scholarly journals Parkinson’s Disease: Can Targeting Inflammation Be an Effective Neuroprotective Strategy?

2021 ◽  
Vol 14 ◽  
Author(s):  
Vidar Gundersen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Brain Inflammation ◽  
Dopamine Neurons ◽  
Early Event ◽  
Peripheral Inflammation ◽  
Neuroprotective Strategy ◽  
Essential Questions

The reason why dopamine neurons die in Parkinson’s disease remains largely unknown. Emerging evidence points to a role for brain inflammation in neurodegeneration. Essential questions are whether brain inflammation happens sufficiently early so that interfering with this process can be expected to slow down neuronal death and whether the contribution from inflammation is large enough so that anti-inflammatory agents can be expected to work. Here I discuss data from human PD studies indicating that brain inflammation is an early event in PD. I also discuss the role of T-lymphocytes and peripheral inflammation for neurodegeneration. I critically discuss the failure of clinical trials targeting inflammation in PD.

scholarly journals The Role of NOX4 in Parkinson’s Disease with Dementia

2019 ◽  
Vol 20 (3) ◽  
pp. 696 ◽  
Author(s):  
Dong-Hee Choi ◽  
In-Ae Choi ◽  
Cheol Lee ◽  
Ji Yun ◽  
Jongmin Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Alpha Synuclein ◽  
Cognitive Status ◽  
Dopamine Neurons ◽  
Parkinson’S Disease With Dementia ◽  
6 Hydroxydopamine ◽  
Nigrostriatal Dopamine Neurons

The neuropathology of Parkinson’s disease with dementia (PDD) has been reported to involve heterogeneous and various disease mechanisms. Alpha-synuclein (α-syn) and amyloid beta (Aβ) pathology are associated with the cognitive status of PDD, and NADPH oxidase (NOX) is known to affect a variety of cognitive functions. We investigated the effects of NOX on cognitive impairment and on α-syn and Aβ expression and aggregation in PDD. In the 6-hydroxydopamine (6-OHDA)-injected mouse model, cognitive and motor function, and the levels of α-syn, Aβ, and oligomer A11 after inhibition of NOX4 expression in the hippocampal dentate gyrus (DG) were measured by the Morris water maze, novel object recognition, rotation, and rotarod tests, as well as immunoblotting and immunohistochemistry. After 6-OHDA administration, the death of nigrostriatal dopamine neurons and the expression of α-syn and NOX1 in the substantia nigra were increased, and phosphorylated α-syn, Aβ, oligomer A11, and NOX4 were upregulated in the hippocampus. 6-OHDA dose-dependent cognitive impairment was observed, and the increased cognitive impairment, Aβ expression, and oligomer A11 production in 6-OHDA-treated mice were suppressed by NOX4 knockdown in the hippocampal DG. Our results suggest that increased expression of NOX4 in the hippocampal DG in the 6-OHDA-treated mouse induces Aβ expression and oligomer A11 production, thereby reducing cognitive function.

scholarly journals Insight Into the Emerging Role of Striatal Neurotransmitters in the Pathophysiology of Parkinson’s Disease and Huntington’s Disease: A Review

2019 ◽  
Vol 17 (2) ◽  
pp. 165-175 ◽  
Author(s):  
Sumit Jamwal ◽  
Puneet Kumar
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Death ◽  
Critical Role ◽  
Altered Level ◽  
Excitotoxic Neuronal Death

Alteration in neurotransmitters signaling in basal ganglia has been consistently shown to significantly contribute to the pathophysiological basis of Parkinson’s disease and Huntington’s disease. Dopamine is an important neurotransmitter which plays a critical role in coordinated body movements. Alteration in the level of brain dopamine and receptor radically contributes to irregular movements, glutamate mediated excitotoxic neuronal death and further leads to imbalance in the levels of other neurotransmitters viz. GABA, adenosine, acetylcholine and endocannabinoids. This review is based upon the data from clinical and preclinical studies to characterize the role of various striatal neurotransmitters in the pathogenesis of Parkinson’s disease and Huntington’s disease. Further, we have collected data of altered level of various neurotransmitters and their metabolites and receptor density in basal ganglia region. Although the exact mechanisms underlying neuropathology of movement disorders are not fully understood, but several mechanisms related to neurotransmitters alteration, excitotoxic neuronal death, oxidative stress, mitochondrial dysfunction, neuroinflammation are being put forward. Restoring neurotransmitters level and downstream signaling has been considered to be beneficial in the treatment of Parkinson’s disease and Huntington’s disease. Therefore, there is an urgent need to identify more specific drugs and drug targets that can restore the altered neurotransmitters level in brain and prevent/delay neurodegeneration.

