellular signal-regulated kinase (ERK) and mechanistic target of rapamycin complex 1 (mTORC1)/4EBP1 pathways, while it reduced the prosurvival mTORC2/AKT signaling. Finally, trehalose enhanced oxidative stress, mitochondrial damage, and apoptosis without decreasing JNK, p38 MAPK, AMPK, or AKT activation in SH-SY5Y cells exposed to MPP + . In conclusion, trehalose protects SH-SY5Y cells from 6-OHDA-induced oxidative stress, mitochondrial damage, and apoptosis through autophagy/p62-independent inhibition of JNK, p38 MAPK, and AMPK. The opposite effects of trehalose on the neurotoxicity of 6-OHDA and MPP+ suggest caution in its potential development as a neuroprotective agent.

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., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that sub-anesthetic ketamine produces acute anti-parkinsonian, and acute anti-dyskinetic effects in preclinical models of Parkinson's disease (PD). Ketamine is a multifunctional drug and exerts effects through blockade of N-methyl-d-aspartate receptors but also through interaction with the opioid system. In this report, we provide detailed pharmacokinetic rodent data on ketamine and its main metabolites following an intraperitoneal injection, and second, we explore the pharmacodynamic properties of ketamine in a rodent PD model with respect to the opioid system, using naloxone, a pan-opioid receptor antagonist, in unilateral 6-hydroxydopamine-lesioned male rats, treated with 6 mg/kg levodopa (l-DOPA) to establish a model of l-DOPA-induced dyskinesia (LID). As previously reported, we showed that ketamine (20 mg/kg) is highly efficacious in reducing LID and now report that the magnitude of this effect is resistant to naloxone (3 and 5 mg/kg). The higher naloxone dose of 5 mg/kg, however, led to an extension of the time-course of the LID, indicating that opioid receptor activation, while not a prerequisite for the anti-dyskinetic effects of ketamine, still exerts an acute modulatory effect. In contrast to the mild modulatory effect on LID, we found that naloxone added to the anti-parkinsonian activity of ketamine, further reducing the akinetic phenotype. In conclusion, our data show opioid receptor blockade differentially modulates the acute anti-parkinsonian and anti-dyskinetic actions of ketamine, providing novel mechanistic information to support repurposing ketamine for individuals with LID., Competing Interests: Declaration of competing interest SJS and TF have a patent for the use of ketamine as a novel treatment for levodopa-induced dyskinesia associated with Parkinson's disease that was licensed to PharmaTher Inc. in 2020. They have consulted for PharmaTher Inc. in 2021 and 2023. TF also received travel support in 2022 and 2023., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Synucleins, including α-synuclein (α-syn), β-syn, and γ-syn, have been implicated in various synucleinopathies, notably Parkinson's disease (PD), which has generated increased interest in understanding their roles. Although α-syn and β-syn have contrasting neuropathological consequences, the precise role of γ-syn remains unclear. This study validated non-motor symptoms, specifically anxiety-like behavior, along with the degradation of dopaminergic (DAergic) neurons in the nigrostriatal system and DAergic neurites in the prefrontal cortex and hippocampus of rats infused with striatal 6-hydroxydopamine (6-OHDA). Our study further investigated the alterations in γ-syn expression levels in the prefrontal cortices and hippocampi of these 6-OHDA-treated rats, aiming to establish foundational insights into the neuropathophysiology of DA depletion, a central feature of PD. Our findings revealed a significant increase in the expression of γ-syn mRNA and protein in these brain regions, in contrast to unaltered α- and β-syn expression levels. This suggests a distinct role of γ-syn within the neurobiological milieu under conditions of DA deficiency. Overall, our data shed light on the neurobiological changes observed in the hemiparkinsonian rat model induced with 6-OHDA, underscoring the potential significance of γ-syn in PD pathology., 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.)

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.)

Background: 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)., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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.)

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.

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., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

There is some evidence that the serotonin receptor subtype 7 (5-HT 7 ) could be new therapeutic target for neuroprotection. The aim of this study was to compare the neuroprotective and neurite outgrowth potential of new 5-HT 7 receptor agonists (AH-494, AGH-238, AGH-194) with 5-CT (5-carboxyamidotryptamine) in human neuroblastoma SH-SY5Y cells. The results revealed that 5-HT 7 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 H 2 O 2 -evoked cell damage by all tested 5-HT 7 agonists. However, 5-HT 7 -mediated neuroprotection was not associated with inhibition of caspase-3 activity and was not observed in RA-SH-SY5Y cells exposed to H 2 O 2 . Furthermore, none of the tested 5-HT 7 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-HT 7 agonists., (© 2024. The Author(s).)

Introduction: 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., Material and Methods: 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., Results: 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., Conclusion: 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.

Introduction: 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., Methods: 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., Results and Discussion: 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., Conclusion: 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., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

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.

