Parkinson’s Treatment Report

www.ParkinsonsTreatmentReport.com

Research

Asparagine endopeptidase inhibitor protects against fenpropathrin-induced neurodegeneration via suppressing α-synuclein aggregation and neuroinflammation

https://www.sciencedirect.com/science/article/abs/pii/S0014299920306786?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32971086?dopt=Abstract

TITLE:
Asparagine endopeptidase inhibitor protects against fenpropathrin-induced neurodegeneration via suppressing α-synuclein aggregation and neuroinflammation.

DESCRIPTION:
Asparagine endopeptidase inhibitor protects against fenpropathrin-induced neurodegeneration via suppressing α-synuclein aggregation and neuroinflammation.

Eur J Pharmacol. 2020 Sep 21;:173586

Authors: Yu T, Wan F, Liu C, Zhang X, Liu Z, Zhang J, Xiong J, Wang T, Zhang Z

Abstract

Exposure to fenpropathrin (Fen), one of the most widely used pyrethroid pesticides, has been reported to increase the incidence of Parkinson’s disease (PD). However, the molecular mechanisms underlying Fen-induced Parkinsonism remain unknown. Here we investigated the role of the lysosomal protease asparagine endopeptidase (AEP) in Fen-induced neurodegeneration and tested the protective effect of an AEP inhibitor Compound #11 (CP11). Fen induced AEP activation, α-synuclein aggregation, and dopaminergic neuronal degeneration both in vitro and in vivo. CP11 alleviated Fen-induced cell injury in cultured SH-SY5Y cells and A53T α-synuclein transgenic mice. CP11 protected SH-SY5Y cells against Fen-induced toxicity and decreased α-synuclein aggregation in HEK293 cells stably transfected with α-synuclein. In Fen-treated mice, CP11 attenuated the degeneration of dopaminergic neurons and reduced neuroinflammation. Our findings demonstrate that neurodegeneration in Fen-treated models might be attributed to the activation of AEP. AEP might be a novel therapeutic target in PD induced by Fen and other environmental factors.

PMID: 32971086 [PubMed – as supplied by publisher]

PMID:
PubMed:32971086

DATE FOUND:
09/25/20 06:01AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/32971086?dopt=Abstract

Gene Therapy in the Management of Parkinson’s Disease: Potential of GDNF as a Promising Therapeutic Strategy

https://www.eurekaselect.com/184936/article

https://www.ncbi.nlm.nih.gov/pubmed/32811394?dopt=Abstract

TITLE:
Gene Therapy in the Management of Parkinson’s Disease: Potential of GDNF as a Promising Therapeutic Strategy.

DESCRIPTION:
Related Articles

Gene Therapy in the Management of Parkinson’s Disease: Potential of GDNF as a Promising Therapeutic Strategy.

Curr Gene Ther. 2020 Aug 17;:

Authors: Behl T, Kaur I, Kumar A, Mehta V, Zengin G, Arora S

Abstract

The limitations of conventional treatment therapies in Parkinson’s disorder, a common neurodegenerative disorder, lead to the development of an alternative gene therapy approach. Multiple treatment options targeting dopaminergic neuronal regeneration, production of enzymes linked with dopamine synthesis, subthalamic nucleus neurons, regulation of astrocytes and microglial cells and potentiating neurotrophic factors, were established. Viral vector-based dopamine delivery, prodrug approaches, fetal ventral mesencephalon tissue transplantation and dopamine synthesizing enzyme encoding gene delivery are significant therapies evidently supported by numerous trials. The review primarily elaborates the significant role of glial cell-line derived neurotrophic factor in alleviating motor symptoms and loss of dopaminergic neurons in Parkinson’s disease. Neuroprotective and neuroregenerative effects of GDNF were established via preclinical and clinical study outcomes. The binding of GDNF family ligands with associated receptors lead to the formation of a receptor-ligand complex activating Ret receptor of tyrosine kinase family, which is only expressed in dopaminergic neurons, playing an important role in Parkinson’s disease, via its association with essential protein encoded genes. Furthermore, the review establishes delivery aspects, like ventricular delivery of recombinant GDNF, intraparenchymal and intraputaminal delivery using infusion catheters. The review highlights problems and challenges of GDNF delivery, and essential measures to overcome them, like gene therapy combinations, optimization of delivery vectors, newer targeting devices, motor symptoms curbing focused ultrasound techniques, modifications in patient selection criteria and development of novel delivery strategies based on liposomes and encapsulated cells, to promote safe and effective delivery of neurotrophic factor and establishment of a routine treatment therapy for patients.

PMID: 32811394 [PubMed – as supplied by publisher]

PMID:
PubMed:32811394

DATE FOUND:
08/20/20 06:03AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/32811394?dopt=Abstract

Recent developments in the treatment of Parkinson’s Disease

https://f1000research.com/articles/9-862/v1

https://www.ncbi.nlm.nih.gov/pubmed/32789002?dopt=Abstract

TITLE:
Recent developments in the treatment of Parkinson’s Disease.

DESCRIPTION:
Recent developments in the treatment of Parkinson’s Disease.

F1000Res. 2020;9:

Authors: Stoker TB, Barker RA

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disease typified by a movement disorder consisting of bradykinesia, rest tremor, rigidity, and postural instability. Treatment options for PD are limited, with most of the current approaches based on restoration of dopaminergic tone in the striatum. However, these do not alter disease course and do not treat the non-dopamine-dependent features of PD such as freezing of gait, cognitive impairment, and other non-motor features of the disorder, which often have the greatest impact on quality of life. As understanding of PD pathogenesis grows, novel therapeutic avenues are emerging. These include treatments that aim to control the symptoms of PD without the problematic side effects seen with currently available treatments and those that are aimed towards slowing pathology, reducing neuronal loss, and attenuating disease course. In this latter regard, there has been much interest in drug repurposing (the use of established drugs for a new indication), with many drugs being reported to affect PD-relevant intracellular processes. This approach offers an expedited route to the clinic, given that pharmacokinetic and safety data are potentially already available. In terms of better symptomatic therapies that are also regenerative, gene therapies and cell-based treatments are beginning to enter clinical trials, and developments in other neurosurgical strategies such as more nuanced deep brain stimulation approaches mean that the landscape of PD treatment is likely to evolve considerably over the coming years. In this review, we provide an overview of the novel therapeutic approaches that are close to, or are already in, clinical trials.

PMID: 32789002 [PubMed – as supplied by publisher]

PMID:
PubMed:32789002

DATE FOUND:
08/14/20 06:03AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/32789002?dopt=Abstract

Neuroprotective and neurogenic effects of novel tetramethylpyrazine derivative T-006 in Parkinson’s disease models through activating the MEF2-PGC1α and BDNF/CREB pathways

https://www.aging-us.com/article/103551

https://www.ncbi.nlm.nih.gov/pubmed/32710729?dopt=Abstract

TITLE:
Neuroprotective and neurogenic effects of novel tetramethylpyrazine derivative T-006 in Parkinson’s disease models through activating the MEF2-PGC1α and BDNF/CREB pathways.

DESCRIPTION:
Related Articles

Neuroprotective and neurogenic effects of novel tetramethylpyrazine derivative T-006 in Parkinson’s disease models through activating the MEF2-PGC1α and BDNF/CREB pathways.

Aging (Albany NY). 2020 Jul 24;12:

Authors: Chen H, Cao J, Zha L, Wang P, Liu Z, Guo B, Zhang G, Sun Y, Zhang Z, Wang Y

Abstract

T-006, a new derivative of tetramethylpyrazine, has been recently found to protect against 6-hydroxydopamine (6-OHDA)-induced neuronal damage and clear α-synuclein (α-syn) by enhancing proteasome activity in an α-syn transgenic Parkinson’s disease (PD) model. The effect of T-006 on the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD model, however, has not been tested and T-006’s neuroprotective mechanisms have not been fully elucidated. In this study, we further investigated the neuroprotective and neurogenic effects of T-006 and explored its underlying mechanism of action in both cellular and animal PD models. T-006 was able to improve locomotor behavior, increase survival of nigra dopaminergic neurons and boost striatal dopamine levels in both MPTP- and 6-OHDA-induced animals. T-006 treatment restored the altered expressions of myocyte enhancer factor 2D (MEF2D), peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α (PGC1α) and NF-E2-related factor 1/2 (Nrf1/2) via modulation of Akt/GSK3β signaling. T-006 stimulated MEF2, PGC1α and Nrf2 transcriptional activities, inducing Nrf2 nuclear localization. Interestingly, T-006 promoted endogenous adult neurogenesis toward a dopaminergic phenotype by activating brain-derived neurotrophic factor (BDNF) and cAMP responsive element-binding protein (CREB) in 6-OHDA rats. Our work demonstrated that T-006 is a potent neuroprotective and neuroregenerative agent that may have therapeutic potential in the treatment of PD.

PMID: 32710729 [PubMed – as supplied by publisher]

PMID:
PubMed:32710729

DATE FOUND:
07/28/20 06:01AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/32710729?dopt=Abstract

Identifying and predicting Parkinson’s disease subtypes through trajectory clustering via bipartite networks

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233296

https://www.ncbi.nlm.nih.gov/pubmed/32555729?dopt=Abstract

TITLE:
Identifying and predicting Parkinson’s disease subtypes through trajectory clustering via bipartite networks.

DESCRIPTION:
Identifying and predicting Parkinson’s disease subtypes through trajectory clustering via bipartite networks.

