scholarly journals Nardosinone Alleviates Parkinson’s Disease Symptoms in Mice by Regulating Dopamine D2 Receptor

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Li-hua Bian ◽  
Zi-wei Yao ◽  
Cheng-bowen Zhao ◽  
Qiu-yu Li ◽  
Jin-li Shi ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Interaction Network ◽  
Network Pharmacology ◽  
Cognitive Symptoms ◽  
Behavioral Tests ◽  
Disease Symptoms ◽  
Nardostachys Jatamansi ◽  
The Brain ◽  
Orbitrap Ms

Nardostachyos Radix et Rhizoma (nardostachys) is the root and rhizome of Nardostachys jatamansi DC. Recent studies have shown that nardostachys may exert an anti-PD effect. In this study, the UHPLC-LTQ-Orbitrap-MS method was used to analyze the brain components of nardostachys in rats. Based on the results of UHPLC-LTQ-Orbitrap-MS analysis, nardosinone was identified to be the most effective anti-PD compound in nardostachys. To further verify this inference, a mouse PD model was established and the effect of nardosinone on PD mice was determined using classic behavioral tests. The results showed that nardosinone was indeed effective for relieving PD symptoms in mice. Moreover, network pharmacology analysis was used to elucidate the mechanism underlying the anti-PD effect of nardosinone. Dopamine receptor D2 (DRD2) was identified as the key target of nardosinone-PD interaction network, which was further verified by molecular docking and Western blotting. The results demonstrated that nardosinone and DRD2 could interact with each other. Furthermore, the expression level of DRD2 was decreased in the brain tissue of PD mice, and nardosinone could restore its expression to a certain extent. In conclusion, our findings suggest that nardosinone may reduce the motor and cognitive symptoms in the animal PD model by regulating DRD2 expression.

scholarly journals Presence of a D2 receptor truncated protein in the brain of the D2 receptor functional knockout mouse, revisiting its molecular and neurochemical features

2019 ◽  
Author(s):  
Natalia Sánchez ◽  
Montserrat Olivares-Costa ◽  
Marcela P González ◽  
Angélica P Escobar ◽  
Rodrigo Meza ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Knockout Mouse ◽  
Transmembrane Domain ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Wild Type ◽  
Intracellular Loop ◽  
Protein Protein Interaction ◽  
Acute Injection ◽  
The Brain

AbstractNull mice for the dopamine D2 receptor (D2R) have been instrumental in understanding the function of this protein in the central nervous system. Several lines of D2R knockout mice have been generated, which share some characteristics but differ in others. The D2R functional knockout mouse, first described in 1997, is functionally null for D2R-mediated signaling but the Drd2 gene was interrupted at the most extreme distal end leaving open the question about whether transcript and protein are produced. We decided to determine if there are D2R transcripts, the characteristics of these transcripts and whether they are translated in the brain of D2R functional knockout mice. Sequence analysis of 3’ Rapid Amplification of cDNA Ends showed that D2R functional knockout mice express transcripts that lack only the exon eight. Immunofluorescence showed D2R-like protein in the brain of the knockout mice. As previously reported, D2R functional knockout mice are hypoactive and insensitive to the D2R agonist quinpirole (QNP). However, the heterozygous showed locomotor activity and response to QNP similar to the wild-type mice. Intriguingly, microdialysis experiments showed that heterozygous mice, such as knockouts, have half the normal levels of synaptic dopamine in the striatum. However, heterozygous mice responded similarly to wild-type mice to an acute injection of QNP, showing a 50% decrease in synaptic dopamine. In conclusion, D2R functional knockout mice express transcripts that lead to a truncated D2R protein that lacks from the sixth transmembrane domain to the C-terminal end but retains the third intracellular loop. We discuss the implications of this truncated D2R coexisting with the native D2R that may explain the unexpected outcomes observed in the heterozygous. Finally, we suggest that the D2R functional knockout mouse can be a useful model for studying protein-protein interaction and trafficking of D2R.

scholarly journals Knockout or Knock-in? A Truncated D2 Receptor Protein Is Expressed in the Brain of Functional D2 Receptor Knockout Mice

NeuroSci ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 193-206
Author(s):  
Natalia Sánchez ◽  
Montserrat Olivares-Costa ◽  
Marcela P González ◽  
Roberto Munita ◽  
Angélica P Escobar ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Mouse Strain ◽  
Knockout Mice ◽  
Biochemical Characterization ◽  
Transmembrane Domain ◽  
Dopamine D2 Receptor ◽  
Intracellular Localization ◽  
D2 Receptor ◽  
Receptor Protein ◽  
The Brain

