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 Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson’s disease

2015 ◽  
Vol 26 (24) ◽  
pp. 4478-4491 ◽  
Author(s):  
BK. Binukumar ◽  
Varsha Shukla ◽  
Niranjana D. Amin ◽  
Philip Grant ◽  
M. Bhaskar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Selective Inhibition ◽  
Motor Dysfunction ◽  
Dopamine Neurons ◽  
Dopamine Depletion ◽  
Neuroprotective Effects

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer’s disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 ­hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson’s disease.

scholarly journals Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson's Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 206 ◽  
Author(s):  
Tsung-Hsun Hsieh ◽  
Chi-Wei Kuo ◽  
Kai-Hsuan Hsieh ◽  
Meng-Jyh Shieh ◽  
Chih-Wei Peng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Motor Coordination ◽  
Dopamine Neurons ◽  
Motor Symptoms ◽  
Neuroprotective Effects ◽  
Motor Functions ◽  
Term Administration ◽  
Nigrostriatal Dopamine Neurons

Parkinson’s disease (PD) is one of the common long-term degenerative disorders that primarily affect motor systems. Gastrointestinal (GI) symptoms are common in individuals with PD and often present before motor symptoms. It has been found that gut dysbiosis to PD pathology is related to the severity of motor and non-motor symptoms in PD. Probiotics have been reported to have the ability to improve the symptoms related to constipation in PD patients. However, the evidence from preclinical or clinical research to verify the beneficial effects of probiotics for the motor functions in PD is still limited. An experimental PD animal model could be helpful in exploring the potential therapeutic strategy using probiotics. In the current study, we examined whether daily and long-term administration of probiotics has neuroprotective effects on nigrostriatal dopamine neurons and whether it can further alleviate the motor dysfunctions in PD mice. Transgenic MitoPark PD mice were chosen for this study and the effects of daily probiotic treatment on gait, beam balance, motor coordination, and the degeneration levels of dopaminergic neurons were identified. From the results, compared with the sham treatment group, we found that the daily administration of probiotics significantly reduced the motor impairments in gait pattern, balance function, and motor coordination. Immunohistochemically, a tyrosine hydroxylase (TH)-positive cell in the substantia nigra was significantly preserved in the probiotic-treated PD mice. These results showed that long-term administration of probiotics has neuroprotective effects on dopamine neurons and further attenuates the deterioration of motor dysfunctions in MitoPark PD mice. Our data further highlighted the promising possibility of the potential use of probiotics, which could be the relevant approach for further application on human PD subjects.

scholarly journals Neuroprotective effects of Shende’an tablet in the Parkinson’s disease model

2021 ◽  
Author(s):  
Xiao Yan Sheng ◽  
Shui Yuan Yang ◽  
Xiao Min Wen ◽  
Xin Zhang ◽  
Yong Feng Ye ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pc12 Cells ◽  
Motor Behavior ◽  
Neuroprotective Effect ◽  
Signal Pathway ◽  
Dopamine Neurons ◽  
Therapeutic Modality ◽  
Neuroprotective Effects

Abstract Background: Shende’an tablet (SDA) is a newly capsuled Chinese herbal formula derived from the Chinese traditional medicine Zhengan Xifeng Decoction which is approved for the treatment of neurasthenia and insomnia in China. This study aimed to investigate the neuroprotective effects of SDA against Parkinson’s disease (PD) in vitro and in vivo.Methods: In the present work, the neuroprotective effects and mechanism of SDA were evaluated in the cellular PD model. Male C57BL/6J mice were subject to a partial MPTP lesion alongside treatment with SDA. Behavioural test and tyrosine-hydroxylase immunohistochemistry were used to evaluate nigrostriatal tract integrity. HPLC analysis and Western blotting were used to assess the effect of SDA on dopamine metabolism and the expression of HO-1, PGC-1α and Nrf2, respectively.Results: Our results demonstrated that SDA had neuroprotective effect in dopaminergic PC12 cells with 6-OHDA lesion. It had also displayed efficient dopaminergic neuronal protection and motor behavior alleviation properties in MPTP-induced PD mice. In the PC12 cells and MPTP-induced Parkinson’s disease animal models, SDA was highly efficacious in α-synuclein clearance associated with the activation of PGC-1α/Nrf2 signal pathway.Conclusion: SDA demonstrated potential as a future therapeutic modality in PD through protecting dopamine neurons and alleviating the motor symptoms, mediated by the activation of PGC-1α/Nrf2 signal pathway.