PLoS One. 2020;15(6):e0233296

Authors: Krishnagopal S, Coelln RV, Shulman LM, Girvan M

Abstract

Chronic medical conditions show substantial heterogeneity in their clinical features and progression. We develop the novel data-driven, network-based Trajectory Profile Clustering (TPC) algorithm for 1) identification of disease subtypes and 2) early prediction of subtype/disease progression patterns. TPC is an easily generalizable method that identifies subtypes by clustering patients with similar disease trajectory profiles, based not only on Parkinson’s Disease (PD) variable severity, but also on their complex patterns of evolution. TPC is derived from bipartite networks that connect patients to disease variables. Applying our TPC algorithm to a PD clinical dataset, we identify 3 distinct subtypes/patient clusters, each with a characteristic progression profile. We show that TPC predicts the patient’s disease subtype 4 years in advance with 72% accuracy for a longitudinal test cohort. Furthermore, we demonstrate that other types of data such as genetic data can be integrated seamlessly in the TPC algorithm. In summary, using PD as an example, we present an effective method for subtype identification in multidimensional longitudinal datasets, and early prediction of subtypes in individual patients.

PMID: 32555729 [PubMed – in process]

PMID:
PubMed:32555729

DATE FOUND:
06/20/20 06:00AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/32555729?dopt=Abstract

Discovery and optimization of 3-thiophenylcoumarins as novel agents against Parkinson’s disease

https://www.sciencedirect.com/science/article/abs/pii/S0045206820312839?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32569895?dopt=Abstract

TITLE:
Discovery and optimization of 3-thiophenylcoumarins as novel agents against Parkinson’s disease: Synthesis, in vitro and in vivo studies.

DESCRIPTION:
Discovery and optimization of 3-thiophenylcoumarins as novel agents against Parkinson’s disease: Synthesis, in vitro and in vivo studies.

Bioorg Chem. 2020 Jun 02;101:103986

Authors: Rodríguez-Enríquez F, Viña D, Uriarte E, Fontenla JA, Matos MJ

Abstract

Monoamine oxidase B (MAO-B) inhibitors are still receiving great attention as promising therapeutic agents for central nervous system disorders. This study explores, for the first time, the potential of 3-thiophenylcoumarins as in vitro and in vivo agents against Parkinsońs disease. Twelve compounds were synthesized via Perkin-Oglialoro reaction, and in vitro evaluation of six hydroxylated molecules was performed. MAO-A and MAO-B inhibition, DPPH scavenging and inhibition of ROS formation, neurotoxicity on motor cortex neurons and neuroprotection against H2O2, were studied. In vivo effect on locomotor activity using the open field test was also evaluated for the best candidate [3-(4′-bromothiophen-2′-yl)-7-hydroxycoumarin, 5], a potent, selective and reversible MAO-B inhibitor (IC50 = 140 nM). This compound proved to have a slightly better in vivo profile than selegiline, one of the currently treatments for Parkinson’s disease, in reserpinized mice pretreated with levodopa and benserazide. Results suggested that, comparing positions 7 and 8, substitution at position 7 of the coumarin scaffold is better for the enzymatic inhibition. However, the presence of a catechol at positions 7 and 8 exponentially increases the antioxidant potential and the neuroprotective properties. Finally, all the molecules present good theoretical physicochemical properties that make them excellent candidates for the optimization of a lead compound.

PMID: 32569895 [PubMed – as supplied by publisher]

PMID:
PubMed:32569895

DATE FOUND:
06/23/20 06:03AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/32569895?dopt=Abstract

Targeting Ubiquitin-Proteasome Pathway by Natural Products: Novel Therapeutic Strategy for Treatment of Neurodegenerative Diseases such as Parkinson’s disease

https://www.frontiersin.org/articles/10.3389/fphys.2020.00361/full

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199656/

https://www.ncbi.nlm.nih.gov/pubmed/32411012?dopt=Abstract

TITLE:
Targeting Ubiquitin-Proteasome Pathway by Natural Products: Novel Therapeutic Strategy for Treatment of Neurodegenerative Diseases.

DESCRIPTION:
Targeting Ubiquitin-Proteasome Pathway by Natural Products: Novel Therapeutic Strategy for Treatment of Neurodegenerative Diseases.

Front Physiol. 2020;11:361

Authors: Momtaz S, Memariani Z, El-Senduny FF, Sanadgol N, Golab F, Katebi M, Abdolghaffari AH, Farzaei MH, Abdollahi M

Abstract

Misfolded proteins are the main common feature of neurodegenerative diseases, thereby, normal proteostasis is an important mechanism to regulate the neural survival and the central nervous system functionality. The ubiquitin-proteasome system (UPS) is a non-lysosomal proteolytic pathway involved in numerous normal functions of the nervous system, modulation of neurotransmitter release, synaptic plasticity, and recycling of membrane receptors or degradation of damaged and regulatory intracellular proteins. Aberrant accumulation of intracellular ubiquitin-positive inclusions has been implicated to a variety of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington disease (HD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Myeloma (MM). Genetic mutation in deubiquitinating enzyme could disrupt UPS and results in destructive effects on neuron survival. To date, various agents were characterized with proteasome-inhibitory potential. Proteins of the ubiquitin-proteasome system, and in particular, E3 ubiquitin ligases, may be promising molecular targets for neurodegenerative drug discovery. Phytochemicals, specifically polyphenols (PPs), were reported to act as proteasome-inhibitors or may modulate the proteasome activity. PPs modify the UPS by means of accumulation of ubiquitinated proteins, suppression of neuronal apoptosis, reduction of neurotoxicity, and improvement of synaptic plasticity and transmission. This is the first comprehensive review on the effect of PPs on UPS. Here, we review the recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders. This review attempts to summarize the latest reports on the neuroprotective properties involved in the proper functioning of natural polyphenolic compounds with implication for targeting ubiquitin-proteasome pathway in the neurodegenerative diseases. We highlight the evidence suggesting that polyphenolic compounds have a dose and disorder dependent effects in improving neurological dysfunctions, and so their mechanism of action could stimulate the UPS, induce the protein degradation or inhibit UPS and reduce protein degradation. Future studies should focus on molecular mechanisms by which PPs can interfere this complex regulatory system at specific stages of the disease development and progression.

PMID: 32411012 [PubMed]

PMID:
PubMed:32411012

DATE FOUND:
05/16/20 06:01AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/32411012?dopt=Abstract

Glucocerebrosidase as a Therapeutic Target for Parkinson’s Disease

https://www.tandfonline.com/doi/abs/10.1080/14728222.2020.1733970?journalCode=iett20

https://www.ncbi.nlm.nih.gov/pubmed/32106725?dopt=Abstract

TITLE:
Glucocerebrosidase as a therapeutic target for Parkinson’s disease.

DESCRIPTION:
Related Articles

Glucocerebrosidase as a therapeutic target for Parkinson’s disease.

Expert Opin Ther Targets. 2020 Feb 27;:1-8

Authors: Chen Y, Sam R, Sharma P, Chen L, Do J, Sidransky E

Abstract

Introduction: The association between Gaucher disease, caused by the inherited deficiency of glucocerebrosidase, and Parkinson’s disease was first recognized in the clinic, noting that patients with Gaucher disease and their carrier relatives had an increased incidence of Parkinson’s disease. Currently, mutations in glucocerebrosidase (GBA1) are the most common genetic risk factor for Parkinson’s disease and dementia with Lewy bodies, with an inverse relationship between glucocerebrosidase and α-synuclein, a key factor in Parkinson pathogenesis. The hypothesis that therapeutic enhancement of brain glucocerebrosidase levels might reduce the aggregation, accumulation or spread of α-synuclein has spurred great interest in glucocerebrosidase as a novel therapeutic target.Area covered: This article explores the potential molecular mechanisms underlying the association between GBA1 mutations and Parkinson’s disease and outlines therapeutic strategies to increase brain glucocerebrosidase, including gene therapy, targeted delivery of recombinant glucocerebrosidase to the brain, small-molecule chaperones to rescue mutant glucocerebrosidase, and small-molecule modulators to activate wild-type glucocerebrosidase.Expert opinion: Although an improved understanding of the mechanistic basis for GBA1-associated parkinsonism is essential, enhancing levels of brain glucocerebrosidase may have wide therapeutic implications. While gene therapy may ultimately be effective, less expensive and invasive small-molecule non-inhibitory chaperones or activators could significantly impact the disease course.

PMID: 32106725 [PubMed – as supplied by publisher]

PMID:
PubMed:32106725

DATE FOUND:
02/29/20 06:01AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/32106725?dopt=Abstract

Neuroprotective effects of Bacopa monnieri in Parkinson’s disease model

https://link.springer.com/article/10.1007%2Fs11011-019-00526-w

https://www.ncbi.nlm.nih.gov/pubmed/31834548?dopt=Abstract

TITLE:
Neuroprotective effects of Bacopa monnieri in Parkinson’s disease model.

DESCRIPTION:
Neuroprotective effects of Bacopa monnieri in Parkinson’s disease model.

Metab Brain Dis. 2019 Dec 13;:

Authors: Singh B, Pandey S, Rumman M, Mahdi AA

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra region and the presence of α-synuclein aggregates in the striatum and surrounding areas of brain. Evidences suggest that neuroinflammation plays a role in the progression of PD. We examined the neuro-protective effects of Bacopa monnieri (BM) in regulating neuroinflammation. Administration of BM suppressed the level of pro-inflammatory cytokines, decreased the levels of α-synuclein, and reduced reactive oxygen species (ROS) generation in PD animal model. Pre-treatment of BM showed more prominent results as compare to co- and post-treatment. Results suggest that Bacopa can limit inflammation in the different areas of brain, thus, offers a promising source of novel therapeutics for the treatment of many CNS disorders.