Null mice for the dopamine D2 receptor (D2R) have been instrumental in understanding the function of this protein. For our research, we obtained the functional D2R knockout mouse strain described initially in 1997. Surprisingly, our biochemical characterization showed that this mouse strain is not a true knockout. We determined by sequence analysis of the rapid 3′ amplification of cDNA ends that functional D2R knockout mice express transcripts that lack only the eighth exon. Furthermore, immunofluorescence assays showed a D2R-like protein in the brain of functional D2R knockout mice. We verified by immunofluorescence that the recombinant truncated D2R is expressed in HEK293T cells, showing intracellular localization, colocalizing in the Golgi apparatus and the endoplasmic reticulum, but with less presence in the Golgi apparatus compared to the native D2R. As previously reported, functional D2R knockout mice are hypoactive and insensitive to the D2R agonist quinpirole. Concordantly, microdialysis studies confirmed that functional D2R knockout mice have lower extracellular dopamine levels in the striatum than the native mice. In conclusion, functional D2R knockout mice express transcripts that lead to a truncated D2R protein lacking from the sixth transmembrane domain to the C-terminus. We share these findings to avoid future confusion and the community considers this mouse strain in D2R traffic and protein–protein interaction studies.

scholarly journals Novel Combination of HuanglianJiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

2021 ◽  
Author(s):  
Su-Ya Ma ◽  
Xu Wang ◽  
Jing Shi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Psychological Symptoms ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Binding Activity ◽  
Network Pharmacology ◽  
Scutellariae Radix ◽  
Coptidis Rhizoma ◽  
Behavioral And Psychological Symptoms

Abstract Alzheimer's disease (AD) is characterized by progressive cognitive decline. Besides cognitive deficit, AD is also characterized by behavioral and psychological symptoms in dementia (BPSD). However, therapeutic management of BPSD remains challenging. HuanglianJiedu decoction (HLJDD), a traditional Chinese prescription, consisting of four herbs, is applied to treat AD, especially AD with BPSD. Though HLJDD, has the traditional combination with the principal herb Coptidis rhizoma (Huang-lian), it might, however, not be suitable for treating BPSD. Elucidating the mechanism underlying each herb is critical to the disease-matched combination of HLJDD. In this study, network pharmacology was used to determine the targets and biological processes regulated by HLJDD in the treatment of BPSD. Moreover, molecular docking was utilized to evaluate the binding activity between the herbs' main active ingredients and neurotransmitter receptors. The results showed that Scutellariae radix (Huang-qin) and Phellodendri chinrnsis cortex (Huang-bai) exhibited better anti-BPSD effects when compared to Coptidis rhizoma and Gardeniae fructus (Zhi-zi). Scutellariae radix exhibited superior anti-neuroinflammation functions, with better blood vessel regulation effects. Phellodendri chinrnsis cortex showed a higher binding affinity to the dopamine D2 receptor (DRD2) and 5-hydroxytryptamine receptor 2A (HTR2A). Coptidis rhizoma and Gardeniae fructus were better in neuronal signaling. In conclusion, for treating BPSD, Scutellariae radix and Phellodendri chinrnsis cortex are the principal herbs while Coptidis rhizoma and Gardeniae fructus are the ancillary herbs.

scholarly journals CRISPR/Cas9 mediated intersectional knockout of GSK3β in D2 receptor expressing mPFC neurons reveals contributions to emotional regulation

2019 ◽  
Author(s):  
Jivan Khlghatyan ◽  
Jean-Martin Beaulieu
Keyword(s):  
Emotional Regulation ◽  
Large Scale ◽  
Dopamine D2 Receptor ◽  
Glycogen Synthase ◽  
D2 Receptor ◽  
Dependent Manner ◽  
Targeted Deletion ◽  
Conventional Animal ◽  
Cortical Regions ◽  
The Brain

AbstractBackgroundGlycogen synthase kinase 3β (GSK3β) regulates neurodevelopment, synaptic plasticity as well as mood, cognition, social interaction, and depressive-like behaviors. Inhibition of GSK3β is a shared consequence of treatment by lithium, SSRIs, ketamine and antipsychotics. GSK3β activity is regulated by dopamine D2 receptor signaling and can be inhibited by psychoactive drugs in a D2 receptor dependent manner. Functions of GSK3β in striatal D2 neurons has been studied extensively. However, GSK3β is ubiquitously expressed in the brain and D2 receptor expressing cells are distributed as a mosaic in multiple cortical regions. This complicates the interrogation of GSK3β functions in cortical D2 cells in a circuit defined manner using conventional animal models.MethodsWe have used a CRISPR/Cas9 mediated intersectional approach to achieve targeted deletion of GSK3β in D2 expressing neurons of the adult medial prefrontal cortex (mPFC).ResultsIsolation and analysis of ribosome associated RNA specifically from mPFC D2 neurons lacking GSK3β demonstrated large scale translatome alterations. Deletion of GSK3β in mPFC D2 neurons revealed its contribution to anxiety-related, cognitive, and social behaviors.ConclusionsOur results underscore the viability of intersectional knockout approach to study functions of a ubiquitous gene in a network defined fashion while uncovering a contribution of GSK3β expressed in mPFC D2 neurons in the regulation of behavioral dimensions related to mood and emotions. This advances our understanding of GSK3β action at a brain circuit level and can potentially lead to the development of circuit selective therapeutics.