scholarly journals Vagus Nerve Stimulation with Mild Stimulation Intensity Exerts Anti-Inflammatory and Neuroprotective Effects in Parkinson’s Disease Model Rats

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 789
Author(s):  
Ittetsu Kin ◽  
Tatsuya Sasaki ◽  
Takao Yasuhara ◽  
Masahiro Kameda ◽  
Takashi Agari ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Vagus Nerve ◽  
Nerve Stimulation ◽  
Vagus Nerve Stimulation ◽  
Dopamine Neurons ◽  
Therapeutic Effects ◽  
Neuroprotective Effects ◽  
Stimulation Intensity ◽  
Anti Inflammatory

Background: The major surgical treatment for Parkinson’s disease (PD) is deep brain stimulation (DBS), but a less invasive treatment is desired. Vagus nerve stimulation (VNS) is a relatively safe treatment without cerebral invasiveness. In this study, we developed a wireless controllable electrical stimulator to examine the efficacy of VNS on PD model rats. Methods: Adult female Sprague-Dawley rats underwent placement of a cuff-type electrode and stimulator on the vagus nerve. Following which, 6-hydroxydopamine (6-OHDA) was administered into the left striatum to prepare a PD model. VNS was started immediately after 6-OHDA administration and continued for 14 days. We evaluated the therapeutic effects of VNS with behavioral and immunohistochemical outcome assays under different stimulation intensity (0.1, 0.25, 0.5 and 1 mA). Results: VNS with 0.25–0.5 mA intensity remarkably improved behavioral impairment, preserved dopamine neurons, reduced inflammatory glial cells, and increased noradrenergic neurons. On the other hand, VNS with 0.1 mA and 1 mA intensity did not display significant therapeutic efficacy. Conclusions: VNS with 0.25–0.5 mA intensity has anti-inflammatory and neuroprotective effects on PD model rats induced by 6-OHDA administration. In addition, we were able to confirm the practicality and effectiveness of the new experimental device.

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 Neuroprotective effects of Shende’an tablet in the Parkinson’s disease model

2020 ◽  
Author(s):  
Yan Xiao Sheng ◽  
Yuan Shui Yang ◽  
Min Xiao Wen ◽  
Xin Zhang ◽  
Feng Yong Ye ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pc12 Cells ◽  
Motor Behavior ◽  
Signal Pathway ◽  
Dopamine Neurons ◽  
Chinese Herbs ◽  
Therapeutic Drug ◽  
Protective Effects ◽  
Neuroprotective Effects

Abstract Background Shende’an tablet (SDA) is a newly developed Chinese herbs formula derived from the chinese traditional medicine Zhenganxifeng Decoction, which is approved for treatment of neurasthenia and insomnia in China. The aim of this study was to investigate the in vitro and in vivo neuroprotective effects of SDA against Parkinson’s disease (PD). Methods In the present work, PC12 cells transfected with or without A53T α-syn genes and MPTP-induced PD mice were used as models to elucidate protective effects of SDA on dopamine (DA) neurons, and the involvement of PGC-1α/Nrf2 signaling in α-syn clearance in PC12/α-syn cells stimulated with Doxycycline (Dox) and reversal of MPTP-induced toxicity in PD mice. Results Our results demonstrated that SDA had neuroprotection effect in dopaminergic PC12 cells with 6-OHDA. It had also displayed efficient dopaminergic neuronal protection and motor behavior alleviation properties in MPTP-induced PD mice. In the PC12/α-syn cells and MPTP-induced PD animal models, SDA was highly efficacious in α-syn clearance associated with activation of PGC-1α/Nrf2 signal pathway. Conclusion The results of our study suggest that SDA could be a potential therapeutic drug for PD through protecting dopamine neurons and alleviating the motor symptoms, and the mechanism might be related to the activation of PGC-1α/Nrf2 signal pathway.

scholarly journals Da-Bu-Yin-Wan and Qian-Zheng-San to Neuroprotect the Mouse Model of Parkinson’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Xiao-Gang Gong ◽  
Hong-Mei Sun ◽  
Yi Zhang ◽  
Shu-Jing Zhang ◽  
Yu-Shan Gao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Neuroprotective Effect ◽  
Firefly Luciferase ◽  
Dopamine Neurons ◽  
Behavioral Impairment ◽  
Neuroprotective Effects ◽  
Atp Level ◽  
Protein Levels