PMID: 31834548 [PubMed – as supplied by publisher]

PMID:
PubMed:31834548

DATE FOUND:
12/14/19 06:02AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31834548?dopt=Abstract

Blocking CXCL12/CXCR4 may be a potential therapeutic approach for Parkinson’s disease progression

https://www.ncbi.nlm.nih.gov/pubmed/31831012?dopt=Abstract

TITLE:
CXCL12 is involved in α-synuclein-triggered neuroinflammation of Parkinson’s disease.

DESCRIPTION:
Related Articles

CXCL12 is involved in α-synuclein-triggered neuroinflammation of Parkinson’s disease.

J Neuroinflammation. 2019 Dec 12;16(1):263

Authors: Li Y, Niu M, Zhao A, Kang W, Chen Z, Luo N, Zhou L, Zhu X, Lu L, Liu J

Abstract

BACKGROUND: The mechanisms underlying the pathogenesis and progression of Parkinson’s disease (PD) remain elusive, but recent opinions and perspectives have focused on whether the inflammation process induced by microglia contributes to α-synuclein-mediated toxicity. Migration of microglia to the substantia nigra (SN) could precede neurodegeneration in A53T mice. We hypothesized that CXCL12 could be a mediator in the α-synuclein-induced migration of microglia.

METHODS: After establishing appropriate animal and cell culture models, we explored the relationship between α-synuclein and CXCL12 in A53T mice, primary microglia, and BV-2 cell lines. We also explored the mechanisms of these interactions and the signaling processes involved in neuroinflammation.

RESULTS: We confirmed the positive correlation between α-synuclein and CXCL12 in the postmortem brain tissue of PD patients and the upregulated CXCR4 expression in SN microglia of A53T mice. In addition, as expected, α-synuclein increased the production of CXCL12 in microglia via TLR4/IκB-α/NF-κB signaling. Importantly, CXCL12/CXCR4/FAK/Src/Rac1 signaling was shown to be involved in α-synuclein-induced microglial accumulation.

CONCLUSIONS: Our study suggests that CXCL12 could be a novel target for the prevention of α-synuclein-triggered ongoing microglial responses. Blocking CXCL12/CXCR4 may be a potential therapeutic approach for PD progression.

PMID: 31831012 [PubMed – in process]

PMID:
PubMed:31831012

DATE FOUND:
12/14/19 06:02AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31831012?dopt=Abstract

Targeting the microglial NLRP3 inflammasome and its role in Parkinson’s disease

https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.27874

https://www.ncbi.nlm.nih.gov/pubmed/31680318?dopt=Abstract

TITLE:
Targeting the microglial NLRP3 inflammasome and its role in Parkinson’s disease.

DESCRIPTION:
Related Articles

Targeting the microglial NLRP3 inflammasome and its role in Parkinson’s disease.

Mov Disord. 2019 Nov 04;:

Authors: Haque ME, Akther M, Jakaria M, Kim IS, Azam S, Choi DK

Abstract

Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson’s disease (PD). Components of the nucleotide-binding oligomerization domain and leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome complex, leucine-rich-repeat- and pyrin-domain-containing 3, caspase-1, and apoptosis-associated speck-like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α-synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome activation and release of interleukin-1β and interleukin-18 caspase-1-mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society.

PMID: 31680318 [PubMed – as supplied by publisher]

PMID:
PubMed:31680318

DATE FOUND:
11/05/19 06:00AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31680318?dopt=Abstract

Systemic activation of Nrf2 pathway in Parkinson’s disease

https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.27878

https://www.ncbi.nlm.nih.gov/pubmed/31682033?dopt=Abstract

TITLE:
Systemic activation of Nrf2 pathway in Parkinson’s disease.

DESCRIPTION:
Systemic activation of Nrf2 pathway in Parkinson’s disease.

Mov Disord. 2019 Nov 04;:

Authors: Petrillo S, Schirinzi T, Di Lazzaro G, D’Amico J, Colona VL, Bertini E, Pierantozzi M, Mari L, Mercuri NB, Piemonte F, Pisani A

Abstract

BACKGROUND: Preclinical studies underlined the relevance of Nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor pathway in the pathogenesis of Parkinson’s disease (PD).

OBJECTIVE: The objective of this study was to explore Nrf2 pathway in vivo in PD, looking for novel disease biomarkers and therapeutic targets.

METHODS: The levels of Nrf2, the downstream effectors (NAD(P)H dehydrogenase [quinone] 1 (Nqo1) enzyme, glutathione metabolism enzymes Glutamate-cysteine ligase (GCL) and Glutathione Reductase (GR)), the upstream activators (redox state and mitochondrial dysfunction), and α-synuclein oligomers were assessed in the blood leukocytes of PD patients comparatively to controls. Biochemical data were correlated to clinical parameters.

RESULTS: In PD, Nrf2 was highly transcribed and expressed as well as its target effectors. The mitochondrial complex I activity was reduced and the oxidized form of glutathione prevailed, disclosing the presence of pathway’s activators. Also, α-synuclein oligomers levels were increased. Nrf2 transcript and oligomers levels correlated with PD duration.

CONCLUSIONS: Blood leukocytes mirror pathogenic mechanisms of PD, showing the systemic activation of the Nrf2 pathway and its link with synucleinopathy and clinical events. © 2019 International Parkinson and Movement Disorder Society.

PMID: 31682033 [PubMed – as supplied by publisher]

PMID:
PubMed:31682033

DATE FOUND:
11/05/19 06:05AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31682033?dopt=Abstract

Editorial: Peripheral Immunity in Parkinson’s Disease: Emerging Role and Novel Target for Therapeutics

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804273/

https://www.ncbi.nlm.nih.gov/pubmed/31681151?dopt=Abstract

TITLE:
Editorial: Peripheral Immunity in Parkinson’s Disease: Emerging Role and Novel Target for Therapeutics.

DESCRIPTION:
Related Articles

Editorial: Peripheral Immunity in Parkinson’s Disease: Emerging Role and Novel Target for Therapeutics.

Front Neurol. 2019;10:1080

Authors: Comi C, Cosentino M, Pacheco R

PMID: 31681151 [PubMed]

PMID:
PubMed:31681151

DATE FOUND:
11/05/19 07:43AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31681151?dopt=Abstract

Targeting BDNF signaling by natural products: novel synaptic repair therapeutics for neurodegeneration and behavior disorders

https://www.sciencedirect.com/science/article/abs/pii/S1043661819318225?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31546015?dopt=Abstract

TITLE:
Targeting BDNF signaling by natural products: novel synaptic repair therapeutics for neurodegeneration and behavior disorders.

DESCRIPTION:
Targeting BDNF signaling by natural products: novel synaptic repair therapeutics for neurodegeneration and behavior disorders.

Pharmacol Res. 2019 Sep 20;:104458

Authors: Bawari S, Tewari D, Argüelles S, Sah AN, Fazel Nabavi S, Xu S, Vacca RA, Nabavi SM, Shirooie S

Abstract

Neurodegenerative disorders like Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, frontotemporal dementia to prion diseases, Friedreich’s ataxia, hereditary spastic paraplegia and optic atrophy type 1, and behavior disorders like neuropsychiatric, hyperactivity and autism spectrum disorders are closely associated with neurobiological deficits. Brain derived neurotrophic factor (BDNF) is an extensively studied neurotrophin. BDNF is essential for neuronal genesis, differentiation, survival, growth, plasticity, synaptic viability and transmission. BDNF has emerged as a promising target for regulating synaptic activity and plasticity. An overview of effects and mechanisms of the natural products targeting BDNF is described. This review is an attempt to enumerate the effects of various natural products on BDNF as a novel therapeutic approach for neurodegenerative and neuropsychiatric disorders.

PMID: 31546015 [PubMed – as supplied by publisher]

PMID:
PubMed:31546015

DATE FOUND:
09/24/19 06:03AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31546015?dopt=Abstract

Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications

https://journals.sagepub.com/doi/abs/10.1177/1073858419871214?journalCode=nroa

https://www.ncbi.nlm.nih.gov/pubmed/31526091?dopt=Abstract

TITLE:
Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications.

DESCRIPTION:
Related Articles

Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications.

Neuroscientist. 2019 Sep 16;:1073858419871214

Authors: Zhou W, Ma D, Tan EK

Abstract

CHCHD2 mutations have been identified in various neurological diseases such as Parkinson’s disease (PD), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). It is also the first mitochondrial gene whose mutations lead to PD. CHCHD10 is a homolog of CHCHD2; similar to CHCHD2, various mutations of CHCHD10 have been identified in a broad spectrum of neurological disorders, including FTD and AD, with a high frequency of CHCHD10 mutations found in motor neuron diseases. Functionally, CHCHD2 and CHCHD10 have been demonstrated to interact with each other in mitochondria. Recent studies link the biological functions of CHCHD2 to the MICOS complex (mitochondrial inner membrane organizing system). Multiple experimental models suggest that CHCHD2 maintains mitochondrial cristae and disease-associated CHCHD2 mutations function in a loss-of-function manner. However, both CHCHD2 and CHCHD10 knockout mouse models appear phenotypically normal, with no obvious mitochondrial defects. Strategies to maintain or enhance mitochondria cristae could provide opportunities to correct the associated cellular defects in disease state and unravel potential novel targets for CHCHD2-linked neurological conditions.

