Pathophysiology Of Parkinson's Disease Research Articles

Globus pallidus, but not entopeduncular nucleus, 6-OHDA-induced lesion attenuates L-Dopa-induced dyskinesia in the rat model of Parkinson's disease

Although extrastriatal dopaminergic (DAergic) systems are being recognized as contributors to Parkinson's disease (PD) pathophysiology, the role of extrastriatal DA depletion in L-Dopa-induced dyskinesia (LID) is still unknown. In view of the physiologic actions of DA on pallidal neuronal activity and the effects on motor behavior of local injection of DA drugs, the loss of the external (GPe, GP in rodents) and internal (GPi, entopeduncular nucleus (EP) in rodents) pallidal DAergic innervation might differentially contribute to LID. A role of pallidal serotonergic (SER) terminals in LID has been highlighted, however, the effect of DAergic innervation is unknown.We investigated the role of DAergic pallidal depletion on LID. Rats were distributed in groups which were concomitantly lesioned with 6-OHDA or vehicle (sham) in the GP, or EP, and in the medial forebrain bundle (MFB) as follows: a) MFB-sham+GP-sham, b) MFB-sham+GP-lesion, c) MFB-lesion+GP-sham, d) MFB-lesion+GP-lesion, e) MFB-sham+EP-sham, f) MFB-sham+EP-lesion, g) MFB-lesion+EP-sham, and h) MFB-lesion+EP-lesion. Four weeks later, animals were treated with L-Dopa (6 mg/kg) twice daily for 22 days.. Immunohistochemical studies were performed in order to investigate the changes in pallidal SER and serotonin transporter (SERT) levels.GP, but not EP, DAergic denervation attenuated LID in rats with a concomitant MFB lesion (p < 0.01). No differences were found in GP SERT expression between groups of animals developing or not LID.These results provide evidence of the relevance of GP DAergic innervation in LID. The conversion of levodopa to DA in GP serotonergic nerve fibers appears not to be the major mechanism underlying LID.

Levodopa partially rescues microglial numerical, morphological, and phagolysosomal alterations in a monkey model of Parkinson’s disease

Parkinson’s disease (PD) is the most common neurodegenerative motor disorder. The mechanisms underlying the onset and progression of Levodopa (L-Dopa)-induced dyskinesia (LID) during PD treatment remain elusive. Emerging evidence implicates functional modification of microglia in the development of LID. Thus, understanding the link between microglia and the development of LID may provide the knowledge required to preserve or promote beneficial microglial functions, even during a prolonged L-Dopa treatment. To provide novel insights into microglial functional alterations in PD pathophysiology, we characterized their density, morphology, ultrastructure, and degradation activity in the sensorimotor functional territory of the putamen, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cynomolgus monkeys. A subset of MPTP monkeys was treated orally with L-Dopa and developed LID similar to PD patients. Using a combination of light, confocal and transmission electron microscopy, our quantitative analyses revealed alterations of microglial density, morphology and phagolysosomal activity following MPTP intoxication that were partially normalized with L-Dopa treatment. In particular, microglial density, cell body and arborization areas were increased in the MPTP monkeys, whereas L-Dopa-treated MPTP animals presented a microglial phenotype similar to the control animals. At the ultrastructural level, microglia did not differ between groups in their markers of cellular stress or aging. Nevertheless, microglia from the MPTP monkeys displayed reduced numbers of endosomes, compared with control animals, that remained lower after L-Dopa treatment. Microglia from MPTP monkeys treated with L-Dopa also had increased numbers of primary lysosomes compared with non-treated MPTP animals, while secondary and tertiary lysosomes remained unchanged. Moreover, a decrease microglial immunoreactivity for CD68, considered a marker of phagocytosis and lysosomal activity, was measured in the MPTP monkeys treated with L-Dopa, compared with non-treated MPTP animals. Taken together, these findings revealed significant changes in microglia during PD pathophysiology that were partially rescued by L-Dopa treatment. Albeit, this L-Dopa treatment conferred phagolysosomal insufficiency on microglia in the dyskinetic Parkinsonian monkeys.

