scholarly journals The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4674
Author(s):  
Md Ezazul Haque ◽  
Shofiul Azam ◽  
Mahbuba Akther ◽  
Duk-Yeon Cho ◽  
In-Su Kim ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Dopaminergic Neurons ◽  
Apoptotic Cell ◽  
Substantia Nigra Pars Compacta ◽  
Parp Cleavage ◽  
Protein Levels ◽  
Bax Protein ◽  
Apoptotic Marker

The proton-activated G protein-coupled receptor (GPCR) 4 (GPR4) is constitutively active at physiological pH, and GPR4 knockout protected dopaminergic neurons from caspase-dependent mitochondria-associated apoptosis. This study explored the role of GPR4 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson’s disease (PD). In mice, subchronic MPTP administration causes oxidative stress-induced apoptosis in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), resulting in motor deficits. NE52-QQ57, a selective GPR4 antagonist, reduced dopaminergic neuronal loss in MPTP-treated mice, improving motor and memory functions. MPTP and NE52-QQ57 co-treatment in mice significantly decreased pro-apoptotic marker Bax protein levels and increased anti-apoptotic marker Bcl-2 protein levels in the SNpc and striatum. MPTP-induced caspase 3 activation and poly (ADP-ribose) polymerase (PARP) cleavage significantly decreased in the SNpc and striatum of mice co-treated with NE52-QQ57. MPTP and NE52-QQ57 co-treatment significantly increased tyrosine hydroxylase (TH)-positive cell numbers in the SNpc and striatum compared with MPTP alone. NE52-QQ57 and MPTP co-treatment improved rotarod and pole test–assessed motor performance and improved Y-maze test–assessed spatial memory. Our findings suggest GPR4 may represent a potential therapeutic target for PD, and GPR4 activation is involved in caspase-mediated neuronal apoptosis in the SNpc and striatum of MPTP-treated mice.

scholarly journals Enhanced Hexokinase 2 Expression and Lactate Production Promote The Apoptosis of Dopaminergic Neurons in Parkinson’s Disease

2021 ◽  
Author(s):  
Jingyi Li ◽  
Longmin Chen ◽  
Qixiong Qin ◽  
Danlei Wang ◽  
Jingwei Zhao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Dopaminergic Neurons ◽  
Lactate Production ◽  
Substantia Nigra Pars Compacta ◽  
Hexokinase 2 ◽  
Lactate Levels

Abstract Background: Parkinson’s disease (PD) is characterized by impaired mitochondrial function and decreased ATP levels. Glycolysis is upregulated and lactate production is enhanced in PD. Since lactate promotes apoptosis and α-synuclein accumulation in neurons, we hypothesized that the increased lactate resulted from upregulated glycolysis is involved in the apoptosis of dopaminergic neurons in PD.Methods: We examined the expression of hexokinase 2 (HK2) and lactate dehydrogenase (LDH), the key enzymes in glycolysis, and lactate levels in the substantia nigra pars compacta (SNpc) of MPTP-induced mouse model of PD and in MPP+-treated SH-SY5Y cells. We investigated the role of HK2, lactate and AMPK pathway in the apoptosis of dopaminergic neurons by intervened with 3-Brpa, the HK2 inhibitor, in in vivo and in vitro systems.Results: We found that the expression of HK2 and LDHA, and lactate levels were markedly increased in brain SNpc of MPTP-treated mouse and in MPP+-treated SH-SY5Y cells. Meanwhile, the apoptosis of dopaminergic neurons in the mouse model and the apoptosis of the SH-SY5Y in vitro system were increased. Intriguingly, using HK2 inhibitor or siRNA can decrease the lactate levels and suppressed the apoptosis of dopaminergic neurons both in vivo and in vitro. Mechanistically, lactate increased the activity of adenosine monophosphate activated protein kinase (AMPK), and suppressed the phosphorylation of serine/threonine kinase 1 (Akt) and mammalian target of rapamycin (mTOR). Conclusion：Inhibition of HK2 ameliorate the apoptosis of dopaminergic neurons through downregulating the lactate production and AMPK/ Akt/ mTOR pathway activation in PD.