PMID: 31526091 [PubMed – as supplied by publisher]

PMID:
PubMed:31526091

DATE FOUND:
09/19/19 06:01AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31526091?dopt=Abstract

Protective and Regenerative Roles of T Cells in Central Nervous System Disorders

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751344/

https://www.ncbi.nlm.nih.gov/pubmed/31572381?dopt=Abstract

TITLE:
Protective and Regenerative Roles of T Cells in Central Nervous System Disorders.

DESCRIPTION:
Protective and Regenerative Roles of T Cells in Central Nervous System Disorders.

Front Immunol. 2019;10:2171

Authors: Evans FL, Dittmer M, de la Fuente AG, Fitzgerald DC

Abstract

Pathogenic mechanisms of T cells in several central nervous system (CNS) disorders are well-established. However, more recent studies have uncovered compelling beneficial roles of T cells in neurological diseases, ranging from tissue protection to regeneration. These divergent functions arise due to the diversity of T cell subsets, particularly CD4+ T cells. Here, we review the beneficial impact of T cell subsets in a range of neuroinflammatory and neurodegenerative diseases including multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and CNS trauma. Both T cell-secreted mediators and direct cell contact-dependent mechanisms deliver neuroprotective, neuroregenerative and immunomodulatory signals in these settings. Understanding the molecular details of these beneficial T cell mechanisms will provide novel targets for therapeutic exploitation that can be applied to a range of neurological disorders.

PMID: 31572381 [PubMed – in process]

PMID:
PubMed:31572381

DATE FOUND:
10/02/19 06:50AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31572381?dopt=Abstract

Essential role of phosphodiesterase 7 (PDE7) enzyme in neurodegeneration and inflammatory-mediated brain damage opens door to new therapeutic interventions for Parkinson’s disease

https://link.springer.com/article/10.1007%2Fs12035-019-01745-z

https://www.ncbi.nlm.nih.gov/pubmed/31473904?dopt=Abstract

TITLE:
Phosphodiesterase 7 Regulation in Cellular and Rodent Models of Parkinson’s Disease.

DESCRIPTION:
Phosphodiesterase 7 Regulation in Cellular and Rodent Models of Parkinson’s Disease.

Mol Neurobiol. 2019 Aug 31;:

Authors: Morales-Garcia JA, Alonso-Gil S, Santos Á, Perez-Castillo A

Abstract

Parkinson’s disease is characterized by a loss of dopaminergic neurons in the ventral midbrain. This disease is diagnosed when around 50% of these neurons have already died; consequently, therapeutic treatments start too late. Therefore, an urgent need exists to find new targets involved in the onset and progression of the disease. Phosphodiesterase 7 (PDE7) is a key enzyme involved in the degradation of intracellular levels of cyclic adenosine 3′, 5′-monophosphate in different cell types; however, little is known regarding its role in neurodegenerative diseases, and specifically in Parkinson’s disease. We have previously shown that chemical as well as genetic inhibition of this enzyme results in neuroprotection and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson’s disease. Here, we have used in vitro and in vivo models of Parkinson’s disease to study the regulation of PDE7 protein levels. Our results show that PDE7 is upregulated after an injury both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures and after lipopolysaccharide or 6-hidroxydopamine injection in the Substantia nigra pars compacta of adult mice. PDE7 increase takes place mainly in degenerating dopaminergic neurons and in microglia cells. This enhanced expression appears to be direct since 6-hydroxydopamine and lipopolysaccharide increase the expression of a 962-bp fragment of its promoter. Taking together, these results reveal an essential function for PDE7 in the pathways leading to neurodegeneration and inflammatory-mediated brain damage and suggest novel roles for PDE7 in neurodegenerative diseases, specifically in PD, opening the door for new therapeutic interventions.

PMID: 31473904 [PubMed – as supplied by publisher]

PMID:
PubMed:31473904

DATE FOUND:
09/02/19 06:02AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31473904?dopt=Abstract

Hepcidin and its therapeutic potential in neurodegenerative disorders

https://onlinelibrary.wiley.com/doi/abs/10.1002/med.21631

https://www.ncbi.nlm.nih.gov/pubmed/31471929?dopt=Abstract

TITLE:
Hepcidin and its therapeutic potential in neurodegenerative disorders.

DESCRIPTION:
Related Articles

Hepcidin and its therapeutic potential in neurodegenerative disorders.

Med Res Rev. 2019 Aug 30;:

Authors: Qian ZM, Ke Y

Abstract

Abnormally high brain iron, resulting from the disrupted expression or function of proteins involved in iron metabolism in the brain, is an initial cause of neuronal death in neuroferritinopathy and aceruloplasminemia, and also plays a causative role in at least some of the other neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Friedreich’s ataxia. As such, iron is believed to be a novel target for pharmacological intervention in these disorders. Reducing iron toward normal levels or hampering the increases in iron associated with age in the brain is a promising therapeutic strategy for all iron-related neurodegenerative disorders. Hepcidin is a crucial regulator of iron homeostasis in the brain. Recent studies have suggested that upregulating brain hepcidin levels can significantly reduce brain iron content through the regulation of iron transport protein expression in the blood-brain barrier and in neurons and astrocytes. In this review, we focus on the discussion of the therapeutic potential of hepcidin in iron-associated neurodegenerative diseases and also provide a systematic overview of recent research progress on how misregulated brain iron metabolism is involved in the development of multiple neurodegenerative disorders.

PMID: 31471929 [PubMed – as supplied by publisher]

PMID:
PubMed:31471929

DATE FOUND:
09/01/19 06:03AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31471929?dopt=Abstract

Current Progress of Mitochondrial Quality Control Pathways Underlying the Pathogenesis of Parkinson’s Disease

https://www.hindawi.com/journals/omcl/2019/4578462/

https://www.ncbi.nlm.nih.gov/pubmed/31485291?dopt=Abstract

TITLE:
Current Progress of Mitochondrial Quality Control Pathways Underlying the Pathogenesis of Parkinson’s Disease.

DESCRIPTION:
Related Articles

Current Progress of Mitochondrial Quality Control Pathways Underlying the Pathogenesis of Parkinson’s Disease.

Oxid Med Cell Longev. 2019;2019:4578462

Authors: Jiang X, Jin T, Zhang H, Miao J, Zhao X, Su Y, Zhang Y

Abstract

Parkinson’s disease (PD), clinically characterized by motor and nonmotor symptoms, is a common progressive and multisystem neurodegenerative disorder, which is caused by both genetic and environmental risk factors. The main pathological features of PD are the loss of dopaminergic (DA) neurons and the accumulation of alpha-synuclein (α-syn) in the residual DA neurons in the substantia nigra pars compacta (SNpc). In recent years, substantial progress has been made in discovering the genetic factors of PD. In particular, a total of 19 PD-causing genes have been unraveled, among which some members have been regarded to be related to mitochondrial dysfunction. Mitochondria are key regulators of cellular metabolic activity and are critical for many important cellular processes including energy metabolism and even cell death. Their normal function is basically maintained by the mitochondrial quality control (MQC) mechanism. Accordingly, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a kind of neurotoxin, exerts its neurotoxic effects at least partially by producing its toxic metabolite, namely, 1-methyl-4-phenylpyridine (MPP+), which in turn causes mitochondrial dysfunction by inhibiting complex I and mimicking the key features of PD pathogenesis. This review focused on three main aspects of the MQC signaling pathways, that is, mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy; hence, it demonstrates in detail how genetic and environmental factors result in PD pathogenesis by interfering with MQC pathways, thereby hopefully contributing to the discovery of novel potential therapeutic targets for PD.

PMID: 31485291 [PubMed – in process]

PMID:
PubMed:31485291

DATE FOUND:
09/06/19 07:13AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31485291?dopt=Abstract

The gut microbiota: A novel therapeutic target in Parkinson’s disease?

https://www.prd-journal.com/article/S1353-8020(19)30366-9/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31445904?dopt=Abstract

TITLE:
The gut microbiota: A novel therapeutic target in Parkinson’s disease?

DESCRIPTION:
Related Articles

The gut microbiota: A novel therapeutic target in Parkinson’s disease?

Parkinsonism Relat Disord. 2019 Aug 12;:

Authors: Lubomski M, Davis RL, Sue CM

PMID: 31445904 [PubMed – as supplied by publisher]

PMID:
PubMed:31445904

DATE FOUND:
08/26/19 06:02AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31445904?dopt=Abstract

P1 Receptor Agonists/Antagonists – Potential Parkinson’s Drug Candidates of the Future

http://www.eurekaselect.com/173523/article

https://www.ncbi.nlm.nih.gov/pubmed/31333097?dopt=Abstract

TITLE:
P1 Receptor Agonists/Antagonists in Clinical Trials – Potential Drug Candidates of the Future.

DESCRIPTION:
Related Articles

P1 Receptor Agonists/Antagonists in Clinical Trials – Potential Drug Candidates of the Future.

Curr Pharm Des. 2019 Jul 16;:

Authors: Borah P, Deka S, Mailavaram RP, Deb PK

Abstract

BACKGROUND: Adenosine mediates various physiological and pathological conditions by acting on its four P1 receptors (A1, A2A, A2B and A3 receptors). Omnipresence of P1 receptors and their activation, exert a wide range of biological activities. Thus its modulation is implicated in various disorders like Parkinson’s disease, asthma, cardiovascular disorders, cancer etc. Hence this has become an interesting target for the researchers to develop potential therapeutic agents. Number of molecules were designed and developed in the past few years and evaluated for their efficacy in various disease conditions.