Ferroptosis and its potential role in the physiopathology of Parkinson's Disease.

Parkinson's Disease (PD) is a common and progressive neurodegenerative disorder characterised by motor impairments as well as non-motor symptoms. While dopamine-based therapies are effective in fighting the symptoms in the early stages of the disease, a lack of neuroprotective drugs means that the disease continues to progress. Along with the traditionally recognised pathological hallmarks of dopaminergic neuronal death and intracellular α-synuclein (α-syn) depositions, iron accumulation, elevated oxidative stress and lipid peroxidation damage are further conspicuous features of PD pathophysiology. However, the underlying mechanisms linking these pathological hallmarks with neurodegeneration still remain unclear. Ferroptosis, a regulated iron dependent cell death pathway involving a lethal accumulation of lipid peroxides, shares several features with PD pathophysiology. Interestingly, α-syn has been functionally linked with the metabolism of both iron and lipid, suggesting a possible interplay between dysregulated α-syn and other PD pathological hallmarks related to ferroptosis. This review will address the importance for understanding these disease mechanisms that could be targeted therapeutically. Anti-ferroptosis molecules are neuroprotective in PD animal models and the anti-ferroptotic iron chelator, deferiprone, slowed disease progression and improved motor function in two independent clinical trials for PD. An ongoing larger multi-centre phase 2 clinical trial will confirm the therapeutic potential of deferiprone and the relevance of ferroptosis in PD. This review addresses the known pathological features of PD in relation to the ferroptosis pathway with therapeutic implications of targeting this cell death pathway.

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA.

Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson's disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes is unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.

Lysosomal Storage Disorders Shed Light on Lysosomal Dysfunction in Parkinson's Disease.

The lysosome is a central player in the cell, acting as a clearing house for macromolecular degradation, but also plays a critical role in a variety of additional metabolic and regulatory processes. The lysosome has recently attracted the attention of neurobiologists and neurologists since a number of neurological diseases involve a lysosomal component. Among these is Parkinson’s disease (PD). While heterozygous and homozygous mutations in GBA1 are the highest genetic risk factor for PD, studies performed over the past decade have suggested that lysosomal loss of function is likely involved in PD pathology, since a significant percent of PD patients have a mutation in one or more genes that cause a lysosomal storage disease (LSD). Although the mechanistic connection between the lysosome and PD remains somewhat enigmatic, significant evidence is accumulating that lysosomal dysfunction plays a central role in PD pathophysiology. Thus, lysosomal dysfunction, resulting from mutations in lysosomal genes, may enhance the accumulation of α-synuclein in the brain, which may result in the earlier development of PD.

Purine molecules in Parkinson's disease: Analytical techniques and clinical implications

Parkinson's disease (PD) is a neurodegenerative disorder that primarily affects patients over the age of 65. PD is characterized by loss of neurons in the substantia nigra and dopamine deficiency in the striatum. Once PD is clinically diagnosed by the observation of motor dysfunction, the disease is already in its advance stages. Consequently, there is a major push to identify clinical biomarkers that are useful for the earlier detection of PD. Using untargeted metabolomics, several research groups have identified purine molecules, and specifically urate, as important biomarkers related to PD. This review will summarize recent findings in the field of purine metabolomics and biomarker identification for PD, including in the areas of PD pathophysiology, diagnosis, prognosis and treatment. In addition, this article will summarize and examine the primary research techniques that are employed to quantify purine molecules in both experimental systems and human subjects.

Antidiabetic Agents for Treatment of Parkinson's Disease: A Meta-Analysis.