scholarly journals Neuroprotective Effects of Salidroside in the MPTP Mouse Model of Parkinson’s Disease: Involvement of the PI3K/Akt/GSK3βPathway

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Wei Zhang ◽  
Hong He ◽  
Hujie Song ◽  
Junjie Zhao ◽  
Tao Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Dopaminergic Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Potential Candidate ◽  
Primary Role ◽  
Protective Mechanisms ◽  
Neuroprotective Effects

The degenerative loss through apoptosis of dopaminergic neurons in the substantia nigra pars compacta plays a primary role in the progression of Parkinson’s disease (PD). Our in vitro experiments suggested that salidroside (Sal) could protect against 1-methyl-4-phenylpyridine-induced cell apoptosis in part by regulating the PI3K/Akt/GSK3βpathway. The current study aims to increase our understanding of the protective mechanisms of Sal in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine- (MPTP-) induced PD mouse model. We found that pretreatment with Sal could protect against MPTP-induced increase of the time of turning downwards and climbing down to the floor. Sal also prevented MPTP-induced decrease of locomotion frequency and the increase of the immobile time. Sal provided a protection of in MPTP-induced loss of tyrosine hydroxylase-positive neurons in SNpc and the level of DA, DOPAC, and HVA in the striatum. Furthermore, Sal could increase the phosphorylation level of Akt and GSK3β, upregulate the ratio of Bcl-2/Bax, and inhibit the activation of caspase-3, caspase-6, and caspase-9. These results show that Sal prevents the loss of dopaminergic neurons and the PI3K/Akt/GSK3βpathway signaling pathway may have mediated the protection of Sal against MPTP, suggesting that Sal may be a potential candidate in neuroprotective treatment for PD.

scholarly journals Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs

2015 ◽  
Vol 73 (7) ◽  
pp. 616-623 ◽  
Author(s):  
Taysa Bervian Bassani ◽  
Maria A.B.F. Vital ◽  
Laryssa K. Rauh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Inflammatory Process ◽  
Epidemiological Studies ◽  
Substantia Nigra Pars Compacta ◽  
Fine Motor ◽  
Progressive Degeneration ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD.

scholarly journals Simvastatin Inhibits the Activation of p21ras and Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson's Disease

2009 ◽  
Vol 29 (43) ◽  
pp. 13543-13556 ◽  
Author(s):  
A. Ghosh ◽  
A. Roy ◽  
J. Matras ◽  
S. Brahmachari ◽  
H. E. Gendelman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Dopaminergic Neurons

scholarly journals p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Jialong Chen ◽  
Kanmin Mao ◽  
Honglin Yu ◽  
Yue Wen ◽  
Hua She ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nlrp3 Inflammasome ◽  
Dopaminergic Neurons ◽  
Microglia Activation ◽  
Microglial Cells ◽  
Substantia Nigra Pars Compacta ◽  
Mice Model ◽  
Chaperone Mediated Autophagy

