scholarly journals Crocetin Alleviates Inflammation in MPTP-Induced Parkinson’s Disease Models through Improving Mitochondrial Functions

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Na Dong ◽  
Zhong Dong ◽  
Ying Chen ◽  
Xiaosu Gu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Permeability Transition ◽  
Therapeutic Potential ◽  
Adenine Nucleotide ◽  
Motor Deficits ◽  
Dependent Manner ◽  
Cyclophilin D ◽  
Mitochondrial Functions

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Crocetin, derived from saffron, exerts multiple pharmacological properties, such as anti-inflammatory, antioxidant, antifatigue, and anticancer effects. However, the effect of crocetin on PD remains unclear. In this study, we designed experiments to investigate the effect of crocetin against MPTP-induced PD models and the underlying mechanisms. Our results showed that crocetin treatment attenuates MPTP-induced motor deficits and protects dopaminergic neurons. Both in vivo and in vitro experiments demonstrated that crocetin treatment decreased the expression of inflammatory associated genes and inflammatory cytokines. Furthermore, crocetin treatment protected mitochondrial functions against MPP+ induced damage by regulating the mPTP (mitochondrial permeability transition pore) viability in the interaction of ANT (adenine nucleotide translocase) and Cyp D (Cyclophilin D) dependent manner. Therefore, our results demonstrate that crocetin has therapeutic potential in Parkinson’s disease.

scholarly journals The Ameliorative Effects of the Ethyl Acetate Extract ofSalicornia europaeaL. and Its Bioactive Candidate, Irilin B, on LPS-Induced Microglial Inflammation and MPTP-Intoxicated PD-Like Mouse Model

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Joonsoo Kim ◽  
Govindarajan Karthivashan ◽  
Mee-Hyang Kweon ◽  
Deuk-Hoi Kim ◽  
Dong-Kug Choi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Potential ◽  
Motor Deficits ◽  
Resonance Spectroscopy ◽  
Potential Candidate ◽  
Nigrostriatal Pathway ◽  
Salicornia Europaea ◽  
Isolation And Purification

Hyperactivation of microglia, the resident innate immune cells of the central nervous system, exacerbates various neurodegenerative disorders, including Parkinson’s disease (PD). Parkinson’s disease is generally characterized by a severe loss of dopaminergic neurons in the nigrostriatal pathway, with substantial neuroinflammation and motor deficits. This was experimentally replicated in animal models, using neurotoxins, i.e., LPS (lipopolysaccharides) and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).Salicornia europaeaL. (SE) has been used as a dietary supplement in Korea and Europe for several years, due to its nutritional and therapeutic value. In this study, we intend to investigate the antineuroinflammatory and anti-PD-like effects of the bioactive fraction/candidate of the SE extract. Initially, we screened various fractions of SE extract using anin vitroantioxidant assay. The optimal fraction was investigated for itsin vitroantineuroinflammatory potential in LPS-stimulated BV-2 microglial cells andin vivoanti-PD-like potential in MPTP-intoxicated mice. Subsequently, to identify the potential candidate responsible for the elite therapeutic potential of the optimal fraction, we conducted antioxidant activity-guided isolation and purification; the bioactive candidate was structurally characterized using nuclear magnetic resonance spectroscopy and chromatographic techniques and further investigated for itsin vitroantioxidative and antineuroinflammatory potential. The results of our study indicate that SE-EA and its bioactive candidate, Irilin B, effectively alleviate the deleterious effect of microglia-mediated neuroinflammation and promote antioxidative effects. Thus, they exhibit potential as therapeutic candidates against neuroinflammatory and oxidative stress-mediated PD-like neurodegenerative complications.

scholarly journals Targeting Histone Deacetylases: A Novel Approach in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Sorabh Sharma ◽  
Rajeev Taliyan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Clinical Manifestations ◽  
Future Research

The worldwide prevalence of movement disorders is increasing day by day. Parkinson’s disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in bothin vivoandin vitromodels of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.

scholarly journals special feature: from in vitro curiosity to contributor to cell pathology

2006 ◽  
Vol 28 (4) ◽  
pp. 33-36
Author(s):  
Meredith F. Ross ◽  
Michael P. Murphy
Keyword(s):  
Mitochondrial Function ◽  
Matrix Protein ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Ischaemia Reperfusion Injury ◽  
Mitochondrial Inner Membrane ◽  
Biochemical Journal

The MPT (mitochondrial permeability transition) occurs when a protein pore opens in the mitochondrial inner membrane in response to calcium overloading, adenine nucleotide depletion and oxidative stress, causing the disruption of mitochondrial function. For a number of years, this intriguing phenomenon was thought to be an in vitro curiosity of uncertain relevance to mitochondrial function within cells and tissues. However, this view was fundamentally altered with the help of three papers published in the Biochemical Journal in the 1980s and 1990s. Together, these studies demonstrated that CsA (cyclosporin A) selectively blocked induction of the MPT, that the mitochondrial matrix protein cyclophilin D was required for induction of the MPT, and that the MPT contributed to tissue damage during IR (ischaemia–reperfusion) injury.

Arylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2845-2859 ◽  
Author(s):  
Jun Sung Lee ◽  
Kazuaki Kanai ◽  
Mari Suzuki ◽  
Woojin S Kim ◽  
Han Soo Yoo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Modifier ◽  
Ectopic Expression ◽  
Physical Interaction ◽  
Dependent Manner ◽  
Arylsulfatase A ◽  
Lysosomal Storage ◽  
Protein Levels

AbstractMutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson’s disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson’s disease. Plasma ARSA protein levels were changed in Parkinson’s disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson’s disease pathogenesis, acting as a molecular chaperone for α-synuclein.

The Deficiency of Maged1 Attenuates Parkinson's Disease Progression by Inhibiting Apoptosis and Enhancing Autophagy in Mice

2020 ◽  
Author(s):  
Jie Wang ◽  
Wei-Yan You ◽  
Qing Ye ◽  
Jia-Qi Zhang ◽  
Chuan He ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Signaling Pathway ◽  
Knockout Mice ◽  
Gene Transfection ◽  
Motor Deficits ◽  
Mice Model

Abstract Background: Melanoma-associated antigen D1 (Maged1) is expressed in most adult tissues, predominantly in the brain, and has critical functions in the central nervous system in both developmental and adult stages. Loss of Maged1 in mice has been linked to depression, cognitive disorder, circadian rhythm, and drug addiction. However, the role of Maged1 in Parkinson’s disease (PD) remains unclear.Methods: Immunostaining was performed to investigate the expression of Maged1 in the samples from mice and human. To make the acute mice model of PD, C57BL/6 mice and Maged1 knockout mice were injected with 20 mg/kg 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) four times, every 2-hour intervals. SY5Y cells were treated by 200 μM 1-Methyl-4-phenylpyridinium iodide (MPP+). To examine motor balance and coordination, the rotarod test and pole test were used. Then we further investigated the role of Maged1 deficiency in DA neurons by high-performance liquid chromatography, immunohistochemistry, western blot, CCK8 assay, and gene transfection in vivo or in vitro.Results: Maged1 was expressed in DA neurons of samples from mice and human. And the expression of Maged1 was time-dependently upregulated by the treatment with MPTP or MPP+ in vivo or in vitro. Knockout of Maged1 in mice partly rescued the motor deficits and the reduced levels of striatal dopamine and its metabolites by MPTP treatment. Moreover, Maged1 deficiency protected primary DA neurons and differentiated ReNcell VM cells from MPP+ toxicity. Furthermore, along with the overexpression or downregulation of Maged1 in cultured SH-SY5Y cells, the reduced the cell viability by MPP+ treatment was relatively aggerated or attenuated. The effect of Maged1 deficiency may be attributed to the upregulated Akt signaling pathway and the downregulated mTOR signaling pathway, which further attenuated the MPTP or MPP+ -induced cell apoptosis and impairment of autophagy. Consistent with the above data, the degeneration of midbrain and striatum among 15-m Maged1 knockout mice was relatively mild compared to those in 15-m wild-type mice under physiological conditions.Conclusions: Maged1 deficiency-mediated apoptosis inhibition and autophagy enhancement may be a potential pro-survival mechanism during the progression of PD.

scholarly journals Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

2017 ◽  
Vol 114 (15) ◽  
pp. 3999-4004 ◽  
Author(s):  
Athanasios D. Spathis ◽  
Xenophon Asvos ◽  
Despina Ziavra ◽  
Theodoros Karampelas ◽  
Stavros Topouzis ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Induced Pluripotent Stem Cell ◽  
Symptomatic Improvement ◽  
Acid Decarboxylase ◽  
Dependent Manner ◽  
Amino Acid Decarboxylase

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.

scholarly journals Parkinson’s disease recovery by GM1 oligosaccharide treatment in the B4galnt1+/− mouse model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Elena Chiricozzi ◽  
Laura Mauri ◽  
Giulia Lunghi ◽  
Erika Di Biase ◽  
Maria Fazzari ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Potential ◽  
Physical Symptoms ◽  
Wild Type ◽  
Ganglioside Content ◽  
Sporadic Parkinson’S Disease ◽  
Specific Membrane ◽  
The Brain