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., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

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., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ullah, Zhao, Uddin, Zhou, Wang and Li.)

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 H 2 O 2 -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 (H 2 O 2 ). Neuroprotection mediated by CBD in primary neurons against H 2 O 2 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 H 2 O 2 - 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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Fauser, Payonk, Weber, Statz, Winter, Hadar, Appali, van Rienen, Brandt and Storch.)

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., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Objective: 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., Methods: 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., Results: 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)., Conclusion: 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., Competing Interests: Conflict of interest The authors declare that they have no conflict of interests., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

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-NH 2 ) 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., (© 2023. The Author(s).)

Objectives: Enhanced beta oscillations in cortical-basal ganglia (BG) thalamic circuitries have been linked to clinical symptoms of Parkinson's disease. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces beta band activity in BG regions, whereas little is known about activity in cortical regions. In this study, we investigated the effect of STN DBS on the spectral power of oscillatory activity in the motor cortex (MCtx) and sensorimotor cortex (SMCtx) by recording via an electrocorticogram (ECoG) array in free-moving 6-hydroxydopamine (6-OHDA) lesioned rats and sham-lesioned controls., Materials and Methods: Male Sprague-Dawley rats (250-350 g) were injected either with 6-OHDA or with saline in the right medial forebrain bundle, under general anesthesia. A stimulation electrode was then implanted in the ipsilateral STN, and an ECoG array was placed subdurally above the MCtx and SMCtx areas. Six days after the second surgery, the free-moving rats were individually recorded in three conditions: 1) basal activity, 2) during STN DBS, and 3) directly after STN DBS., Results: In 6-OHDA-lesioned rats (N = 8), the relative power of theta band activity was reduced, whereas activity of broad-range beta band (12-30 Hz) along with two different subbeta bands, that is, low (12-30 Hz) and high (20-30 Hz) beta band and gamma band, was higher in MCtx and SMCtx than in sham-lesioned controls (N = 7). This was, to some extent, reverted toward control level by STN DBS during and after stimulation. No major differences were found between contacts of the electrode grid or between MCtx and SMCtx., Conclusion: Loss of nigrostriatal dopamine leads to abnormal oscillatory activity in both MCtx and SMCtx, which is compensated by STN stimulation, suggesting that parkinsonism-related oscillations in the cortex and BG are linked through their anatomic connections., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: 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., (© 2024 The Author(s).)

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., Competing Interests: The authors declare no competing financial interests., (© 2024 The Authors.)

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., Competing Interests: 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., (© 2024 The Author(s).)

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., (© 2024. The Author(s).)

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., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Pain is one of the key non-motor symptoms experienced by a large proportion of people living with Parkinson's disease (PD), yet the mechanisms behind this pain remain elusive and as such its treatment remains suboptimal. It is hoped that through the study of animal models of PD, we can start to unravel some of the contributory mechanisms, and perhaps identify models that prove useful as test beds for assessing the efficacy of potential new analgesics. However, just how far along this journey are we right now? Is it even possible to model pain in PD in animal models of the disease? And have we gathered any insight into pain mechanisms from the use of animal models of PD so far? In this chapter we intend to address these questions and in particular highlight the findings generated by others, and our own group, following studies in a range of rodent models of PD., (Copyright © 2024. Published by Elsevier Inc.)

Dopamine (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., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

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.

The debilitating effects of Parkinson's disease (PD) progress over time and are pathophysiologically characterized by the formation of Lewy bodies due to the accumulation of α-synuclein aggregates resulting in the death of dopaminergic neurons. In the present study, we determined cell death pathways activated by acute exposure to 6-hydroxydopamine (6-OHDA) in differentiated LUHMES cells empirically followed by a 24 h toxin free interval, henceforth termed as washout/recovery period. Acute 6-OHDA exposure led to morphological changes in LUHMES cells and resulted in significant loss of neurite length and neurite thickness. Generation of reactive oxygen species and loss of mitochondrial membrane potential in the neuronal processes were persistent even after the recovery period. Our results show that 6-OHDA exposure leads to significant reduction in expression of mitochondrial OXPHOS complexes I, II, and IV and activation of caspase mediated apoptotic cell death cascade as observed by enhanced protein expression of cleaved-PARP-1 and cleaved-Caspase-3. Immunofluorescence microscopy approach confirmed that cell death occurs independent of the AIF translocation to the nucleus. Our experimental model, led to a ∼5-fold lower α-synuclein monomer expression and, interestingly, resulted in loss of protein ubiquitination in whole cell lysates. Altogether, this work provides evidence of multiple pathways targeted by 6-OHDA in differentiated LUHMES cells and expands research avenues for addressing the knowledge gap regarding the effect of 6-OHDA in the ubiquitin proteasome system for PD therapies., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is characterized by both motor and non-motor symptoms, including hypokinesia, postural instability, dopaminergic (DA) neurons loss, and α-synuclein (α-syn) accumulation. A growing number of patients show negative responses towards the current therapies. Thus, preventative or disease-modifying treatment agents are worth to further research. In recent years, compounds extracted from natural sources become promising candidates to treat PD. Chlorogenic acid (CGA) is a phenolic compound appearing in coffee, honeysuckle, and eucommia that showed their potential as antioxidants and neuroprotectors. In this study, we investigated the anti-PD activity of CGA by testing its effect on 1-methyl-4-phenyl-1-1,2,3,6-tetrahydropyridine (MPTP) zebrafish model of PD. It was shown that CGA relieved MPTP-induced PD-like symptoms including DA neurons and blood vessel loss, locomotion reduction, and apoptosis events in brain. Moreover, CGA modulated the expression of PD- and autophagy-related genes (α-syn, lc3b, p62, atg5, atg7, and ulk1b), showing its ability to promote the autophagy which was interrupted in the PD pathology. The unblocked effect of CGA on autophagy was further verified in 6-hydroxydopamine (6-OHDA)-modeled SHSY5Y cells. Our findings indicated that CGA might relieve PD by boosting the autophagy in neuronal cells that makes CGA a potential candidate for anti-PD treatment., 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 © 2023 Elsevier B.V. All rights reserved.)

Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson's disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson's disease by inhibiting microglia-mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine-induced rat model of Parkinson's disease. We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1β and interleukin-18 secretion, prevented the adoption of pyroptosis-associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson's disease, and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation., Competing Interests: None

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been a highly effective treatment option for mid-to-late-stage Parkinson's disease (PD) for decades. Besides direct effects on brain networks, neuroprotective effects of STN-DBS - potentially via alterations of growth factor expression levels - have been proposed as additional mechanisms of action., Objective: In the context of clarifying DBS mechanisms, we analyzed brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) levels in the basal ganglia, motor and parietal cortices, and dentate gyrus in an animal model of stable, severe dopaminergic deficiency., Methods: We applied one week of continuous unilateral STN-DBS in a group of stable 6-hydroxydopamine (6-OHDA) hemiparkinsonian rats (6-OHDA STIM ) in comparison to a 6-OHDA control group (6-OHDA SHAM ) as well as healthy controls (CTRL STIM and CTRL SHAM ). BDNF and GDNF levels were determined via ELISAs., Results: The 6-OHDA lesion did not result in a persistent alteration in either BDNF or GDNF levels in a model of severe dopaminergic deficiency after completion of the dopaminergic degeneration. STN-DBS modestly increased BDNF levels in the entopeduncular nucleus, but even impaired BDNF and GDNF expression in cortical areas., Conclusions: STN-DBS does not increase growth factor expression when applied to a model of completed, severe dopaminergic deficiency in contrast to other studies in models of modest and ongoing dopaminergic degeneration. In healthy controls, STN-DBS does not influence BDNF or GDNF expression. We consider these findings relevant for clinical purposes since DBS in PD is usually applied late in the course of the disease., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

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 Ca 2+ 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.

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., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

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., Competing Interests: Disclosure statement The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: None

Parkinson's disease (PD) is a progressive and debilitating neurodegenerative disorder associated with motor and non-motor complaints. Dysregulation of neurotrophic factors and related signaling cascades have been reported to be common events in PD which is accompanied by dopaminergic (DA) neuron demise. However, the restoration of neurotrophic factors has several limitations. Bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylenediamide (BHME) is a dipeptide mimetic of brain-derived neurotrophic factor (BDNF) with reported anti-oxidant and neuroprotective effects in several experimental models. The current study has investigated the effect of BHME on 6-hydroxydopamine (6-OHDA)-caused motor anomalies in Wistar rats. In this regard, rats were treated daily with BHME (0.1 or 1 mg/kg) 1 h after 6-OHDA-caused damage until the twelfth day. Afterwards, motor behavior and DA neuron survival were evaluated via behavioral tests and immunohistochemistry (IHC) staining, respectively. Moreover, the activity of Akt, mitogen-activated protein kinases (MAPKs) family, and Bax/Bcl-2 ratio were evaluated by Western blotting. Our results indicated that BHME prevents motor dysfunction and DA cell death following 6-OHDA injection, and this improvement was in parallel with an enhancement in Akt activity, decrement of P38 phosphorylation, along with a reduction in Bax/Bcl-2 ratio. In conclusion, our findings indicated that BHME, as a mimetic of BDNF, can be considered for further research and is a promising therapeutic agent for PD therapy., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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 (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., (© 2023 John Wiley & Sons Ltd.)

