scholarly journals Patients with high inflammatory tendency induced by malignant stimulation through imbalance of CD28 and CTLA-4 / PD-1 leading to dopamine neuron injury

2021 ◽  
Author(s):  
Li Dong ◽  
Yumin Zheng ◽  
Xiaoguang Luo ◽  
Zhiyi He
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Inflammatory Factors ◽  
High Tendency ◽  
Activated State ◽  
Neuron Injury

Abstract Background Parkinson's Disease is a common neurodegenerative disease in elderly. Parkinson's Disease patients were supposed to have a higher risk of malignant transformation, however, actually the incidence of various cancers in Parkinson's Disease patients is significantly lower than common people.Parkinson's Disease patients are individuals with a high tendency of inflammation, whose peripheral immune represented in an activated state. The secretion of inflammatory factors in peripheral blood of Parkinson's Disease patients is significantly increased. We hypothesized that the hyperinflammatory predisposition of Parkinson's Disease patients is one of pathogenesis. Method: DBA/1 mice were used to simulate highly inflammatory individuals, and the carcinogen DEN was treated for malignant stimulation.HE staining was used to observe the formation of lung tumors.Apoptosis of neurons was observed by TUNEL staining.Immunohistochemical and Flow cytometrywere used to observed the expression of CD4, CD28, MHCII, CTLA-4 and PD-1. IBA-1 + iNOS was used to label M1 type microglias, and IBA-1 + Arg1 was used to label M2 type microglias by immunofluorescence. The contents of pro-inflammatory cytokines TNF-α, IL-1β and anti-inflammatory cytokines IL-10 and IL-4 in serum and brain tissues of mice in each group were detected by ELISA. Results DBA/1 mice with high inflammatory tendency showed continuous increasing of peripheral inflammation, promoting of intracranial inflammation, decreasing the tumor incidence and increasing the neurodegeneration under induction of malignant change.CD28 and CTLA-4/PD-1 reduced the T-cell-dominated inflammatory response, reduce intracerebral inflammatory response, protected the neurodegeneration, and increased the incidence of tumor.Combination of CTLA-4 and PD-1 blocker can over-activate T cells, worsen peripheral and intracranial inflammation, reduce the incidence of tumor, and cause damage to dopamine neurons, promotethe occurrence of neurodegeneration. Conclusions High inflammatory tendency induced by malignant stimulation through imbalance of CD28 and CTLA-4 / PD-1 leading to dopamine neuron injury.

scholarly journals The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3548
Author(s):  
Hao Yu ◽  
Xiaojie Liu ◽  
Bixuan Chen ◽  
Casey R. Vickstrom ◽  
Vladislav Friedman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Action Potential ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Great Promise ◽  
Action Potential Firing ◽  
Neuroprotective Effects ◽  
Potential Firing ◽  
Cb2 Agonist

Parkinson’s disease (PD) is a chronic neurodegenerative disorder associated with dopamine neuron loss and motor dysfunction. Neuroprotective agents that prevent dopamine neuron death hold great promise for slowing the disease’s progression. The activation of cannabinoid (CB) receptors has shown neuroprotective effects in preclinical models of neurodegenerative disease, traumatic brain injury, and stroke, and may provide neuroprotection against PD. Here, we report that the selective CB2 agonist GW842166x exerted protective effects against the 6-hydroxydopamine (6-OHDA)-induced loss of dopamine neurons and its associated motor function deficits in mice, as shown by an improvement in balance beam walking, pole, grip strength, rotarod, and amphetamine-induced rotation tests. The neuroprotective effects of GW842166x were prevented by the CB2 receptor antagonist AM630, suggesting a CB2-dependent mechanism. To investigate potential mechanisms for the neuroprotective effects of GW842166x, we performed electrophysiological recordings from substantia nigra pars compacta (SNc) dopamine neurons in ex vivo midbrain slices prepared from drug-naïve mice. We found that the bath application of GW842166x led to a decrease in action potential firing, likely due to a decrease in hyperpolarization-activated currents (Ih) and a shift of the half-activation potential (V1/2) of Ih to a more hyperpolarized level. Taken together, the CB2 agonist GW842166x may reduce the vulnerability of dopamine neurons to 6-OHDA by decreasing the action potential firing of these neurons and the associated calcium load.

scholarly journals Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters

2019 ◽  
Author(s):  
Rebecca D. Howell ◽  
Sergio Dominguez-Lopez ◽  
Sarah Ocañas ◽  
Willard M. Freeman ◽  
Michael J. Beckstead
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Disease Risk ◽  
Brain Slices ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Central Feature ◽  
Neuron Firing

SUMMARYThe degeneration of substantia nigra (SN) dopamine neurons is a central feature in the pathology associated with Parkinson’s disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinson’s disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. While much research in Parkinson’s has focused on the mechanisms underlying dopamine neuron degeneration, very little work has considered the influence of these two risk factors to disease risk and presentation. In this work, we performed whole cell patch clamp recordings in brain slices to study the alterations in intrinsic firing properties of single dopamine neurons in C57BL/6 mice across ages and between sexes. We observed a progressive decline in dopamine neuron firing activity in males by 18 months of age, while dopamine neurons from females remained largely unaffected. A semiquantitative analysis of midbrain dopamine neuron populations revealed a slight decrease only in substantia nigra dopamine neurons in males, while females did not change. This was also accompanied by increases in the expression of genes that have been linked to Parkinson’s including PTEN-induced kinase 1 (PINK1) in both males and females, and the ubiquitin ligase parkin, primarily in the substantia nigra of males. These impairments in dopamine neuron function in males may represent a vulnerability to further insults that could predispose these cells to neurodegenerative diseases such as in Parkinson’s.

scholarly journals Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson’s disease model

2011 ◽  
Vol 192 (5) ◽  
pp. 873-882 ◽  
Author(s):  
Won-Seok Choi ◽  
Richard D. Palmiter ◽  
Zhengui Xia
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Complex I ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Neuron Death ◽  
Complex I Activity

Mitochondrial complex I dysfunction is regarded as underlying dopamine neuron death in Parkinson’s disease models. However, inactivation of the Ndufs4 gene, which compromises complex I activity, does not affect the survival of dopamine neurons in culture or in the substantia nigra pars compacta of 5-wk-old mice. Treatment with piericidin A, a complex I inhibitor, does not induce selective dopamine neuron death in either Ndufs4+/+ or Ndufs4−/− mesencephalic cultures. In contrast, rotenone, another complex I inhibitor, causes selective toxicity to dopamine neurons, and Ndufs4 inactivation potentiates this toxicity. We identify microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species as alternative mechanisms underlying rotenone-induced dopamine neuron death. Enhanced rotenone toxicity to dopamine neurons from Ndufs4 knockout mice may involve enhanced dopamine synthesis caused by the accumulation of nicotinamide adenine dinucleotide reduced. Our results suggest that the combination of disrupting microtubule dynamics and inhibiting complex I, either by mutations or exposure to toxicants, may be a risk factor for Parkinson’s disease.

scholarly journals α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Abeer Dagra ◽  
Douglas R. Miller ◽  
Min Lin ◽  
Adithya Gopinath ◽  
Fatemeh Shaerzadeh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Activity ◽  
Dopaminergic Neurons ◽  
Prolonged Exposure ◽  
D2 Receptor ◽  
Neuronal Firing ◽  
Dopamine Neurons ◽  
Loss Of Function ◽  
Therapeutic Implications

AbstractPathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

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