OBJECTIVE: The main objective is to provide an overview of new chemical entities which have crossed preclinical studies and reached clinical trials stage following their current status and future prospective.

METHODS: In this review we discuss current status of the drug candidates which have undergone clinical trials and their prospects.

RESULTS: Many chemical entities targeting various subtypes of P1 receptors are patented; twenty of them have crossed preclinical studies and reached clinical trials stage. Two of them viz adenosine and regadenoson are approved by Food and Drug Administration.

CONCLUSION: This review is an attempt to highlight the current status, progress and probable future of P1 receptor ligands which are under clinical trials as promising novel therapeutic agents and the direction in which research should proceed with a view to come out with novel therapeutic agents.

PMID: 31333097 [PubMed – as supplied by publisher]

PMID:
PubMed:31333097

DATE FOUND:
07/24/19 10:11AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31333097?dopt=Abstract

Antioxidant, Anti-inflammatory, and Neuroprotective Effects of Novel Vinyl Sulfonate Compounds as Nrf2 Activator

https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00163

https://www.ncbi.nlm.nih.gov/pubmed/31312409?dopt=Abstract

TITLE:
Antioxidant, Anti-inflammatory, and Neuroprotective Effects of Novel Vinyl Sulfonate Compounds as Nrf2 Activator.

DESCRIPTION:
Antioxidant, Anti-inflammatory, and Neuroprotective Effects of Novel Vinyl Sulfonate Compounds as Nrf2 Activator.

ACS Med Chem Lett. 2019 Jul 11;10(7):1061-1067

Authors: Choi JW, Shin SJ, Kim HJ, Park JH, Kim HJ, Lee EH, Pae AN, Bahn YS, Park KD

Abstract

The main pathway responsible for cellular regulation against oxidative stress is nuclear factor E2-related factor-2 (Nrf2) signaling. We previously synthesized and reported a novel vinyl sulfone (1) as an Nrf2 activator with therapeutic potential for Parkinson’s disease (PD). In this study, we changed the vinyl sulfone to vinyl sulfonamide or vinyl sulfonate to improve Nrf2 activating efficacy. We observed that the introduction of vinyl sulfonamide led to a reduction of the effects on Nrf2 activation, whereas vinyl sulfonate compounds exhibited superior activity compared to the vinyl sulfone compounds. Among the vinyl sulfonates, 3c exhibited 6.9- and 83.5-fold higher effects on Nrf2 activation than the corresponding vinyl sulfone (1) and vinyl sulfonamide (2c), respectively. Compound 3c was confirmed to induce expression of the Nrf2-dependent antioxidant enzymes at the protein level in cells. In addition, 3c mitigated PD-associated behavioral deficits by protecting DAergic neurons in the MPTP-induced mouse model of PD.

PMID: 31312409 [PubMed]

PMID:
PubMed:31312409

DATE FOUND:
07/18/19 06:03AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31312409?dopt=Abstract

Cysteamine as a novel disease-modifying compound for Parkinson’s disease: Over a decade of research supporting a clinical trial

https://www.sciencedirect.com/science/article/pii/S0969996119301986?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31301344?dopt=Abstract

TITLE:
Cysteamine as a novel disease-modifying compound for Parkinson’s disease: Over a decade of research supporting a clinical trial.

DESCRIPTION:
Cysteamine as a novel disease-modifying compound for Parkinson’s disease: Over a decade of research supporting a clinical trial.

Neurobiol Dis. 2019 Jul 10;:104530

Authors: Cicchetti F, David LS, Siddu A, Denis HL

Abstract

To date, medical and surgical interventions offered to patients with Parkinson’s disease (PD) serve only to manage clinical symptoms; they have not shown the capacity to halt nor reverse degenerative processes. There is therefore an urgent need to identify and/or develop therapeutic strategies that will demonstrate ‘disease modifying’ capacities. The molecule cystamine, and its reduced form cysteamine, act via a number of pathways identified as being critical to the pathogenesis of PD. In particular, these agents are capable of crossing the blood-brain barrier, promoting the secretion of neurotrophic factors, the inhibition of oxidative stress, the reduction of inflammatory responses and importantly, have already been trialed in humans for a number of other clinical indications. In the last decade, our laboratory has accumulated compelling evidence that both cystamine and cysteamine can halt, and even reverse, ongoing neurodegenerative processes in a number of different models of PD, and as such, should now be taken forward to clinical trials in PD.

PMID: 31301344 [PubMed – as supplied by publisher]

PMID:
PubMed:31301344

DATE FOUND:
07/14/19 06:01AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31301344?dopt=Abstract

Potential Benefits of Nobiletin, A Citrus Flavonoid, against Parkinson’s Disease

https://www.mdpi.com/1422-0067/20/14/3380/htm

https://www.ncbi.nlm.nih.gov/pubmed/31295812?dopt=Abstract

TITLE:
Potential Benefits of Nobiletin, A Citrus Flavonoid, against Alzheimer’s Disease and Parkinson’s Disease.

DESCRIPTION:
Potential Benefits of Nobiletin, A Citrus Flavonoid, against Alzheimer’s Disease and Parkinson’s Disease.

Int J Mol Sci. 2019 Jul 10;20(14):

Authors: Nakajima A, Ohizumi Y

Abstract

Alzheimer’s disease (AD), which is characterized by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles, accompanied by neurodegeneration, is the most common form of age-related neurodegenerative disease. Parkinson’s disease (PD) is the second most common neurodegenerative disease after AD, and is characterized by early prominent loss of dopaminergic neurons in the substantia nigra pars compacta. As currently available treatments are not able to significantly alter the progression of these diseases, successful therapeutic and preventive interventions are strongly needed. In the course of our survey of substances from natural resources having anti-dementia and neuroprotective activity, we found nobiletin, a polymethoxylated flavone from the peel of Citrus depressa. Nobiletin improved cognitive deficits and the pathological features of AD, such as Aβ pathology, hyperphosphorylation of tau, and oxidative stress, in animal models of AD. In addition, nobiletin improved motor and cognitive deficits in PD animal models. These observations suggest that nobiletin has the potential to become a novel drug for the treatment and prevention of neurodegenerative diseases such as AD and PD.

PMID: 31295812 [PubMed – in process]

PMID:
PubMed:31295812

DATE FOUND:
07/13/19 06:01AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31295812?dopt=Abstract

Brain-targeted intranasal delivery of dopamine with borneol and lactoferrin co-modified nanoparticles for treating Parkinson’s disease

https://www.tandfonline.com/doi/full/10.1080/10717544.2019.1636420

https://www.ncbi.nlm.nih.gov/pubmed/31290705?dopt=Abstract

TITLE:
Brain-targeted intranasal delivery of dopamine with borneol and lactoferrin co-modified nanoparticles for treating Parkinson’s disease.

DESCRIPTION:
Brain-targeted intranasal delivery of dopamine with borneol and lactoferrin co-modified nanoparticles for treating Parkinson’s disease.

Drug Deliv. 2019 Dec;26(1):700-707

Authors: Tang S, Wang A, Yan X, Chu L, Yang X, Song Y, Sun K, Yu X, Liu R, Wu Z, Xue P

Abstract

Efficient delivery of brain-targeted drugs is highly important for successful therapy in Parkinson’s disease (PD). This study was designed to formulate borneol and lactoferrin co-modified nanoparticles (Lf-BNPs) encapsulated dopamine as a novel drug delivery system to achieve maximum therapeutic efficacy and reduce side effects for PD. Dopamine Lf-BNPs were prepared using the double emulsion solvent evaporation method and evaluated for physicochemical and pharmaceutical properties. In vitro cytotoxicity studies indicated that treatment with dopamine Lf-BNPs has relatively low cytotoxicity in SH-SY5Y and 16HBE cells. Qualitative and quantitative cellular uptake experiments indicated that Lf modification of NPs increased cellular uptake of SH-SY5Y cells and 16HBE cells, and borneol modification can promote the cellular uptake of 16HBE. In vivo pharmacokinetic studies indicated that AUC0-12 h in the rat brain for dopamine Lf-BNPs was significantly higher (p < .05) than that of dopamine nanoparticles. Intranasal administration of dopamine Lf-BNPs effectively alleviated the 6-hydroxydopamine-induced striatum lesion in rats as indicated by the contralateral rotation behavior test and results for striatal monoamine neurotransmitter content detection. Taken together, intranasal administration of dopamine Lf-BNPs may be an effective drug delivery system for Parkinson’s disease.

PMID: 31290705 [PubMed – in process]

PMID:
PubMed:31290705

DATE FOUND:
07/11/19 02:42PM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31290705?dopt=Abstract

The role of high-intensity focused ultrasound as a symptomatic treatment for Parkinson’s disease

https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.27779

https://www.ncbi.nlm.nih.gov/pubmed/31291491?dopt=Abstract

TITLE:
The role of high-intensity focused ultrasound as a symptomatic treatment for Parkinson’s disease.

DESCRIPTION:
The role of high-intensity focused ultrasound as a symptomatic treatment for Parkinson’s disease.