Background: Clinical and epidemiological studies suggest that two of the most common geriatric diseases, type 2 diabetes and Parkinson’s disease (PD), are linked. These studies notably suggest that treatment of insulin resistance in type 2 diabetes may beneficially modify the pathophysiology of PD and help to maintain motor and nonmotor function. In this meta-analysis, we evaluate the efficacy of new antidiabetic agents in the treatment of PD. Methods: We systematically searched PubMed, Medline, ProQuest, ScienceDirect, ClinicalKey, and Cochrane Library from the date of their inception until 15 March 2020. Multiple efficacy parameters were compared between treatment groups. The results are expressed as mean differences with 95% confidence intervals (CIs) in a random-effects model. Results: A meta-analysis of the data extracted from three randomized control trials revealed that treatment with exenatide yielded significant improvements in scores on the Unified Parkinson’s Disease Rating Scale Part I (UPDRS-I) (−0.438, 95% CI, −0.828 to −0.048, p = 0.028), UPDRS Part IV (UPDRS-IV) (−0.421, 95% CI, −0.811 to −0.032, p = 0.034) and the Mattis Dementia Rating Scale (MDRS) (−0.595, 95% CI, −1.038 to −0.151, p = 0.009). At the 12-month follow-up, the UPDRS Part III (UPDRS-III) scores in the off-medication phase revealed significant improvements in patients using exenatide (−0.729; 95% CI, −1.233 to −0.225, p = 0.005). Treatment with pioglitazone did not yield significant improvements in UPDRS, MDRS, or Parkinson’s Disease Questionnaire scores. Conclusion: This meta-analysis suggests that exenatide use is associated with the alleviation of cognitive, motor and nonmotor symptoms. However, long-term studies with a large sample size of patients with PD of varying severity are required.

Inhibition of NADPH oxidase within midbrain periaqueductal gray decreases pain sensitivity in Parkinson's disease via GABAergic signaling pathway.

Hypersensitive pain response is observed in patients with Parkinson's disease (PD). However, the signal pathways leading to hyperalgesia still need to be clarified. Chronic oxidative stress is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role NADPH oxidase (NOX) of the PAG in regulating exaggerated pain evoked by PD. PD was induced by central microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle of rats. Then, Western Blot analysis and ELISA were used to determine NOXs and products of oxidative stress (i.e., 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine). Pain responses to mechanical and thermal stimulation were further examined in control rats and PD rats. In results, among the NOXs, protein expression of NOX4 in the PAG of PD rats was significantly upregulated, thereby the products of oxidative stress were increased. Blocking NOX4 pathway in the PAG attenuated mechanical and thermal pain responses in PD rats and this was accompanied with decreasing production of oxidative stress. In addition, inhibition of NOX4 largely restored the impaired GABA within the PAG. Stimulation of GABA receptors in the PAG of PD rats also blunted pain responses. In conclusions, NOX4 activation of oxidative stress in the PAG of PD rats is likely to impair the descending inhibitory GABAergic pathways in regulating pain transmission and thereby plays a role in the development of pain hypersensitivity in PD. Inhibition of NOX4 has beneficial effects on the exaggerated pain evoked by PD.

Interactions Between the Serotonergic and Other Neurotransmitter Systems in the Basal Ganglia: Role in Parkinson's Disease and Adverse Effects of L-DOPA.

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. However, other non-dopaminergic neuronal systems such as the serotonergic system are also involved. Serotonergic dysfunction is associated with non-motor symptoms and complications, including anxiety, depression, dementia, and sleep disturbances. This pathology reduces patient quality of life. Interaction between the serotonergic and other neurotransmitters systems such as dopamine, noradrenaline, glutamate, and GABA controls the activity of striatal neurons and are particularly interesting for understanding the pathophysiology of PD. Moreover, serotonergic dysfunction also causes motor symptoms. Interestingly, serotonergic neurons play an important role in the effects of L-DOPA in advanced PD stages. Serotonergic terminals can convert L-DOPA to dopamine, which mediates dopamine release as a “false” transmitter. The lack of any autoregulatory feedback control in serotonergic neurons to regulate L-DOPA-derived dopamine release contributes to the appearance of L-DOPA-induced dyskinesia (LID). This mechanism may also be involved in the development of graft-induced dyskinesias (GID), possibly due to the inclusion of serotonin neurons in the grafted tissue. Consistent with this, the administration of serotonergic agonists suppressed LID. In this review article, we summarize the interactions between the serotonergic and other systems. We also discuss the role of the serotonergic system in LID and if therapeutic approaches specifically targeting this system may constitute an effective strategy in PD.

A novel multi-marker discovery approach identifies new serum biomarkers for Parkinson's disease in older people: an EXosomes in PArkiNson Disease (EXPAND) ancillary study.

