Early ghrelin intervention protects against the progressive dopaminergic neuron loss in Parkinson’s disease mice

2020 ◽  
Author(s):  
Lingling Jiao ◽  
Fengju Jia ◽  
Xixun Du ◽  
Pei Zhang ◽  
Yong Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Weight Loss ◽  
Parkinson's Disease ◽  
Inflammatory Cytokine ◽  
Protective Factor ◽  
Subcutaneous Administration ◽  
Protein Levels ◽  
Potential Applications ◽  
Anti Oxidant ◽  
Anti Inflammatory

Abstract BackgroundGhrelin has been identified as a multifunctional peptide that has many potential applications for the treatment of various diseases, including Parkinson’s disease (PD). However, little is known about the pathophysiological function and mechanism of ghrelin in PD. MethodELISA was used for detecting plasma total and active ghrelin levels, dopamine (DA) content was measured by HPLC-ECD, immunofluorescence staining and Western blot were used to detect protein expressions, and cytokine was tested by Bio-PlexPro™ assay.ResultsHere, we reported a PD model that overexpressing mutant human A53T α-syn mice exhibited a decreased levels of total and active ghrelin in plasma, fewer tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN), lower DA content in the striatum (Str), and less weight. These changes were rescued by the subcutaneous administration of low-dose ghrelin. Interestingly, ghrelin had no effect on weight gain in wild-type mice but improved weight loss in A53T mice. In addition, ghrelin administration also attenuated the decreased Bcl-2/Bax ratio and superoxide dismutase1 (SOD1) protein levels and inhibited the upregulation pro-inflammatory cytokine interleukin-6 (IL-6) and tumour necrosis factor a (TNFa) and the downregulation of anti-inflammatory cytokine IL-10. In addition, ghrelin inhibited the increase in Iba1-positive cells in mice with PD.ConclusionsHere we reported that ghrelin had a protective effect on dopaminergic neurons and against weight loss from PD via anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms, which suggested that ghrelin could be an endogenous protective factor that prevents the onset or the progression of PD.

scholarly journals Anti-inflammatory and Anti-oxidant Activity of Hidrox® in Rotenone-Induced Parkinson’s Disease in Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 824 ◽  
Author(s):  
Rosalba Siracusa ◽  
Maria Scuto ◽  
Roberta Fusco ◽  
Angela Trovato ◽  
Maria Laura Ontario ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Human Life ◽  
Developed Countries ◽  
Progressive Increase ◽  
Behavioral Alterations ◽  
Anti Oxidant ◽  
Anti Inflammatory ◽  
Main Component

Background: In developed countries, the extension of human life is increasingly accompanied by a progressive increase in neurodegenerative diseases, most of which do not yet have effective therapy but only symptomatic treatments. In recent years, plant polyphenols have aroused considerable interest in the scientific community. The mechanisms currently hypothesized for the pathogenesis of Parkinson’s disease (PD) are neuroinflammation, oxidative stress and apoptosis. Hydroxytyrosol (HT), the main component of Hidrox® (HD), has been shown to have some of the highest free radical evacuation and anti-inflammatory activities. Here we wanted to study the role of HD on the neurobiological and behavioral alterations induced by rotenone. Methods: A study was conducted in which mice received HD (10 mg/kg, i.p.) concomitantly with rotenone (5 mg/kg, o.s.) for 28 days. Results: Locomotor activity, catalepsy, histological damage and several characteristic markers of the PD, such as the dopamine transporter (DAT) content, tyrosine hydroxylase (TH) and accumulation of α-synuclein, have been evaluated. Moreover, we observed the effects of HD on oxidative stress, neuroinflammation, apoptosis and inflammasomes. Taken together, the results obtained highlight HD’s ability to reduce the loss of dopaminergic neurons and the damage associated with it by counteracting the three main mechanisms of PD pathogenesis. Conclusion: HD is subject to fewer regulations than traditional drugs to improve patients’ brain health and could represent a promising nutraceutical choice to prevent PD.