Mov Disord. 2019 Jul 10;:

Authors: Moosa S, Martínez-Fernández R, Elias WJ, Del Alamo M, Eisenberg HM, Fishman PS

Abstract

MR-guided focused ultrasound is a novel, minimally invasive surgical procedure for symptomatic treatment of PD. With this technology, the ventral intermediate nucleus, STN, and internal globus pallidus have been targeted for therapeutic cerebral ablation, while also minimizing the risk of hemorrhage and infection from more invasive neurosurgical procedures. In a double-blinded, prospective, sham-controlled randomized controlled trial of MR-guided focused ultrasound thalamotomy for treatment of tremor-dominant PD, 62% of treated patients demonstrated improvement in tremor scores from baseline to 3 months postoperatively, as compared to 22% in the sham group. There has been only one open-label trial of MR-guided focused ultrasound subthalamotomy for patients with PD, demonstrating improvements of 71% for rigidity, 36% for akinesia, and 77% for tremor 6 months after treatment. Among the two open-label trials of MR-guided focused ultrasound pallidotomy for patients with PD, dyskinesia and overall motor scores improved up to 52% and 45% at 6 months postoperatively. Although MR-guided focused ultrasound thalamotomy is now approved by the U.S. Food and Drug Administration for treatment of parkinsonian tremor, additional high-quality randomized controlled trials are warranted and are underway to determine the safety and efficacy of MR-guided focused ultrasound subthalamotomy and pallidotomy for treatment of the cardinal features of PD. These studies will be paramount to aid clinicians to determine the ideal ablative target for individual patients. Additional work will be required to assess the durability of MR-guided focused ultrasound lesions, ideal timing of MR-guided focused ultrasound ablation in the course of PD, and the safety of performing bilateral lesions. © 2019 International Parkinson and Movement Disorder Society.

PMID: 31291491 [PubMed – as supplied by publisher]

PMID:
PubMed:31291491

DATE FOUND:
07/11/19 02:42PM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31291491?dopt=Abstract

Recently identified therapeutic targets in dystonia based on recent preclinical animal studies and clinical trials investigating novel therapeutics

https://www.ncbi.nlm.nih.gov/pubmed/31279827?dopt=Abstract

TITLE:
The neurobiological basis for novel experimental therapeutics in dystonia.

DESCRIPTION:
Related Articles

The neurobiological basis for novel experimental therapeutics in dystonia.

Neurobiol Dis. 2019 Jul 04;:104526

Authors: Downs AM, Roman KM, Campbell SA, Pisani A, Hess EJ, Bonsi P

Abstract

Dystonia is a movement disorder characterized by involuntary muscle contractions, twisting movements, and abnormal postures that may affect one or multiple body regions. Dystonia is the third most common movement disorder after Parkinson’s disease and essential tremor. Despite its relative frequency, small molecule therapeutics for dystonia are limited. Development of new therapeutics is further hampered by the heterogeneity of both clinical symptoms and etiologies in dystonia. Recent advances in both animal and cell-based models have helped clarify divergent etiologies in dystonia and have facilitated the identification of new therapeutic targets. Advances in medicinal chemistry have also made available novel compounds for testing in biochemical, physiological, and behavioral models of dystonia. Here, we briefly review motor circuit anatomy and the anatomical and functional abnormalities in dystonia. We then discuss recently identified therapeutic targets in dystonia based on recent preclinical animal studies and clinical trials investigating novel therapeutics.

PMID: 31279827 [PubMed – as supplied by publisher]

PMID:
PubMed:31279827

DATE FOUND:
07/08/19 06:00AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31279827?dopt=Abstract

Protein glycation: An emerging new medicinal target area for Parkinson’s disease

https://www.ncbi.nlm.nih.gov/pubmed/31272349?dopt=Abstract

http://www.eurekaselect.com/173223/article

TITLE:
Protein glycation: An old villain is shedding secrets.

DESCRIPTION:
Related Articles

Protein glycation: An old villain is shedding secrets.

Comb Chem High Throughput Screen. 2019 Jul 03;:

Authors: Lushington GH, Barnes AC

Abstract

The glycation of proteins is a non-physiological post-translational incorporation of carbohydrates onto the free amines or guanidines of proteins and some lipids. Although the existence of glycated proteins has been known for forty years, a full understanding of their pathogenic nature has been slow in accruing. In recent years, however, glycation has gained wide-spread acceptance as a contributing factor in numerous metabolic, autoimmune and neurological disorders, tying together several confounding aspects of disease etiology. From diabetes, arthritis and lupus, to multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s and Parkinson’s diseases, an emerging glycation / inflammation paradigm now offers significant new insight into a physiologically important toxicological phenomenon. It exposes novel drug targets and treatment options, and may even lay foundations for long-awaited breakthroughs. This ‘current frontier’ article briefly profiles current knowledge regarding the underlying causes of glycation, the structural biology implications of such modifications and their pathological consequences. Although several emerging therapeutic strategies for addressing glycation pathologies are introduced, the primary purpose of this mini-review is to raise awareness of the challenges and opportunities inherent in this emerging new medicinal target area.

PMID: 31272349 [PubMed – as supplied by publisher]

PMID:
PubMed:31272349

DATE FOUND:
07/06/19 06:00AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31272349?dopt=Abstract

Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism

https://science.sciencemag.org/content/364/6445/eaau6323

RESEARCH ARTICLE
Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism
Vayu Maini Rekdal1, Elizabeth N. Bess2,3,4, Jordan E. Bisanz2, Peter J. Turnbaugh2,5,*, Emily P. Balskus1,*
See all authors and affiliations

Science 14 Jun 2019:
Vol. 364, Issue 6445, eaau6323
DOI: 10.1126/science.aau6323

Gut microbes metabolize Parkinson’s disease drug

https://science.sciencemag.org/content/364/6445/1030

Gut microbes metabolize Parkinson’s disease drug
Cora O’Neill1,2,3
See all authors and affiliations

Science 14 Jun 2019:
Vol. 364, Issue 6445, pp. 1030-1031
DOI: 10.1126/science.aax8937

Current Drugs and Potential Future Neuroprotective Compounds for Parkinson’s Disease

https://www.ncbi.nlm.nih.gov/pubmed/30479218?dopt=Abstract

http://www.eurekaselect.com/167781/article

TITLE:
Current Drugs and Potential Future Neuroprotective Compounds for Parkinson’s Disease.

DESCRIPTION:
Related Articles

Current Drugs and Potential Future Neuroprotective Compounds for Parkinson’s Disease.

Curr Neuropharmacol. 2019;17(3):295-306

Authors: Carrera I, Cacabelos R

Abstract

The research progress of understanding the etiology and pathogenesis of Parkinson’s disease (PD) has yet lead to the development of some clinical approaches intended to treat cognitive and behavioral symptoms, such as memory and perception disorders. Despite the major advances in different genetic causes and risk factors for PD, which share common pathways to cell dysfunction and death, there is not yet a complete model of PD that can be used to accurately predict the effect of drugs on disease progression. Clinical trials are also important to test any novel neuro-protective agent, and recently there have been great advances in the use of anti-inflammatory drugs and plant flavonoid antioxidants to protect against specific neuronal degeneration and its interference with lipid and cholesterol metabolism. The increasing knowledge of the molecular events underlying the degenerative process of PD has stimulated research to identify natural compounds capable of halting or slowing the progress of neural deterioration. Polyphenols and flavonoids, which play a neuroprotective role in a wide array of in vitro and in vivo models of neurological disorders, emerged from among the multi-target bio-agents found mainly in plants and microorganisms. This review presents a detailed overview of the multimodal activities of neuroprotective bio-agents tested so far, emphasizing their neurorescue/neuroregenerative activity. The brain-penetrating property of bioagents may make these compounds an important class of natural drugs for the treatment of neurodegenerative diseases. Although there are numerous studies demonstrating beneficial effects in the laboratory by identifying critical molecular targets, the clinical efficacy of these neuroprotective treatments remains to be proven accurately.

PMID: 30479218 [PubMed – indexed for MEDLINE]

PMID:
PubMed:30479218

DATE FOUND:
06/04/19 06:01AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/30479218?dopt=Abstract

Focused ultrasound opening of the blood-brain barrier for treatment of Parkinson’s disease

https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.27722

https://www.ncbi.nlm.nih.gov/pubmed/31136023?dopt=Abstract

TITLE:
Focused ultrasound opening of the blood-brain barrier for treatment of Parkinson’s disease.

DESCRIPTION:
Focused ultrasound opening of the blood-brain barrier for treatment of Parkinson’s disease.

Mov Disord. 2019 May 28;:

Authors: LeWitt PA, Lipsman N, Kordower JH

Abstract

The expanding landscape of options for Parkinson’s disease (PD) therapeutics calls for novel ways to improve delivery of treatments to counteract neurodegeneration or enhance symptomatic control. This unmet need is particularly relevant for opportunities in gene therapy, which, in recent PD clinical trials, has required invasive neurosurgical approaches into the CNS. One of the promising techniques to bring new therapies into the brain for PD therapeutics involves an evolving technology, focused ultrasound. Focused ultrasound has been used to alleviate tremor by thermal ablation with high-energy sonication. Using similar equipment but much lower sonication energy, focused ultrasound assisted with micro-bubbles can temporarily open the blood-brain barrier at specific brain targets to facilitate real-time magnetic resonance-guided delivery of therapeutic agents. To explore the current status and future of focused ultrasound in transvascular therapeutics for PD, a November 2018 workshop reviewed its accomplishments and challenges. This report summarizes key points of discussion and provides further background to the promising roles focused ultrasound offers. © 2019 International Parkinson and Movement Disorder Society.

PMID: 31136023 [PubMed – as supplied by publisher]

PMID:
PubMed:31136023

DATE FOUND:
05/29/19 06:03AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31136023?dopt=Abstract

Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease

https://www.nature.com/articles/s41598-019-43772-9

https://www.ncbi.nlm.nih.gov/pubmed/31110191?dopt=Abstract

TITLE:
Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease.

DESCRIPTION:
Related Articles

Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease.