Dopaminergic nigrostriatal denervation and widespread intracellular α-synuclein accumulation are neuropathologic hallmarks of Parkinson's disease (PD). A constellation of peripheral processes, including metabolic and inflammatory changes, are thought to contribute to neurodegeneration. In the present study, we sought to obtain insight into the multifaceted pathophysiology of PD through the application of a multi-marker discovery approach. Fifty older adults aged 70+, 20 with PD and 30 age-matched controls were enrolled as part of the EXosomes in PArkiNson Disease (EXPAND) study. A panel of 68 circulating mediators of inflammation, neurogenesis and neural plasticity, and amino acid metabolism was assayed. Biomarker selection was accomplished through sequential and orthogonalized covariance selection (SO-CovSel), a multi-platform regression method developed to handle highly correlated variables organized in multi-block datasets. The SO-CovSel model with the best prediction ability using the smallest number of variables was built with seven biomolecules. The model allowed correct classification of 94.2 ± 3.1% participants with PD and 100% controls. The biomarker profile of older adults with PD was defined by higher circulating levels of interleukin (IL) 8, macrophage inflammatory protein (MIP)-1β, phosphoethanolamine, and proline, and by lower concentrations of citrulline, IL9, and MIP-1α. Our innovative approach allowed identifying and evaluating the classification performance of a set of potential biomarkers for PD in older adults. Future studies are warranted to establish whether these biomolecules could serve as biomarkers for PD as well as unveil new targets for interventions.

Tau accumulates in Crohn's disease gut.

A sizeable body of evidence has recently emerged to suggest that gastrointestinal (GI) inflammation might be involved in the development of Parkinson's disease (PD). There is now strong epidemiological and genetical evidence linking PD to inflammatory bowel diseases and we recently demonstrated that the neuronal protein alpha-synuclein, which is critically involved in PD pathophysiology, is upregulated in inflamed segments of Crohn's colon. The microtubule associated protein tau is another neuronal protein critically involved in neurodegenerative disorders but, in contrast to alpha-synuclein, no data are available about its expression and phosphorylation patterns in inflammatory bowel diseases. Here, we examined the expression levels of tau isoforms, their phosphorylation profile and truncation in colon biopsy specimens from 16 Crohn's disease (CD) and 6 ulcerative colitis (UC) patients and compared them to samples from 16 controls. Additional experiments were performed in full thickness segments of colon of five CD and five control subjects, in primary cultures of rat enteric neurons and in nuclear factor erythroid 2-related factor (Nrf2) knockout mice. Our results show the upregulation of two main human tau isoforms in the enteric nervous system (ENS) in CD but not in UC. This upregulation was not transcriptionally regulated but instead likely resulted from a decrease in protein clearance via an Nrf2 pathway. Our findings, which provide the first detailed characterization of tau in CD, suggest that the key proteins involved in neurodegenerative disorders such as alpha-synuclein and tau, might also play a role in CD.

Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits

Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the α-synuclein (α-syn)-preformed fibril (PFF) model, which better reflects the α-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a “two-hit” model to determine whether developmental dieldrin exposure increases susceptibility to α-syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3–4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal α-syn PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated PFF-induced motor deficits on the challenging beam and increased DA turnover in the striatum 6 months after PFF injection. However, male offspring showed neither exacerbation of phosphorylated α-syn aggregation (pSyn) in the substantia nigra (SN) at 1 or 2 months post-PFF injection, nor exacerbation of PFF-induced TH and NeuN loss in the SN 6 months post-PFF injection. Collectively, these data indicate that developmental dieldrin exposure produces a male-specific exacerbation of synucleinopathy-induced behavioral and biochemical deficits. This sex-specific result is consistent with both previous work in the MPTP model, our previously reported sex-specific effects of this exposure paradigm on the male and female epigenome, and the higher prevalence and more severe course of PD in males. The novel two-hit environmental toxicant/PFF exposure paradigm established in this project can be used to explore the mechanisms by which other PD-related exposures alter neuronal vulnerability to synucleinopathy in sporadic PD.