Introduction: Parkinson's disease (PD) is a progressive neuronal illness often linked to increased cardiovascular complications, such as myocardial infarction, cardiomyopathy, congestive heart failure, and coronary heart disease. Platelets, which are the essential components of circulating blood, are considered potential players in regulating these complications, as platelet dysfunction is evident in PD. These tiny blood cell fragments are supposed to play a crucial role in these complications, but the underlying molecular processes are still obscure., Methods: To gain a better understanding of platelet dysfunction in PD, we investigated the impact of 6-hydroxydopamine (6-OHDA), an analog of dopamine that simulates PD by destroying dopaminergic neurons, on human blood platelets. The levels of intraplatelet reactive oxygen species (ROS) were assessed using H 2 DCF-DA (20 μM), while mitochondrial ROS was evaluated using MitoSOX™ Red (5 μM), and intracellular Ca 2+ was measured with Fluo-4-AM (5 μM). The data were acquired through the use of both a multimode plate reader and a laser-scanning confocal microscope., Results: Our findings showed that 6-OHDA treatment increased the production of ROS in human blood platelets. The increase in ROS was confirmed by the ROS scavenger, NAC, and was also reduced by inhibiting the NOX enzyme with apocynin. Additionally, 6-OHDA potentiated mitochondrial ROS production in platelets. Furthermore, 6-OHDA triggered the intraplatelet Ca 2+ elevation. This effect was mitigated by the Ca 2+ chelator BAPTA, which decreased the ROS production triggered by 6-OHDA in human blood platelets, while the IP 3 receptor blocker, 2-APB, reduced the formation of ROS induced by 6-OHDA., Conclusion: Our findings suggest that the 6-OHDA-induced ROS production is regulated by the IP 3 receptor-Ca 2+ -NOX signaling axis in human blood platelets, where the platelet mitochondria also play a significant role. This observation provides a crucial mechanistic understanding of the altered platelet activities that are commonly observed in PD patients., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interests, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Parkinson's Disease (PD) is a neurodegenerative disease with loss of dopaminergic neurons in the nigrostriatal pathway resulting in basal ganglia (BG) dysfunction. This is largely why much of the preclinical and clinical research has focused on pathophysiological changes in these brain areas in PD. The cerebellum is another motor area of the brain. Yet, if and how this brain area responds to PD therapy and contributes to maintaining motor function fidelity in the face of diminished BG function remains largely unanswered. Limited research suggests that dopaminergic signaling exists in the cerebellum with functional dopamine receptors, tyrosine hydroxylase (TH) and dopamine transporters (DATs); however, much of this information is largely derived from healthy animals and humans. Here, we identified the location and relative expression of dopamine 1 receptors (D1R) and dopamine 2 receptors (D2R) in the cerebellum of a hemi-parkinsonian male rat model of PD. D1R expression was higher in PD animals compared to sham animals in both hemispheres in the purkinje cell layer (PCL) and granule cell layer (GCL) of the cerebellar cortex. Interestingly, D2R expression was higher in PD animals than sham animals mostly in the posterior lobe of the PCL, but no discernible pattern of D2R expression was seen in the GCL between PD and sham animals. To our knowledge, we are the first to report these findings, which may lay the foundation for further interrogation of the role of the cerebellum in PD therapy and/or pathophysiology., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Curcumin is a natural compound with extensive pharmacological effects. This research is to verify the optimal dose and administration duration efficacy of curcumin in alleviating the movement symptoms of Parkinson's disease (PD)., Methods: Wistar rats were divided into six groups including control, model, levodopa treatment and low/middle/high (40/80/160 mg/kg/d) curcumin treatment groups. After stereotactic brain injection of 6-hydroxydopamine (6-OHDA), curcumin was given by intragastric administration for 2 weeks. To evaluate the drug effect, the rats received behavioral tests including apomorphine (APO)-induced rotation test, rotarod test and open field test. Then the rats were sacrificed and the brain slices including substantia nigra pars compacta (SNc) were used for immunofluorescence staining., Results: After 6-OHDA injection, the model group showed typical movement symptoms including the severe APO-induced rotation to the healthy side, decreased latency in the rotarod with constant or accelerative mode, and decreased total distance and average speed in the open field test. In the results of immunofluorescence staining, the 6-OHDA induced a severe damage of dopaminergic neurons in SNc. The 160 mg/kg/d treatment of curcumin to intervene for 2 weeks alleviated most of the behavioral disorders but the 40/80 mg/kg/d treatment showed limitations. Then, we compared the effect of 1 week intervention to the 2 weeks with 160 mg/kg/d treatment of curcumin to intervene and results indicated that the treatment of 2 weeks could better alleviate the symptoms., Conclusions: Curcumin alleviated 6-OHDA-induced movement symptoms in a PD rat model. Additionally, the effect of curcumin against PD indicated dose and duration dependent and the intervention of 160 mg/kg/d for 2 weeks showed optimally therapeutic effect., Competing Interests: 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., (© 2023 The Authors.)