Sci Rep. 2019 May 21;9(1):7567

Authors: Uehara T, Choong CJ, Nakamori M, Hayakawa H, Nishiyama K, Kasahara Y, Baba K, Nagata T, Yokota T, Tsuda H, Obika S, Mochizuki H

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. A characteristic pathological feature of PD is cytoplasmic accumulation of α-synuclein (SNCA) protein. Multiplication of the SNCA gene in familial PD and pathological accumulation of SNCA protein during progression of sporadic PD suggest that increased SNCA protein levels increase the risk of PD. Thus, reducing SNCA expression levels could delay PD onset or modify the disease course. For efficient knock down, we designed and synthesized an amido-bridged nucleic acids (AmNA)-modified antisense oligonucleotide (ASO) that targeted SNCA with improved stability and cellular uptake in vivo. AmNA-ASO efficiently downregulated SNCA at both the mRNA and protein level in vitro and in vivo. Notably, AmNA-ASO was efficiently delivered into the mouse brain by intracerebroventricular injection without the aid of additional chemicals. Furthermore, administration of AmNA-ASO ameliorated neurological defects in PD model mice expressing human wild type SNCA. Taken together, these findings suggest that AmNA-ASO is a promising therapeutic strategy for SNCA-associated pathology in PD.

PMID: 31110191 [PubMed – in process]

PMID:
PubMed:31110191

DATE FOUND:
05/22/19 06:00AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31110191?dopt=Abstract

Lysosomal exocytosis is a potential therapeutic target in Parkinson’s and other diseases characterized by the accumulation of a-synuclein

http://www.jneurosci.org/content/early/2019/05/16/JNEUROSCI.3085-18.2019

https://www.ncbi.nlm.nih.gov/pubmed/31097622?dopt=Abstract

TITLE:
Increased lysosomal exocytosis induced by lysosomal Ca2+ channel agonists protects human dopaminergic neurons from α-synuclein toxicity.

DESCRIPTION:
Related Articles

Increased lysosomal exocytosis induced by lysosomal Ca2+ channel agonists protects human dopaminergic neurons from α-synuclein toxicity.

J Neurosci. 2019 May 16;:

Authors: Tsunemi T, Perez-Rosello T, Ishiguro Y, Yoroisaka A, Jeon S, Hamada K, Krishna Vangipuram Suresh M, Wong YC, Xie Z, Akamatsu W, Mazzulli JR, Surmeier DJ, Hattori N, Krainc D

Abstract

The accumulation of misfolded proteins is a common pathological feature of many neurodegenerative disorders, including synucleinopathies such as Parkinson’s disease which is characterized by the presence of α-synuclein (α-syn) containing Lewy bodies. However, while recent studies have investigated α-syn accumulation and propagation in neurons, the molecular mechanisms underlying α-syn transmission have been largely unexplored. Here, we examined a monogenic form of synucleinopathy caused by loss of function mutations in lysosomal ATP13A2/PARK9. These studies revealed that lysosomal exocytosis regulates intracellular levels of α-syn in human neurons. Loss of PARK9 function in patient-derived dopaminergic neurons disrupted lysosomal Ca2+ homeostasis, reduced lysosomal Ca2+ storage, increased cytosolic Ca2+ and impaired lysosomal exocytosis. Importantly, this dysfunction in lysosomal exocytosis impaired α-syn secretion from both axons and soma, promoting α-syn accumulation. However, activation of the lysosomal Ca2+ channel – transient receptor potential mucolipin 1 (TRPML1) – was sufficient to upregulate lysosomal exocytosis, rescue defective α-syn secretion and prevent α-syn accumulation. Together, these results suggest that intracellular α-syn levels are regulated by lysosomal exocytosis in human dopaminergic neurons, and may represent a potential therapeutic target for Parkinson’s disease and other synucleinopathies. Significant Statement: Parkinson’s disease is the second most common neurodegenerative disease linked to the accumulation of a-synuclein in patient neurons. But it is unclear what this mechanism might be. Here, we demonstrate a novel role for lysosomal exocytosis in clearing intracellular a-synuclein, and show that impairment of this pathway by mutations in the Parkinson’s disease-linked gene ATP13A2/PARK9 contributes to a-synuclein accumulation in human dopaminergic neurons. Importantly, upregulating lysosomal exocytosis by increasing lysosomal Ca2+ levels is sufficient to rescue defective a-synuclein secretion and accumulation in patient neurons. These studies identify lysosomal exocytosis as a potential therapeutic target in diseases characterized by the accumulation of a-synuclein including Parkinson’s disease.

PMID: 31097622 [PubMed – as supplied by publisher]

PMID:
PubMed:31097622

DATE FOUND:
05/18/19 06:00AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31097622?dopt=Abstract

Targeting kinases in Parkinson’s disease: A mechanism shared by LRRK2, neurotrophins, exenatide, urate, nilotinib and lithium

https://www.jns-journal.com/article/S0022-510X(19)30232-1/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31129265?dopt=Abstract

TITLE:
Targeting kinases in Parkinson’s disease: A mechanism shared by LRRK2, neurotrophins, exenatide, urate, nilotinib and lithium.

DESCRIPTION:
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Targeting kinases in Parkinson’s disease: A mechanism shared by LRRK2, neurotrophins, exenatide, urate, nilotinib and lithium.

J Neurol Sci. 2019 May 15;402:121-130

Authors: Guttuso T, Andrzejewski KL, Lichter DG, Andersen JK

Abstract

Several kinases have been implicated in the pathogenesis of Parkinson’s disease (PD), most notably leucine-rich repeat kinase 2 (LRRK2), as LRRK2 mutations are the most common genetic cause of a late-onset parkinsonism that is clinically indistinguishable from sporadic PD. More recently, several other kinases have emerged as promising disease-modifying targets in PD based on both preclinical studies and clinical reports on exenatide, the urate precursor inosine, nilotinib and lithium use in PD patients. These kinases include protein kinase B (Akt), glycogen synthase kinases-3β and -3α (GSK-3β and GSK-3α), c-Abelson kinase (c-Abl) and cyclin-dependent kinase 5 (cdk5). Activities of each of these kinases are involved either directly or indirectly in phosphorylating tau or increasing α-synuclein levels, intracellular proteins whose toxic oligomeric forms are strongly implicated in the pathogenesis of PD. GSK-3β, GSK-3α and cdk5 are the principle kinases involved in phosphorylating tau at sites critical for the formation of tau oligomers. Exenatide analogues, urate, nilotinib and lithium have been shown to affect one or more of the above kinases, actions that can decrease the formation and increase the clearance of intraneuronal phosphorylated tau and α-synuclein. Here we review the current preclinical and clinical evidence supporting kinase-targeting agents as potential disease-modifying therapies for PD patients enriched with these therapeutic targets and incorporate LRRK2 physiology into this novel model.

PMID: 31129265 [PubMed – as supplied by publisher]

PMID:
PubMed:31129265

DATE FOUND:
05/28/19 01:23PM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31129265?dopt=Abstract

PDZ Scaffold Protein CAL Couples with Metabotropic Glutamate Receptor 5 to Protect Against Cell Apoptosis and Is a Potential Target in the Treatment of Parkinson’s Disease

https://link.springer.com/article/10.1007%2Fs13311-019-00730-7

https://www.ncbi.nlm.nih.gov/pubmed/31073978

PDZ Scaffold Protein CAL Couples with Metabotropic Glutamate Receptor 5 to Protect Against Cell Apoptosis and Is a Potential Target in the Treatment of Parkinson’s Disease

Abstract
Targeting mGluR5 has been an attractive strategy to modulate glutamate excitotoxicity for neuroprotection. Although human clinical trials using mGluR5 negative allosteric modulators (NAMs) have included some disappointments, recent investigations have added several more attractive small molecules to this field, providing a promise that the identification of more additional strategies to modulate mGluR5 activity might be potentially beneficial for the advancement of PD treatment. Here, we determined the role of the interacting partner CAL (cystic fibrosis transmembrane conductance regulator-associated ligand) in mGluR5-mediated protection in vitro and in vivo. In astroglial C6 cells, CAL deficiency blocked (S)-3, 5-dihydroxyphenylglycine (DHPG)-elicited p-AKT and p-ERK1/2, subsequently prevented group I mGluRs-mediated anti-apoptotic protection, which was blocked by receptor antagonist 1-aminoindan-1, 5-dicarboxylic acid (AIDA), and PI3K or MEK inhibitor LY294002 or U0126. In rotenone-treated MN9D cells, both CAL and mGluR5 expressions were decreased in a time- and dose-dependent manner, and the correlation between these 2 proteins was confirmed by lentivirus-delivered CAL overexpression and knockdown. Moreover, CAL coupled with mGluR5 upregulated mGluR5 protein expression by inhibition of ubiquitin-proteasome-dependent degradation to suppress mGluR5-mediated p-JNK and to protect against cell apoptosis. Additionally, CAL also inhibited rotenone-induced glutamate release to modulate mGluR5 activity. Furthermore, in the rotenone-induced rat model of PD, AAV-delivered CAL overexpression attenuated behavioral deficits and dopaminergic neuronal death, while CAL deficiency aggravated rotenone toxicity. On the other hand, the protective effect of the mGluR5 antagonist MPEP was weakened by knocking down CAL. In vivo experiments also confirmed that CAL inhibited ubiquitination-proteasome-dependent degradation to modulate mGluR5 expression and JNK phosphorylation. Our findings show that CAL protects against cell apoptosis via modulating mGluR5 activity, and may be a new molecular target for an effective therapeutic strategy for PD.