scholarly journals Anti-Inflammatory Cytokine-Eluting Collagen Hydrogel Reduces the Host Immune Response to Dopaminergic Cell Transplants in a Rat Model of Parkinson's Disease

2021 ◽  
Author(s):  
Sílvia Cabré ◽  
Verónica Alamilla ◽  
Niamh Moriarty ◽  
Abhay Pandit ◽  
Eilís Dowd
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inflammatory Cytokine ◽  
Rat Striatum ◽  
In Vivo Evaluation ◽  
Neuroinflammatory Response ◽  
Collagen Hydrogel ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine

In cell replacement approaches for Parkinson's disease, the intra-cerebral implantation of dopamine neuron-rich grafts generates a neuroinflammatory response to the grafted cells that contributes to its varied outcome. Thus, the aim of this study was to fabricate an anti-inflammatory cytokine-eluting collagen hydrogel capable of delivering IL-10 to the brain for reduction of the neuroinflammatory response to intra-cerebral cellular grafts. In vitro assessment revealed that crosslinker concentration affected the microstructure and gelation kinetics of the hydrogels and their IL-10 elution kinetics, but not their cytocompatibility or the functionality of the eluted IL-10. In vivo evaluation revealed that the hydrogels were capable of delivering and retaining IL-10 in the rat striatum, and reducing the neuroinflammatory (microglial) response to hydrogel-encapsulated grafts. In conclusion, IL-10-eluting collagen hydrogels may have beneficial anti-inflammatory effects in the context of cellular brain repair therapies for Parkinson's disease and should be investigated further.

scholarly journals Early low-dose ghrelin intervention via mini-osmotic pumps could protect against the progressive dopaminergic neuron loss in Parkinson’s disease mice

2020 ◽  
Author(s):  
Lingling Jiao ◽  
Xixun Du ◽  
Fengju Jia ◽  
Pei Zhang ◽  
Yong Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Low Dose ◽  
Subcutaneous Administration ◽  
Neuron Loss ◽  
Osmotic Pumps ◽  
Dopamine Content ◽  
Daergic Neuron ◽  
Potential Applications ◽  
Dopaminergic Neuron Loss

Abstract BackgroundGhrelin has been identified as a multifunctional peptide that has a potential applications for the treatment Parkinson’s disease (PD). Method: ELISA was used for detecting plasma total and active ghrelin levels, dopamine (DA) content was measured by HPLC-ECD, immunofluorescence staining and Western blot were used to detect protein expressions, and cytokine was tested by Bio-PlexPro™ assay.ResultsHere, we reported a subcutaneous administration of low-dose ghrelin via mini-osmotic pumps to PD mice. The decreased levels of total and active ghrelin in plasma were rescued by ghrelin administration. Interestingly, ghrelin had no effect on weight gain in wild-type mice but improved weight loss in PD mice. We observed the attenuation of dopaminergic (DAergic) neuron loss in substantia nigra (SN) and low level of dopamine content in the striatum in PD mice with ghrelin treatment. Ghrelin administration could improve the environment of DAergic neuron by inhibiting microglia proliferation and pro-inflammatory cytokine expression, and could enhance cell survival by upregulating Bcl-2/Bax ratio and superoxide dismutase1 (SOD1) protein level in SN in PD mice.ConclusionsOur results suggested that subcutaneous administration of low-dose ghrelin could prevent the onset or the progression of PD, and also provided a possible method for ghrelin application to cure PD.

scholarly journals The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4676
Author(s):  
Katja Badanjak ◽  
Sonja Fixemer ◽  
Semra Smajić ◽  
Alexander Skupin ◽  
Anne Grünewald
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inflammatory Cytokine ◽  
Population Ageing ◽  
Future Research ◽  
Cytokine Release ◽  
Vicious Cycle ◽  
Inflammatory Processes ◽  
Great Evidence