Iroquois Homeobox Protein 2 Identified as a Potential Biomarker for Parkinson's Disease.

The diagnosis of Parkinson’s disease (PD) is initiated after the occurrence of motor symptoms, such as resting tremors, rigidity, and bradykinesia. According to previous reports, non-motor symptoms, notably gastrointestinal dysfunction, could potentially be early biomarkers in PD patients as such symptoms occur earlier than motor symptoms. However, connecting PD to the intestine is methodologically challenging. Thus, we generated in vitro human intestinal organoids from PD patients and ex vivo mouse small intestinal organoids from aged transgenic mice. Both intestinal organoids (IOs) contained the human LRRK2 G2019S mutation, which is the most frequent genetic cause of familial and sporadic PD. By conducting comprehensive genomic comparisons with these two types of IOs, we determined that a particular gene, namely, Iroquois homeobox protein 2 (IRX2), showed PD-related expression patterns not only in human pluripotent stem cell (PSC)-derived neuroectodermal spheres but also in human PSC-derived neuronal cells containing dopaminergic neurons. We expected that our approach of using various cell types presented a novel technical method for studying the effects of multi-organs in PD pathophysiology as well as for the development of diagnostic markers for PD.

Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson's Disease: A New Therapeutic Strategy.

Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one of the most commonly studied EpFAs, with anti-inflammatory properties. Soluble epoxide hydrolase (sEH) is implicated in the hydrolysis of 14,15-EET to its corresponding diol, which lacks anti-inflammatory properties. Preventing EET degradation thus increases its concentration in the brain through sEH inhibition, which represents a novel pharmacological approach to foster the reduction of neuroinflammation and by end neurodegeneration. Recently, it has been shown that sEH levels increase in brains of PD patients. Moreover, the pharmacological inhibition of the hydrolase domain of the enzyme or the use of sEH knockout mice reduced the deleterious effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. This paper overviews the knowledge of sEH and EETs in PD and the importance of blocking its hydrolytic activity, degrading EETs in PD physiopathology. We focus on imperative neuroinflammation participation in the neurodegenerative process in PD and the putative therapeutic role for sEH inhibitors. In this review, we also describe highlights in the general knowledge of the role of sEH in the central nervous system (CNS) and its participation in neurodegeneration. We conclude that sEH is one of the most promising therapeutic strategies for PD and other neurodegenerative diseases with chronic inflammation process, providing new insights into the crucial role of sEH in PD pathophysiology as well as a singular opportunity for drug development.

Current treatment options for Parkinson’s disease and the existing status of nanotechnology

Parkinson's disease (PD) is a neurodegenerative disorder associated with dopaminergic neuron degeneration and/or loss of neuronal activity. Current idiopathic PD treatments focus primarily on the use of pharmacological agents to improve PD patients ' motor symptoms. PD remains to be an incurable disease so far. Therefore, the development of new therapeutic approaches for PD therapy is of utmost significance. Several molecular and gene therapy methods have been established over the past 20 years to counteract or retard the development of PD. Severe side effects are found in many native therapies. Therefore, novel therapeutic strategies remain in demand for development. Nanomedicine seems to be a significant medical application in nanotechnology that demonstrates promising future in drug delivery to the central nervous system. BBB stands throughout the central nervous system as a gateway to drug targeting. Drug delivery, based on nano-particles that always avoids Blood-Brain Barrier protection, Different potential therapies based on nanoparticles and nanosystems are explored various benefits. The scope of this review is to provide an overview of this field of PD-related therapies and significant breakthroughs. To do so, this review will begin by concentrating on PD characterization, pathophysiology, etiology and present therapy choices that subsequently cover molecular, gene therapy, and nanotechnology formulations that are currently being studied in animal PD models or lately tested in clinical trials.