scholarly journals Galectin-3 Deletion Reduces LPS and Acute Colitis-Induced Pro-Inflammatory Microglial Activation in the Ventral Mesencephalon

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana M. Espinosa-Oliva ◽  
Pablo García-Miranda ◽  
Isabel María Alonso-Bellido ◽  
Ana E. Carvajal ◽  
Melania González-Rodríguez ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Microglial Activation ◽  
Peripheral Inflammation ◽  
Ventral Mesencephalon ◽  
Predisposing Factor ◽  
Promising Strategy ◽  
Microglia Polarization ◽  
Galectin 3

Parkinson’s disease is a highly prevalent neurological disorder for which there is currently no cure. Therefore, the knowledge of risk factors as well as the development of new putative molecular targets is mandatory. In this sense, peripheral inflammation, especially the originated in the colon, is emerging as a predisposing factor for suffering this disease. We have largely studied the pleiotropic roles of galectin-3 in driving microglia-associated immune responses. However, studies aimed at elucidating the role of galectin-3 in peripheral inflammation in terms of microglia polarization are lacking. To achieve this, we have evaluated the effect of galectin-3 deletion in two different models of acute peripheral inflammation: intraperitoneal injection of lipopolysaccharide or gut inflammation induced by oral administration of dextran sodium sulfate. We found that under peripheral inflammation the number of microglial cells and the expression levels of pro-inflammatory mediators take place specifically in the dopaminergic system, thus supporting causative links between Parkinson’s disease and peripheral inflammation. Absence of galectin-3 highly reduced neuroinflammation in both models, suggesting an important central regulatory role of galectin-3 in driving microglial activation provoked by the peripheral inflammation. Thus, modulation of galectin-3 function emerges as a promising strategy to minimize undesired microglia polarization states.

scholarly journals Effects of Oxidative Stress and Testosterone on Pro-Inflammatory Signaling in a Female Rat Dopaminergic Neuronal Cell Line

Endocrinology ◽  
2016 ◽  
Vol 157 (7) ◽  
pp. 2824-2835 ◽  
Author(s):  
Shaletha Holmes ◽  
Meharvan Singh ◽  
Chang Su ◽  
Rebecca L. Cunningham
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Androgen Receptor ◽  
Neurodegenerative Disorder ◽  
Dopamine Neurons ◽  
Female Rat ◽  
Stress Environment ◽  
Membrane Androgen Receptor

Parkinson's disease, a progressive neurodegenerative disorder, is associated with oxidative stress and neuroinflammation. These pathological markers can contribute to the loss of dopamine neurons in the midbrain. Interestingly, men have a 2-fold increased incidence for Parkinson's disease than women. Although the mechanisms underlying this sex difference remain elusive, we propose that the primary male sex hormone, testosterone, is involved. Our previous studies show that testosterone, through a putative membrane androgen receptor, can increase oxidative stress–induced neurotoxicity in dopamine neurons. Based on these results, this study examines the role of nuclear factor κ B (NF-κB), cyclooxygenase-2 (COX2), and apoptosis in the deleterious effects of androgens in an oxidative stress environment. We hypothesize, under oxidative stress environment, testosterone via a putative membrane androgen receptor will exacerbate oxidative stress–induced NF-κB/COX2 signaling in N27 dopaminergic neurons, leading to apoptosis. Our data show that testosterone increased the expression of COX2 and apoptosis in dopamine neurons. Inhibiting the NF-κB and COX2 pathway with CAPE and ibuprofen, respectively, blocked testosterone's negative effects on cell viability, indicating that NF-κB/COX2 cascade plays a role in the negative interaction between testosterone and oxidative stress on neuroinflammation. These data further support the role of testosterone mediating the loss of dopamine neurons under oxidative stress conditions, which may be a key mechanism contributing to the increased incidence of Parkinson's disease in men compared with women.

scholarly journals Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice

Gut ◽  
2018 ◽  
Vol 68 (5) ◽  
pp. 829-843 ◽  
Author(s):  
Paula Perez-Pardo ◽  
Hemraj B Dodiya ◽  
Phillip A Engen ◽  
Christopher B Forsyth ◽  
Andrea M Huschens ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Motor Dysfunction ◽  
Brain Inflammation ◽  
Translational Study ◽  
Colonic Biopsy ◽  
Rotenone Treatment