Da-Bu-Yin-Wan (DBYW) and Qian-Zheng-San (QZS), two classic traditional Chinese medicinal formulas, were clinically employed to treat Parkinson’s disease (PD). Our previous studies demonstrated neuroprotective effects of them on mitochondrial function in PD mice induced by1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). The purpose of this research was to investigate their possible mechanisms in the light of mitochondrial ATP-sensitive potassium (mitoKATP) channels. The neuroprotective effect of DBYW and QZS on dopamine (DA) neurons in substantia nigra (SN) in the MPTP-induced PD mice was investigated by behavioral test (pole test) and immunohistochemistry. Adenosine triphosphate (ATP) level in the midbrain tissue was detected by firefly luciferase method. MitoKATPchannel subunits SUR1 and Kir6.2 mRNA and protein expressions were tested by real-time PCR (RT-PCR) and Western blot. It was observed that DBYW and/or QZS served to ameliorate MPTP-induced behavioral impairment and prevent the loss of substantia nigra dopamine neurons, as well as increase ATP level in the midbrain tissue and downregulate SUR1 expression at mRNA and protein levels with no marked influence on Kir6.2. We concluded that DBYW and QZS exhibit neuroprotective effects probably through the regulation of ATP level and mitoKATPchannel subunit expressions.

scholarly journals Neuroprotective effects of Shende’an tablet in the Parkinson’s disease model

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Xiaoyan Sheng ◽  
Shuiyuan Yang ◽  
Xiaomin Wen ◽  
Xin Zhang ◽  
Yongfeng Ye ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pc12 Cells ◽  
Motor Behavior ◽  
Neuroprotective Effect ◽  
Signal Pathway ◽  
Dopamine Neurons ◽  
Therapeutic Modality ◽  
Neuroprotective Effects

Abstract Background Shende’an tablet (SDA) is a newly capsuled Chinese herbal formula derived from the Chinese traditional medicine Zhengan Xifeng Decoction which is approved for the treatment of neurasthenia and insomnia in China. This study aimed to investigate the neuroprotective effects of SDA against Parkinson’s disease (PD) in vitro and in vivo. Methods In the present work, the neuroprotective effects and mechanism of SDA were evaluated in the cellular PD model. Male C57BL/6J mice were subject to a partial MPTP lesion alongside treatment with SDA. Behavioural test and tyrosine-hydroxylase immunohistochemistry were used to evaluate nigrostriatal tract integrity. HPLC analysis and Western blotting were used to assess the effect of SDA on dopamine metabolism and the expression of HO-1, PGC-1α and Nrf2, respectively. Results Our results demonstrated that SDA had neuroprotective effect in dopaminergic PC12 cells with 6-OHDA lesion. It had also displayed efficient dopaminergic neuronal protection and motor behavior alleviation properties in MPTP-induced PD mice. In the PC12 cells and MPTP-induced Parkinson’s disease animal models, SDA was highly efficacious in α-synuclein clearance associated with the activation of PGC-1α/Nrf2 signal pathway. Conclusions SDA demonstrated potential as a future therapeutic modality in PD through protecting dopamine neurons and alleviating the motor symptoms, mediated by the activation of PGC-1α/Nrf2 signal pathway.

scholarly journals Anti-Inflammatory Effects of the Novel Barbiturate Derivative MHY2699 in an MPTP-Induced Mouse Model of Parkinson’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1855
Author(s):  
Seulah Lee ◽  
Yeon Ji Suh ◽  
Yujeong Lee ◽  
Seonguk Yang ◽  
Dong Geun Hong ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Cell Activation ◽  
Motor Dysfunction ◽  
Dopamine Neurons ◽  
Neuroprotective Effects ◽  
Glial Cell Activation ◽  
Anti Inflammatory ◽  
Neuroprotective Treatment

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, and is caused by the death of dopamine neurons and neuroinflammation in the striatum and substantia nigra. Furthermore, the inflammatory response in PD is closely related to glial cell activation. This study examined the neuroprotective effects of the barbiturate derivative, MHY2699 [5-(4-hydroxy 3,5-dimethoxybenzyl)-2 thioxodihydropyrimidine-4,6(1H,5H)-dione] in a mouse model of PD. MHY2699 ameliorated MPP⁺-induced astrocyte activation and ROS production in primary astrocytes and inhibited the MPP⁺-induced phosphorylation of MAPK and NF-κB. The anti-inflammatory effects of MHY2699 in protecting neurons were examined in an MPTP-induced mouse model of PD. MHY2699 inhibited MPTP-induced motor dysfunction and prevented dopaminergic neuronal death, suggesting that it attenuated neuroinflammation. Overall, MHY2699 has potential as a neuroprotective treatment for PD.

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