Neurotherapeutics. 2019 May 9. doi: 10.1007/s13311-019-00730-7. [Epub ahead of print]

First Online: 09 May 2019

FTY720 may reduce Parkinson’s disease progression by inhibiting NLRP3 inflammasome activation

https://www.ncbi.nlm.nih.gov/pubmed/31069623?dopt=Abstract

TITLE:
FTY720 Inhibits MPP+-Induced Microglial Activation by Affecting NLRP3 Inflammasome Activation.

DESCRIPTION:
Related Articles

FTY720 Inhibits MPP+-Induced Microglial Activation by Affecting NLRP3 Inflammasome Activation.

J Neuroimmune Pharmacol. 2019 May 08;:

Authors: Yao S, Li L, Sun X, Hua J, Zhang K, Hao L, Liu L, Shi D, Zhou H

Abstract

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons and excessive microglial activation in the substantia nigra pars compacta (SNpc). In the present study, we aimed to demonstrate the therapeutic effectiveness of the potent sphingosine-1-phosphate receptor antagonist fingolimod (FTY720) in an animal model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and to identify the potential mechanisms underlying these therapeutic effects. C57BL/6J mice were orally administered FTY720 before subcutaneous injection of MPTP. Open-field and rotarod tests were performed to determine the therapeutic effect of FTY720. The damage to dopaminergic neurons and the production of monoamine neurotransmitters were assessed using immunohistochemistry, high-performance liquid chromatography, and flow cytometry. Immunofluorescence (CD68- positive) and enzyme-linked immunosorbent assay were used to analyze the activation of microglia, and the levels of activated signaling molecules were measured using Western blotting. Our findings indicated that FTY720 significantly attenuated MPTP-induced behavioral deficits, reduced the loss of dopaminergic neurons, and increased dopamine release. FTY720 directly inhibited MPTP-induced microglial activation in the SNpc, suppressed the production of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α in BV-2 microglial cells treated with 1-methyl-4-phenylpyridinium (MPP+), and subsequently decreased apoptosis in SH-SY5Y neuroblastoma cells. Moreover, in MPP+-treated BV-2 cells and primary microglia, FTY720 treatment significantly attenuated the increases in the phosphorylation of PI3K/AKT/GSK-3β, reduced ROS generation and p65 activation, and also inhibited the activation of NLRP3 inflammasome and caspase-1. In conclusion, FTY720 may reduce PD progression by inhibiting NLRP3 inflammasome activation via its effects on ROS generation and p65 activation in microglia. These findings provide novel insights into the mechanisms underlying the therapeutic effects of FTY720, suggesting its potential as a novel therapeutic strategy against PD. Graphical Abstract FTY720 may reduce ROS production by inhibiting the PI3K/AKT/GSK-3β signaling pathway, while at the same time reducing p65 phosphorylation, thus decreasing NLRP3 inflammasome activation through these two pathways, ultimately reducing microglia activation-induced neuronal damage.

PMID: 31069623 [PubMed – as supplied by publisher]

PMID:
PubMed:31069623

DATE FOUND:
05/11/19 12:52PM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31069623?dopt=Abstract

Evaluating ADS5102 (amantadine) for the treatment of Parkinson’s disease patients with dyskinesia

https://www.ncbi.nlm.nih.gov/pubmed/31058557?dopt=Abstract

TITLE:
Evaluating ADS5102 (amantadine) for the treatment of Parkinson’s disease patients with dyskinesia.

DESCRIPTION:
Related Articles

Evaluating ADS5102 (amantadine) for the treatment of Parkinson’s disease patients with dyskinesia.

Expert Opin Pharmacother. 2019 May 06;:1-7

Authors: Müller T, Kuhn W, Möhr JD

Abstract

INTRODUCTION: Amantadine is an old, antiviral compound that moderately ameliorates impaired motor behaviour in Parkinson’s disease. Its current resurgence results from the novel retarded release amantadine hydrochloride formulation, ADS5102, which has also received approval for the treatment of levodopa-related involuntary movements known as dyskinesia. Areas covered: This non-systematic, narrative drug evaluation discusses the value of ADS5102 for patients with Parkinson’s disease. ADS5102 is orally applied once daily in the evening. This capsule provides higher and more continuous amantadine plasma concentrations than conventional amantadine immediate release formulations with their two to three times daily intake plan. Expert opinion: ADS5102 was superior to placebo in clinical trials. They aimed for the amelioration of motor complications, particularly at ‘OFF’ periods and with dyskinesia in fluctuating levodopa treated patients with Parkinson’s disease. Side effects and tolerability were similar to the well-known effects of conventional amantadine formulations. ADS5102 simplifies treatment and improves compliance problems in the long run. The marketing of ADS5102 outside the US will be complex for return of research costs and investments required for its manufacturing. Indeed, worldwide institutional price regulation scenarios often only consider new therapeutic mode of actions as being innovative as opposed to old drugs with improved pharmacokinetic behaviour.

PMID: 31058557 [PubMed – as supplied by publisher]

PMID:
PubMed:31058557

DATE FOUND:
05/11/19 12:46PM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31058557?dopt=Abstract
https://www.tandfonline.com/doi/abs/10.1080/14656566.2019.1612365?journalCode=ieop20

Marine-Derived Natural Compounds for the Treatment of Parkinson’s Disease

https://www.mdpi.com/1660-3397/17/4/221/htm

https://www.ncbi.nlm.nih.gov/pubmed/30978965?dopt=Abstract

TITLE:
Marine-Derived Natural Compounds for the Treatment of Parkinson’s Disease.

DESCRIPTION:
Related Articles

Marine-Derived Natural Compounds for the Treatment of Parkinson’s Disease.

Mar Drugs. 2019 Apr 11;17(4):

Authors: Huang C, Zhang Z, Cui W

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons, leading to the motor dysfunctions of patients. Although the etiology of PD is still unclear, the death of dopaminergic neurons during PD progress was revealed to be associated with the abnormal aggregation of α-synuclein, the elevation of oxidative stress, the dysfunction of mitochondrial functions, and the increase of neuroinflammation. However, current anti-PD therapies could only produce symptom-relieving effects, because they could not provide neuroprotective effects, stop or delay the degeneration of dopaminergic neurons. Marine-derived natural compounds, with their novel chemical structures and unique biological activities, may provide anti-PD neuroprotective effects. In this study, we have summarized anti-PD marine-derived natural products which have shown pharmacological activities by acting on various PD targets, such as α-synuclein, monoamine oxidase B, and reactive oxygen species. Moreover, marine-derived natural compounds currently evaluated in the clinical trials for the treatment of PD are also discussed.

PMID: 30978965 [PubMed – indexed for MEDLINE]

PMID:
PubMed:30978965

DATE FOUND:
09/04/19 06:02AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/30978965?dopt=Abstract

Histamine N-Methyltransferase in the Brain

https://www.mdpi.com/1422-0067/20/3/737

https://www.ncbi.nlm.nih.gov/pubmed/30744146?dopt=Abstract

TITLE:
Histamine N-Methyltransferase in the Brain.

DESCRIPTION:
Related Articles

Histamine N-Methyltransferase in the Brain.

Int J Mol Sci. 2019 Feb 10;20(3):

Authors: Yoshikawa T, Nakamura T, Yanai K

Abstract

Brain histamine is a neurotransmitter and regulates diverse physiological functions. Previous studies have shown the involvement of histamine depletion in several neurological disorders, indicating the importance of drug development targeting the brain histamine system. Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed in the brain. Although pharmacological studies using HNMT inhibitors have been conducted to reveal the direct involvement of HNMT in brain functions, HNMT inhibitors with high specificity and sufficient blood⁻brain barrier permeability have not been available until now. Recently, we have phenotyped Hnmt-deficient mice to elucidate the importance of HNMT in the central nervous system. Hnmt disruption resulted in a robust increase in brain histamine concentration, demonstrating the essential role of HNMT in the brain histamine system. Clinical studies have suggested that single nucleotide polymorphisms of the human HNMT gene are associated with several brain disorders such as Parkinson’s disease and attention deficit hyperactivity disorder. Postmortem studies also have indicated that HNMT expression is altered in human brain diseases. These findings emphasise that an increase in brain histamine levels by novel HNMT inhibitors could contribute to the improvement of brain disorders.

PMID: 30744146 [PubMed – indexed for MEDLINE]

PMID:
PubMed:30744146

DATE FOUND:
05/30/19 06:03AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/30744146?dopt=Abstract

The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson’s Disease

https://www.annualreviews.org/doi/10.1146/annurev-pharmtox-010818-021214

https://www.ncbi.nlm.nih.gov/pubmed/30625283?dopt=Abstract

TITLE:
The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson’s Disease.

DESCRIPTION:
Related Articles

The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson’s Disease.

Annu Rev Pharmacol Toxicol. 2019 01 06;59:263-289

Authors: Liss B, Striessnig J

Abstract

The motor symptoms of Parkinson’s disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca2+ channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vivo animal model studies that address PD-protective dihydropyridine effects. We summarize current views about the roles of Cav1.2 and Cav1.3 LTCC isoforms for substantia nigra neuron function, and their high vulnerability to degenerative stressors, and for PD pathophysiology. We discuss different dihydropyridine sensitivities of LTCC isoforms in view of their potential as drug targets for PD neuroprotection, and we conclude by considering how these aspects could guide further drug development.

PMID: 30625283 [PubMed – indexed for MEDLINE]

PMID:
PubMed:30625283

DATE FOUND:
05/15/20 06:00AM

LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/30625283?dopt=Abstract