scholarly journals G-protein coupled receptor 88knock-down in the associative striatum reduces the psychiatric symptoms in a translational model of Parkinson’s disease

2019 ◽  
Author(s):  
Benjamin Galet ◽  
Manuela Ingallinesi ◽  
Jonathan Pegon ◽  
Anh Do Thi ◽  
Philippe Ravassard ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
G Protein ◽  
Rat Model ◽  
Psychiatric Symptoms ◽  
Symptomatic Relief ◽  
Protein Signaling ◽  
G Protein Coupled Receptor ◽  
Motor Disability ◽  
G Protein Coupled

ABSTRACTBeyond the motor disability, Parkinson’s disease (PD) is also characterized by an early appearance of psychiatric symptoms such as apathy, depression, anxiety and cognitive deficits, which can entail dementia and psychosis in later stages. While current treatments may provide some level of symptomatic relief, their use is limited by the development of adverse effects such as impulse-control disorders. There is thus a medical need for targets with novel modes of action to treat these aspects of PD. In this context, we investigated GPR88, an orphan G-protein coupled receptor that is associated with psychiatric disorders and highly enriched in the striatum, where it exerts an inhibitory control over neurotransmitter systems that are compromised in PD. To evaluate the potential of GPR88 as a target for the treatment of the psychiatric symptoms of PD, we knocked-down (KD) its expression in sensorimotor (dorsolateral, DLS) or associative (dorsomedial, DMS) striatal areas in a translational rat model of early PD. Our findings indicate thatGpr88-KD in the DMS, but not DLS, reduced the alterations in mood, motivation and cognition that characterized the model, through modulation of the expression ofregulator of G-protein signaling 4(Rgs4) and of transcription factor ΔFosB. Furthermore, the rat model of PD exhibited allostatic changes in striatal activity markers that may be related to patterns observed in patients, and which were reduced byGpr88-KD. Taken together, these results thus highlight the relevance of GPR88 as a therapeutic target for the psychiatric symptoms of PD.

scholarly journals G-protein coupled receptor 88 knockdown in the associative striatum reduces psychiatric symptoms in a translational male rat model of Parkinson disease

2020 ◽  
Vol 46 (1) ◽  
pp. E44-E55
Author(s):  
Benjamin Galet ◽  
Manuela Ingallinesi ◽  
Jonathan Pegon ◽  
Anh Do Thi ◽  
Philippe Ravassard ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
G Protein ◽  
Rat Model ◽  
Psychiatric Symptoms ◽  
Early Stage ◽  
Male Rat ◽  
G Protein Coupled Receptor ◽  
Motor Disability ◽  
The Impact ◽  
G Protein Coupled

Background: In addition to motor disability, another characteristic feature of Parkinson disease is the early appearance of psychiatric symptoms, including apathy, depression, anxiety and cognitive deficits; treatments for these symptoms are limited by the development of adverse effects such as impulse-control disorders. In this context, we investigated the orphan G protein-coupled receptor 88 (GPR88) as a novel therapeutic target. Methods: We used lentiviral-mediated expression of specifically designed microRNA to knock down Gpr88 in a translational male rat model of early Parkinson disease obtained by dopamine loss in the dorsolateral striatum as a result of 6-hydroxydopamine lesions. We evaluated the impact of Gpr88 knockdown on the Parkinson disease model using behavioural, immunohistochemical and in situ hybridization studies. Results: Knockdown of Gpr88 in associative territories of the dorsal striatum efficiently reduced alterations in mood, motivation and cognition through modulation of the regulator of the G-protein signalling 4 and of the truncated splice variant of the FosB transcription factor. Knockdown of Gpr88 also reduced allostatic changes in striatal activity markers that may be related to patterns observed in patients and that provide support for an “overload” hypothesis for the etiology of the psychiatric symptoms of Parkinson disease. Limitations: Behavioural tests assessing specific cognitive and motivational parameters are needed to further characterize the effects of the lesion and of Gpr88 knockdown in early-stage and advanced Parkinson disease models, presenting more extensive dopamine loss. Additional studies focusing on the direct and indirect striatal output pathways are also required, because little is known about the signalling pathways regulated by GPR88 in different striatal cell types. Conclusion: GPR88 may constitute a highly relevant target for the treatment of the psychiatric symptoms of Parkinson disease.

The effect of intra-striatal administration of GPR55 agonist (LPI) and antagonist (ML193) on sensorimotor and motor functions in a Parkinson’s disease rat model

2020 ◽  
pp. 1-7
Author(s):  
Iman Fatemi ◽  
Abbas Abdollahi ◽  
Ali Shamsizadeh ◽  
Mohammad Allahtavakoli ◽  
Ali Roohbakhsh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Locomotor Activity ◽  
G Protein ◽  
Rat Model ◽  
Field Tests ◽  
Motor Deficits ◽  
G Protein Coupled Receptor ◽  
Motor Functions ◽  
G Protein Coupled