Abstract Background Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction. Previous studies suggested that misfolded α-synuclein induces the inflammatory response and autophagy dysfunction in microglial cells. The NLRP3 inflammasome signaling pathway plays a crucial role in the neuroinflammatory process in the central nervous system. However, the relationship between autophagy deficiency and NLRP3 activation induced by α-synuclein accumulation is not well understood. Methods Through immunoblotting, immunocytochemistry, immunofluorescence, flow cytometry, ELISA and behavioral tests, we investigated the role of p38-TFEB-NLRP3 signaling pathways on neuroinflammation in the α-synuclein A53T PD models. Results Our results showed that increased protein levels of NLRP3, ASC, and caspase-1 in the α-synuclein A53T PD models. P38 is activated by overexpression of α-synuclein A53T mutant, which inhibited the master transcriptional activator of autophagy TFEB. And we found that NLRP3 was degraded by chaperone-mediated autophagy (CMA) in microglial cells. Furthermore, p38-TFEB pathways inhibited CMA-mediated NLRP3 degradation in Parkinson's disease. Inhibition of p38 had a protective effect on Parkinson's disease model via suppressing the activation of NLRP3 inflammasome pathway. Moreover, both p38 inhibitor SB203580 and NLRP3 inhibitor MCC950 not only prevented neurodegeneration in vivo, but also alleviated movement impairment in α-synuclein A53T-tg mice model of Parkinson’s disease. Conclusion Our research reveals p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease, which could be a potential therapeutic strategy for PD. Graphical abstract p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease. In this model, p38 activates NLRP3 inflammasome via inhibiting TFEB in microglia. TFEB signaling negatively regulates NLRP3 inflammasome through increasing LAMP2A expression, which binds to NLRP3 and promotes its degradation via chaperone-mediated autophagy (CMA). NLRP3-mediated microglial activation promotes the death of dopaminergic neurons.

scholarly journals Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model

2018 ◽  
Author(s):  
Michal Wegrzynowicz ◽  
Dana Bar-On ◽  
Laura Calo’ ◽  
Oleg Anichtchik ◽  
Mariangela Iovino ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Dopaminergic Neurons ◽  
Dopamine Release ◽  
Striatal Dopamine ◽  
Substantia Nigra Pars Compacta ◽  
Motor Deficit ◽  
Promising Therapeutic Approach ◽  
Striatal Dopamine Release

SUMMARYParkinson’s Disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. Overt impairment in motor behavior was found in MI2 mice at 20 months of age, when 50% of dopaminergic neurons are lost. These changes were associated with an increase in the number and density of 20-500nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9-12 months of age, restored striatal dopamine release and prevented dopaminergic cell death. These effects were associated with a reduction of the inner density of α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction precedes dopaminergic axonal loss and neuronal death that become associated with a motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b’s function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD.

scholarly journals Detection of Parkinson’s Disease from 3T T1 Weighted MRI Scans Using 3D Convolutional Neural Network

Diagnostics ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 402
Author(s):  
Sabyasachi Chakraborty ◽  
Satyabrata Aich ◽  
Hee-Cheol Kim
Keyword(s):  
Neural Network ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Convolutional Neural Network ◽  
Dopaminergic Neurons ◽  
Aging Population ◽  
Substantia Nigra Pars Compacta ◽  
Progressive Loss ◽  
Mri Scans ◽  
Magnetic Resonance Imaging Mri

Parkinson’s Disease is a neurodegenerative disease that affects the aging population and is caused by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). With the onset of the disease, the patients suffer from mobility disorders such as tremors, bradykinesia, impairment of posture and balance, etc., and it progressively worsens in the due course of time. Additionally, as there is an exponential growth of the aging population in the world the number of people suffering from Parkinson’s Disease is increasing and it levies a huge economic burden on governments. However, until now no therapeutic method has been discovered for completely eradicating the disease from a person’s body after it’s onset. Therefore, the early detection of Parkinson’s Disease is of paramount importance to tackle the progressive loss of dopaminergic neurons in patients to serve them with a better life. In this study, 3T T1-weighted MRI scans were acquired from the Parkinson’s Progression Markers Initiative (PPMI) database of 406 subjects from baseline visit, where 203 were healthy and 203 were suffering from Parkinson’s Disease. Following data pre-processing, a 3D convolutional neural network (CNN) architecture was developed for learning the intricate patterns in the Magnetic Resonance Imaging (MRI) scans for the detection of Parkinson’s Disease. In the end, it was observed that the developed 3D CNN model performed superiorly by completely aligning with the hypothesis of the study and plotted an overall accuracy of 95.29%, average recall of 0.943, average precision of 0.927, average specificity of 0.9430, f1-score of 0.936, and Receiver Operating Characteristic—Area Under Curve (ROC-AUC) score of 0.98 for both the classes respectively.

Sign in / Sign up

Export Citation Format

Share Document