AbstractGiven the recent in vitro discovery that the free soluble oligosaccharide of GM1 is the bioactive portion of GM1 for neurotrophic functions, we investigated its therapeutic potential in the B4galnt1+/− mice, a model of sporadic Parkinson’s disease. We found that the GM1 oligosaccharide, systemically administered, reaches the brain and completely rescues the physical symptoms, reduces the abnormal nigral α-synuclein content, restores nigral tyrosine hydroxylase expression and striatal neurotransmitter levels, overlapping the wild-type condition. Thus, this study supports the idea that the Parkinson’s phenotype expressed by the B4galnt1+/− mice is due to a reduced level of neuronal ganglioside content and lack of interactions between the oligosaccharide portion of GM1 with specific membrane proteins. It also points to the therapeutic potential of the GM1 oligosaccharide for treatment of sporadic Parkinson’s disease.

scholarly journals CRISPR/Cas9-mediated gene editing induces neurological recovery in an A53T-SNCA overexpression rat model of Parkinson’s disease

2020 ◽  
Author(s):  
Hyung Ho Yoon ◽  
Sunghyeok Ye ◽  
Sunhwa Lim ◽  
Seung Eun Lee ◽  
Soo-Jin Oh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Therapeutic Potential ◽  
Negative Control ◽  
Adeno Associated Virus ◽  
Guide Rna ◽  
Dopaminergic Neurodegeneration

AbstractTo date, no publicly available disease-modifying therapy for Parkinson’s disease has been developed. This can be partly attributed to the absence of techniques for in vivo deletion of the SNCA gene (encoding α-synuclein), which is one of the key players in Parkinson’s disease pathology. In particular, A53T-mutated SNCA (A53T-SNCA) is one of the most studied familial pathologic mutations in Parkinson’s disease. Here we utilized a recently discovered genome editing technique, CRISPR/Cas9, to delete A53T-SNCA in vitro and in vivo. Among various CRISPR/Cas9 systems, SaCas9-KKH with a single guide RNA (sgRNA) targeting A53T-SNCA was packaged into adeno-associated virus. Adeno-associated virus carrying SaCas9-KKH significantly reduced A53T-SNCA levels in A53T-SNCA-overexpressed HEK293T cells, without off-target effects on wild-type SNCA. Furthermore, we tested the technique’s in vivo therapeutic potential in a viral A53T-SNCA overexpression rat model of Parkinson’s disease. Gene deletion of A53T-SNCA significantly prevented the overexpression of α-synuclein, dopaminergic neurodegeneration, and parkinsonian motor symptoms, whereas a negative control without sgRNA did not. Our findings propose CRISPR/Cas9 system as a potential therapeutic tool for A53T-SNCA familial Parkinson’s disease.

scholarly journals Gateways for Glutamate Neuroprotection in Parkinson’s Disease (PD): Essential Role of EAAT3 and NCX1 Revealed in an In Vitro Model of PD

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2037
Author(s):  
Silvia Piccirillo ◽  
Simona Magi ◽  
Alessandra Preziuso ◽  
Pasqualina Castaldo ◽  
Salvatore Amoroso ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ischemia Reperfusion Injury ◽  
Excitatory Amino Acid ◽  
Cell Damage ◽  
Glutamate Uptake ◽  
Ischemia Reperfusion ◽  
Amino Acid Transporters ◽  
Mitochondrial Functions

Increasing evidence suggests that metabolic alterations may be etiologically linked to neurodegenerative disorders such as Parkinson’s disease (PD) and in particular empathizes the possibility of targeting mitochondrial dysfunctions to improve PD progression. Under different pathological conditions (i.e., cardiac and neuronal ischemia/reperfusion injury), we showed that supplementation of energetic substrates like glutamate exerts a protective role by preserving mitochondrial functions and enhancing ATP synthesis through a mechanism involving the Na+-dependent excitatory amino acid transporters (EAATs) and the Na+/Ca2+ exchanger (NCX). In this study, we investigated whether a similar approach aimed at promoting glutamate metabolism would be also beneficial against cell damage in an in vitro PD-like model. In retinoic acid (RA)-differentiated SH-SY5Y cells challenged with α-synuclein (α-syn) plus rotenone (Rot), glutamate significantly improved cell viability by increasing ATP levels, reducing oxidative damage and cytosolic and mitochondrial Ca2+ overload. Glutamate benefits were strikingly lost when either EAAT3 or NCX1 expression was knocked down by RNA silencing. Overall, our results open the possibility of targeting EAAT3/NCX1 functions to limit PD pathology by simultaneously favoring glutamate uptake and metabolic use in dopaminergic neurons.

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