Alterations of the Motor and Olfactory Functions Related to Parkinson's Disease in Transgenic Mice With a VMAT2-Deficiency in Dopaminergic Neurons.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, with approximately six million people affected worldwide. Vesicular monoamine transporter 2 (VMAT2) dysfunction has recently become a hot topic in the pathophysiology of PD, and the advent of transgenic mice has also accelerated the development of behavioral studies in animal models. However, there are only a few systematic behavioral tests that embrace abundant motor and non-motor performance in a unique mutant mouse model which correspond to the varied symptoms observed in human PD. The aim of this study is to evaluate the responsibility of the unique reduction of dopamine in the varied motor and non-motor symptoms of PD via a transgenic mice model. We analyzed neurotransmitter concentrations in the brain tissue of 18-month-old mutant mice, with selective inactivation of one allele of Vmat2 in dopaminergic neurons (VMAT2DATcre-HET) to confirm the selective reduction of dopamine, and then examined behavioral functions. Neurochemical tests showed lower dopamine concentrations in specific brain regions of VMAT2DATcre-HET mice, especially the ventral tegmental area/substantia nigra and striatum, together with relatively unchanging concentrations of norepinephrine and serotonin, demonstrating the dopaminergic specificity of this mouse model. Behavioral tasks showed impairments in several motor functions and major defects in olfactory abilities in the VMAT2DATcre-HET mice. However, no significant changes were found in the majority of non-motor tests, such as emotional performance and sleep patterns. We concluded from this study that the selective inactivation of one allele of the Vmat2 gene in dopaminergic neurons was related to dopamine reduction, resulting in phenotypes resembling some of the major deficits in PD, especially those of motor symptoms and olfactory functions.

Plant Polyphenols as Neuroprotective Agents in Parkinson's Disease Targeting Oxidative Stress.

Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the human midbrain. Various ongoing research studies are competing to understand the pathology of PD and elucidate the mechanisms underlying neurodegeneration. Current pharmacological treatments primarily focused on improving dopamine metabolism in PD patients, despite the side effects of long-term usage. In recent years, it is recognized that oxidative stress-mediated pathways lead to neurodegeneration in the brain, which is associated with the pathophysiology of PD. The importance of oxidative stress is often less emphasized when developing potential therapeutic approaches. Natural plant antioxidants have been shown to mediate the oxidative stress-induced effects in PD, which has gained considerable attention in both in vitro and in vivo studies. Yet, clinical trials on natural polyphenol compounds are limited, restricting the potential use of these compounds as an alternative treatment for PD. Therefore, this review provides an understanding of the oxidative stress-induced effects in PD by elucidating the underlying events contributing to oxidative stress and explore the potential use of polyphenols in improving the oxidative status in PD. Preclinical findings have supported the potential of polyphenols in providing neuroprotection against oxidative stress-induced toxicity in PD. However, limiting factors, such as safety and bioavailability of polyphenols, warrant further investigations so as to make them the potential target for clinical applications in the treatment and management of PD.

Identification of biomarkers for early diagnosis of Parkinson's disease by multi-omics joint analysis.

ObjectiveThe purpose of this study is to identify the biomarkers for early diagnosis of Parkinson's disease (PD) by multi-omics joint analysis, so as to identify the biomarkers for early diagnosis of PD, and to help clinicians make early diagnosis and treatment.MethodsIn this study, mice are taken as the study subjects. The model of PD mice is established, and then lymphocyte, striatum, substantia nigra protein and proteolysis are extracted. After that, the experiments of protein imprinting and 418O labeling are carried out. Mass Spectrometry (MS) analysis technology is mainly used to study proteomics and to analyze the quantitative and qualitative situation of differential proteins in striatum, substantia nigra protein and lymphocyte. By this method, biomarkers for early diagnosis of PD are analyzed and identified.ResultsThe biomarkers of Parkinson's early onset are related to the same quantitative differential expression of lymphocyte, striatum, substantia nigra protein, lymphocyte and substantia nigra.ConclusionThis experimental method can analyze and identify the biomarkers of early diagnosis of PD, help to explore the pathophysiology and pathogenesis of PD, effectively help clinicians make timely diagnosis in advance, and improve the prevention and treatment effect of the disease.