With the world’s population ageing, the incidence of Parkinson’s disease (PD) is on the rise. In recent years, inflammatory processes have emerged as prominent contributors to the pathology of PD. There is great evidence that microglia have a significant neuroprotective role, and that impaired and over activated microglial phenotypes are present in brains of PD patients. Thereby, PD progression is potentially driven by a vicious cycle between dying neurons and microglia through the instigation of oxidative stress, mitophagy and autophagy dysfunctions, a-synuclein accumulation, and pro-inflammatory cytokine release. Hence, investigating the involvement of microglia is of great importance for future research and treatment of PD. The purpose of this review is to highlight recent findings concerning the microglia-neuronal interplay in PD with a focus on human postmortem immunohistochemistry and single-cell studies, their relation to animal and iPSC-derived models, newly emerging technologies, and the resulting potential of new anti-inflammatory therapies for PD.

scholarly journals Fibroblasts from idiopathic Parkinson’s disease exhibit deficiency of lysosomal glucocerebrosidase activity associated with reduced levels of the trafficking receptor LIMP2

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ria Thomas ◽  
Elizabeth B. Moloney ◽  
Zachary K. Macbain ◽  
Penelope J. Hallett ◽  
Ole Isacson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Enzyme Activity ◽  
Current Data ◽  
Lysosomal Hydrolase ◽  
Protein Levels ◽  
Control Subjects ◽  
Er Retention ◽  
Trafficking Receptor ◽  
N370s Mutation

AbstractLysosomal dysfunction is a central pathway associated with Parkinson’s disease (PD) pathogenesis. Haploinsufficiency of the lysosomal hydrolase GBA (encoding glucocerebrosidase (GCase)) is one of the largest genetic risk factors for developing PD. Deficiencies in the activity of the GCase enzyme have been observed in human tissues from both genetic (harboring mutations in the GBA gene) and idiopathic forms of the disease. To understand the mechanisms behind the deficits of lysosomal GCase enzyme activity in idiopathic PD, this study utilized a large cohort of fibroblast cells from control subjects and PD patients with and without mutations in the GBA gene (N370S mutation) (control, n = 15; idiopathic PD, n = 31; PD with GBA N370S mutation, n = 6). The current data demonstrates that idiopathic PD fibroblasts devoid of any mutations in the GBA gene also exhibit reduction in lysosomal GCase activity, similar to those with the GBA N370S mutation. This reduced GCase enzyme activity in idiopathic PD cells was accompanied by decreased expression of the GBA trafficking receptor, LIMP2, and increased ER retention of the GBA protein in these cells. Importantly, in idiopathic PD fibroblasts LIMP2 protein levels correlated significantly with GCase activity, which was not the case in control subjects or in genetic PD GBA N370S cells. In conclusion, idiopathic PD fibroblasts have decreased GCase activity primarily driven by altered LIMP2-mediated transport of GBA to lysosome and the reduced GCase activity exhibited by  the genetic GBA N370S derived PD fibroblasts occurs through a different mechanism.

scholarly journals Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110097
Author(s):  
Kui Cui ◽  
Fan Yang ◽  
Turan Tufan ◽  
Muhammad U. Raza ◽  
Yanqiang Zhan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factors ◽  
Disease Model ◽  
Neuronal Loss ◽  
Mrna Levels ◽  
Gene Therapies ◽  
Protein Levels ◽  
Dopaminergic Systems ◽  
And Function

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

scholarly journals TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

2017 ◽  
Vol 114 (40) ◽  
pp. 10773-10778 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Matthew J. Benskey ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Kinase Domain ◽  
Alpha Synuclein ◽  
Mao B ◽  
Protein Levels ◽  
Trkb Receptors ◽  
Alpha Synuclein Aggregation ◽  
Neurotrophic Signaling

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

Increased Striatal mRNA and Protein Levels of the Immunophilin FKBP-12 in Experimental Parkinson's Disease and Identification of FKBP-12-Binding Proteins

2007 ◽  
Vol 6 (10) ◽  
pp. 3952-3961 ◽  
Author(s):  
Anna Nilsson ◽  
Karl Sköld ◽  
Benita Sjögren ◽  
Marcus Svensson ◽  
Johan Pierson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Proteins ◽  
Protein Levels
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