scholarly journals Obesity Is Associated with Decreased  -Opioid But Unaltered Dopamine D2 Receptor Availability in the Brain

2015 ◽  
Vol 35 (9) ◽  
pp. 3959-3965 ◽  
Author(s):  
H. K. Karlsson ◽  
L. Tuominen ◽  
J. J. Tuulari ◽  
J. Hirvonen ◽  
R. Parkkola ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dopamine D2 ◽  
The Brain

scholarly journals The Brain Cytoplasmic RNA BC1 Regulates Dopamine D2 Receptor-Mediated Transmission in the Striatum

2007 ◽  
Vol 27 (33) ◽  
pp. 8885-8892 ◽  
Author(s):  
D. Centonze ◽  
S. Rossi ◽  
I. Napoli ◽  
V. Mercaldo ◽  
C. Lacoux ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dopamine D2 ◽  
Cytoplasmic Rna ◽  
The Brain

Alteration of dopamine transport and dopamine D2 receptor binding in the brain induced by early and late consequences of global ischaemia caused by cardiac arrest in the rat

Resuscitation ◽  
2000 ◽  
Vol 47 (2) ◽  
pp. 195-201 ◽  
Author(s):  
Urszula Rafałowska ◽  
Grzegorz Sulkowski ◽  
Jolanta Waśekiewicz ◽  
Satwomir Januszewski ◽  
Andrzej Kapuościñski
Keyword(s):  
Cardiac Arrest ◽  
Receptor Binding ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dopamine D2 ◽  
Global Ischaemia ◽  
Dopamine Transport ◽  
The Brain

scholarly journals Decrease in Human Striatal Dopamine D2 Receptor Density with Age: A PET Study with [11C]Raclopride

1993 ◽  
Vol 13 (2) ◽  
pp. 310-314 ◽  
Author(s):  
Juha O. Rinne ◽  
Jarmo Hietala ◽  
Ulla Ruotsalainen ◽  
Erkki Säkö ◽  
Arto Laihinen ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Striatal Dopamine ◽  
Scatchard Analysis ◽  
Age Related ◽  
Positron Emission ◽  
Age Dependent ◽  
Pet Scans ◽  
The Brain ◽  
Effect Of Age

The effect of age on human striatal dopamine D2 receptors was investigated with positron emission tomography (PET) using [11C]raclopride as a radioligand. Twenty-one healthy volunteers aged from 20 to 81 years were studied. An equilibrium method was applied and two separate PET scans with different specific activities of [11C]raclopride were performed. The maximal number of receptors ( Bmax) and their dissociation constant ( Kd) were calculated using Scatchard analysis. There was an age-dependent decline in the Bmax ( r = 0.49; p = 0.02) of striatal D2 receptors while the Kd remained unchanged. The results show that there is an age-related loss of striatal D2 receptors, which, together with other changes in the brain nigrostriatal dopaminergic system, may contribute to extrapyramidal symptoms associated with aging.

scholarly journals Cocaine-mediated circadian reprogramming in the striatum through dopamine D2R and PPARγ activation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Karen Brami-Cherrier ◽  
Robert G. Lewis ◽  
Marlene Cervantes ◽  
Yu Liu ◽  
Paola Tognini ◽  
...  
Keyword(s):  
Substance Abuse ◽  
Inflammatory Responses ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Medium Spiny Neurons ◽  
Acute Administration ◽  
Protein Activator ◽  
Pparγ Agonist ◽  
Substance Abuse Disorders ◽  
The Brain

Abstract Substance abuse disorders are linked to alteration of circadian rhythms, although the molecular and neuronal pathways implicated have not been fully elucidated. Addictive drugs, such as cocaine, induce a rapid increase of dopamine levels in the brain. Here, we show that acute administration of cocaine triggers reprogramming in circadian gene expression in the striatum, an area involved in psychomotor and rewarding effects of drugs. This process involves the activation of peroxisome protein activator receptor gamma (PPARγ), a nuclear receptor involved in inflammatory responses. PPARγ reprogramming is altered in mice with cell-specific ablation of the dopamine D2 receptor (D2R) in the striatal medium spiny neurons (MSNs) (iMSN-D2RKO). Administration of a specific PPARγ agonist in iMSN-D2RKO mice elicits substantial rescue of cocaine-dependent control of circadian genes. These findings have potential implications for development of strategies to treat substance abuse disorders.

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