Activity of NADH‐ and FADH2‐linked mitochondrial respiration are significantly decreased in two mice models of Parkinson’s disease

Parkinson’s disease (PD) is a complex neurodegenerative disorder, which etiology is still largely unknown. Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in PD pathophysiology. Here we tested the hypothesis that the activity of complex I and II (NADH‐and FADH2‐linked mitochondrial respiration, respectively) in the substantia nigra are significantly decreased in PD. To test this hypothesis, we used two different mice models of PD: Mice that received a single unilateral intrastriatal injection of 1) 6‐OHDA (9μg ‐ a selective catecholaminergic neurotoxin), or 2) A53T‐α‐synuclein (5.62E12 GC/ml – a molecule that attenuates synaptic vesicle recycling and neurotransmitter release). Control groups were injected with vehicle (fluorescent protein). Mitochondrial oxygen consumption was evaluated by using our oxygraph‐2K system (O2k‐OROBOROS), in 2 mg weight of tissue permeabilized with saponin. Measurements were performed one week after treatment with 6‐OHDA, and five weeks after treatment with A53T‐α‐synuclein. Our preliminary results show that, compared to control animals, substrates of complex I (Pyruvate/Glutamate/Malate), in the presence of ADP (state 3 complex I), induced a reduced oxygen consumption in mice treated with 6‐OHDA,(50.65 ± 2 vs 78 ±3 pmol O2/s/mg tissue, p&lt;0.001). Inline, compared to control animals, oxygen consumption in state 3 complex I, was significantly reduced in mice treated with α‐synuclein (31.05 ± 5 vs 43.56 ± 2 pmol O2/s/mg tissue, p&lt;0.05). Moreover, oxygen consumption in the presence of substrates of the mitochondrial complex II (succinate – state 3‐complex II), was also significantly reduced after treatment with α‐synuclein (30.8 ± 4.5 vs 46.5 ± 5 pmol O2/s/mg tissue, p&lt;0.05). No differences of oxygen consumption were found in the presence of PMG, but the absence of ADP (state 4 – mitochondrial membrane leak) with none of the treatments. We concluded that 6‐OHDA and α‐synuclein, two reliable models of PD, induce mitochondrial dysfunction by decreasing the activity of mitochondrial complexes I and II. Our results contribute to a better understanding of the mitochondrial dysfunction induced by PD, and open the avenue for alternative treatments aiming to avoid the degeneration of dopaminergic neurons in the substantia nigra.Support or Funding InformationJorge Soliz is supported by the “Fonds de recherche du Quebec‐Santé” (FRQ‐S; FQ121919)

A Novel Multi‐marker Discovery Approach Identifies New Biomarkers for Parkinson’s Disease in Older People: an EXosomes in PArkiNson Disease (EXPAND) Ancillary Study

Dopaminergic nigrostriatal denervation and widespread intracellular α‐synuclein accumulation are neuropathologic hallmarks of Parkinson’s disease (PD). A constellation of peripheral processes, including metabolic and inflammatory changes, are thought to contribute to neurodegeneration. In the present study, we sought to obtain insight into the multifaceted pathophysiology of PD through the application of a multi‐marker discovery approach. Fifty older adults aged 70+, 20 with PD and 30 age‐matched controls were enrolled as part of the EXosomes in PArkiNson Disease (EXPAND) study. A panel of 68 circulating mediators of inflammation, neurogenesis and neural plasticity, and amino acid metabolism was assayed. Biomarker selection was accomplished through sequential and orthogonalized covariance selection (SO‐CovSel), a multi‐platform regression method developed to handle highly correlated variables organized in multi‐block datasets. The SO‐CovSel model with the best prediction ability using the smallest number of variables was built with seven biomolecules. The model allowed correct classification of 94.2 ± 3.1% participants with PD and 100% controls. The biomarker profile of older adults with PD was defined by higher circulating levels of interleukin (IL) 8, macrophage inflammatory protein (MIP)‐1β, phosphoethanolamine, and proline, and by lower concentrations of citrulline, IL9, and MIP‐1α. Our innovative approach allowed identifying and evaluating the classification performance of a set of potential biomarkers for PD in older adults. Future studies are warranted to establish whether these biomolecules could serve as valuable biomarkers for PD as well as unveil new targets for interventions.Support or Funding InformationInnovative Medicine Initiative‐Joint Undertaking (IMI‐JU #115621)