ObjectiveRecent evidence suggesting an important role of gut-derived inflammation in brain disorders has opened up new directions to explore the possible role of the gut-brain axis in neurodegenerative diseases. Given the prominence of dysbiosis and colonic dysfunction in patients with Parkinson’s disease (PD), we propose that toll-like receptor 4 (TLR4)-mediated intestinal dysfunction could contribute to intestinal and central inflammation in PD-related neurodegeneration.DesignTo test this hypothesis we performed studies in both human tissue and a murine model of PD. Inflammation, immune activation and microbiota composition were measured in colonic samples from subjects with PD and healthy controls subjects and rotenone or vehicle-treated mice. To further assess the role of the TLR4 signalling in PD-induced neuroinflammation, we used TLR4-knockout (KO) mice in conjunction with oral rotenone administration to model PD.ResultsPatients with PD have intestinal barrier disruption, enhanced markers of microbial translocation and higher pro-inflammatory gene profiles in the colonic biopsy samples compared with controls. In this regard, we found increased expression of the bacterial endotoxin-specific ligand TLR4, CD3+ T cells, cytokine expression in colonic biopsies, dysbiosis characterised by a decrease abundance of SCFA-producing colonic bacteria in subjects with PD. Rotenone treatment in TLR4-KO mice revealed less intestinal inflammation, intestinal and motor dysfunction, neuroinflammation and neurodegeneration, relative to rotenone-treated wild-type animals despite the presence of dysbiotic microbiota in TLR4-KO mice.ConclusionTaken together, these studies suggest that TLR4-mediated inflammation plays an important role in intestinal and/or brain inflammation, which may be one of the key factors leading to neurodegeneration in PD.

Diabetes and Parkinson’s Disease: Debating the Link Through Ca2+/cAMP Signalling

2020 ◽  
Vol 16 (3) ◽  
pp. 238-241 ◽  
Author(s):  
Leandro B. Bergantin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Potential Role ◽  
Insulin Signalling ◽  
Signalling Pathways ◽  
Camp Signalling ◽  
Increased Risk

Background: A link between diabetes and Parkinson´s disease (PD) has been established by several reports. Consistent data report that people diagnosed with diabetes have demonstrated an enhanced risk of manifesting PD in their lifetime. The working principles involved in this link have been extensively discussed. Over the last decade, diabetes has been reported to be correlated with an increased risk of dementia, suggesting a potential role of diabetes, or insulin signalling dysregulations, in neurodegeneration. In addition, it is nowadays highly debated that dysregulations related to Ca2+ signalling may be an upstream issue which could also link diabetes and PD. Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling) control both the neurotransmitters/hormones release and neuronal death. Conclusion: Considering our previous reports about Ca2+/cAMP signalling, the putative contribution of Ca2+/cAMP signalling in this link (between diabetes and PD) is discussed in this paper.

scholarly journals Modeling of Parkinson's disease on D. melanogaster: oxidative stress and the role of isogenization of transgenic lines

2018 ◽  
Vol 22 ◽  
pp. 46-50
Author(s):  
Kh. A. Dronska ◽  
Kh. M. Yavdyk ◽  
O. H. Stasyk ◽  
N. P. Matiytsiv
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein ◽  
Dopamine Neurons ◽  
Significant Difference ◽  
Before And After ◽  
Transgenic Lines ◽  
Stress Susceptibility

Aim. Oxidative stress (OS) is considered one of the main factors that leads to the degeneration of dopamine neurons in Parkinson's disease (PD). The purpose of the work was to test sensitivity to the conditions of the OS of D. melanogaster individuals with expression of human alpha-synuclein in neurons UAS-SNCA/elavGal4; and establish the role of the isogenization of the lines derived from stock collections in the study of this phenotype. Methods. For the isogenyzation of the line, we conducted five generations of sequential crossings of individuals with insertion of human alpha synuclein gene into the w1118 line. A 4-day test using H2O2 as prooxidant was used to test the sensitivity to OS conditions. Results. Individuals with expression of alpha-synuclein gene in neurons were characterized by statistically significant sensitivity to OS conditions, compared with controls. Also, there was a significant difference in the degree of sensitivity to the OS in the second day of the experiment in individuals before and after the isogenization of the effector line. Conclusions. Hypersensitivity to the OS is detected as a specific phenotype under conditions of expression of human alpha-synuclein in Drosophila neurons. The importance of the isogenization of transgenic lines for the characterization of the stress susceptibility phenotype is established.Keywords: Drosophila melanogaster, alpha-synuclein, oxidative stress, isogenization.

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