Abstract Objective: G protein-coupled receptor 55 (GPR55) is an orphan G protein-coupled receptor with various physiological functions. Recent evidence suggests that this receptor may be involved in the control of motor functions. Therefore, in the present study, we evaluated the effects of intra-striatal administration of GPR55 selective ligands in a rat model of Parkinson’s disease. Methods: Experimental Parkinson was induced by unilateral intra-striatal administration of 6-hydroxydopamine (6-OHDA, 10 µg/rat). L-α-lysophosphatidylinositol (LPI, 1 and 5 µg/rat), an endogenous GPR55 agonist, and ML193 (1 and 5 µg/rat), a selective GPR55 antagonist, were injected into the striatum of 6-OHDA-lesioned rats. Motor performance and balance skills were evaluated using the accelerating rotating rod and the ledged beam tests. The sensorimotor function of the forelimbs and locomotor activity were assessed by the adhesive removal and open field tests, respectively. Results: 6-OHDA-lesioned rats had impaired behaviours in all tests. Intra-striatal administration of LPI in 6-OHDA-lesioned rats increased time on the rotarod, decreased latency to remove the label, with no significant effect on slip steps, and locomotor activity. Intra-striatal administration of ML193 also increased time on the rotarod, decreased latency to remove the label and slip steps in 6-OHDA-lesioned rats mostly at the dose of 1 µg/rat. Conclusions: This study suggests that the striatal GPR55 is involved in the control of motor functions. However, considering the similar effects of GPR55 agonist and antagonist, it may be concluded that this receptor has a modulatory role in the control of motor deficits in an experimental model of Parkinson.

scholarly journals Niacin and Butyrate: Nutraceuticals Targeting Dysbiosis and Intestinal Permeability in Parkinson’s Disease

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 28
Author(s):  
Tennekoon B. Karunaratne ◽  
Chijioke Okereke ◽  
Marissa Seamon ◽  
Sharad Purohit ◽  
Chandramohan Wakade ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Tight Junction ◽  
G Protein ◽  
Intestinal Permeability ◽  
Macrophage Polarization ◽  
Tight Junction Proteins ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Junction Proteins

Dysbiosis is implicated by many studies in the pathogenesis of Parkinson’s disease (PD). Advances in sequencing technology and computing have resulted in confounding data regarding pathogenic bacterial profiles in conditions such as PD. Changes in the microbiome with reductions in short-chain fatty acid (SCFA)-producing bacteria and increases in endotoxin-producing bacteria likely contribute to the pathogenesis of PD. GPR109A, a G-protein coupled receptor found on the surface of the intestinal epithelium and immune cells, plays a key role in controlling intestinal permeability and the inflammatory cascade. The absence of GPR109A receptors is associated with decreased concentration of tight junction proteins, leading to increased intestinal permeability and susceptibility to inflammation. In inflammatory states, butyrate acts via GPR109A to increase concentrations of tight junction proteins and improve intestinal permeability. Niacin deficiency is exacerbated in PD by dopaminergic medications. Niacin supplementation has been shown to shift macrophage polarization from pro-inflammatory to an anti-inflammatory profile. Niacin and butyrate, promising nutrients and unique ligands for the G protein-coupled receptor GPR109A, are reviewed in this paper in detail.

scholarly journals GPR4 Knockout Improves the Neurotoxin-Induced, Caspase-Dependent Mitochondrial Apoptosis of the Dopaminergic Neuronal Cell

2020 ◽  
Vol 21 (20) ◽  
pp. 7517
Author(s):  
Md Ezazul Haque ◽  
Mahbuba Akther ◽  
Shofiul Azam ◽  
Dong-Kug Choi ◽  
In-Su Kim
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
G Protein ◽  
Apoptotic Cell ◽  
B Cell Lymphoma ◽  
Apoptotic Cell Death ◽  
G Protein Coupled Receptor ◽  
Human Neuroblastoma ◽  
G Protein Coupled

In Parkinson’s disease, mitochondrial oxidative stress-mediated apoptosis is a major cause of dopaminergic neuronal loss in the substantia nigra (SN). G protein-coupled receptor 4 (GPR4), previously recognised as an orphan G protein coupled-receptor (GPCR), has recently been claimed as a member of the group of proton-activated GPCRs. Its activity in neuronal apoptosis, however, remains undefined. In this study, we investigated the role of GPR4 in the 1-methyl-4-phenylpyridinium ion (MPP+) and hydrogen peroxide (H2O2)-treated apoptotic cell death of stably GPR4-overexpressing and stably GPR4-knockout human neuroblastoma SH-SY5Y cells. In GPR4-OE cells, MPP+ and H2O2 were found to significantly increase the expression levels of both mRNA and proteins of the pro-apoptotic Bcl-2-associated X protein (Bax) genes, while they decreased the anti-apoptotic B-cell lymphoma 2 (Bcl-2) genes. In addition, MPP+ treatment activated Caspase-3, leading to the cleavage of poly (ADP-ribose) polymerase (PARP) and decreasing the mitochondrial membrane potential (ΔΨm) in GPR4-OE cells. In contrast, H2O2 treatment significantly increased the intracellular calcium ions (Ca2+) and reactive oxygen species (ROS) in GPR4-OE cells. Further, chemical inhibition by NE52-QQ57, a selective antagonist of GPR4, and knockout of GPR4 by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 decreased the Bax/Bcl-2 ratio and ROS generation, and stabilised the ΔΨm, thus protecting the SH-SY5Y cells from MPP+- or H2O2-induced apoptotic cell death. Moreover, the knockout of GPR4 decreased the proteolytic degradation of phosphatidylinositol biphosphate (PIP2) and subsequent release of the endoplasmic reticulum (ER)-stored Ca2+ in the cytosol. Our results suggest that the pharmacological inhibition or genetic deletion of GPR4 improves the neurotoxin-induced caspase-dependent mitochondrial apoptotic pathway, possibly through the modulation of PIP2 degradation-mediated calcium signalling. Therefore, GPR4 presents a potential therapeutic target for neurodegenerative disorders such as Parkinson’s disease.

Lack of association between G-protein coupled receptor kinase 5 gene and Parkinson's disease

2010 ◽  
Vol 156 (1) ◽  
pp. 104-107 ◽  
Author(s):  
Patrizia Tarantino ◽  
Elvira Valeria De Marco ◽  
Grazia Annesi ◽  
Francesca Emanuela Rocca ◽  
Ferdinanda Annesi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
G Protein ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled
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