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 Protective Mechanisms of Flavonoids in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Kasthuri Bai Magalingam ◽  
Ammu Kutty Radhakrishnan ◽  
Nagaraja Haleagrahara
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Movement Disorder ◽  
Dopaminergic Neurons ◽  
Target Therapy ◽  
Cellular Damage ◽  
Substantia Nigra Pars Compacta ◽  
Protective Mechanisms

Parkinson’s disease is a chronic, debilitating neurodegenerative movement disorder characterized by progressive degeneration of dopaminergic neurons in thesubstantia nigra pars compactaregion in human midbrain. To date, oxidative stress is the well accepted concept in the etiology and progression of Parkinson’s disease. Hence, the therapeutic agent is targeted against suppressing and alleviating the oxidative stress-induced cellular damage. Within the past decades, an explosion of research discoveries has reported on the protective mechanisms of flavonoids, which are plant-based polyphenols, in the treatment of neurodegenerative disease using bothin vitroandin vivomodels. In this paper, we have reviewed the literature on the neuroprotective mechanisms of flavonoids in protecting the dopaminergic neurons hence reducing the symptoms of this movement disorder. The mechanism reviewed includes effect of flavonoids in activation of endogenous antioxidant enzymes, suppressing the lipid peroxidation, inhibition of inflammatory mediators, flavonoids as a mitochondrial target therapy, and modulation of gene expression in neuronal cells.

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 The DJ1-Nrf2-STING axis mediates the neuroprotective effects of Withaferin A in Parkinson’s disease

2021 ◽  
Author(s):  
Miao Zhao ◽  
Bingwei Wang ◽  
Chenyu Zhang ◽  
Zhijie Su ◽  
Bingbing Guo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Withaferin A ◽  
Motor Deficits ◽  
Whole Genome ◽  
Potential Candidate ◽  
Sequencing Analysis ◽  
Neuroprotective Effects

AbstractThe pathogenesis of Parkinson’s disease (PD) remains unclear, and there is no disease-modifying agent for PD. Withaferin A (WA), a naturally occurring compound, has emerged as a neuroprotective agent. However, the mechanisms by which WA is neuroprotective in PD are unknown. Here we show that WA protected against loss of dopaminergic neurons, neuroinflammation, and motor deficits in MPTP-induced PD mouse models. Whole-genome deep sequencing analysis combined with Meta-analysis of human PD studies reveal that DJ1, Nrf2, and STING in substantia nigra pars compacta (SNc) are linked to anti-PD effect of WA. We found that WA activated DJ1 and Nrf2, and suppressed STING within SNc; and overexpression of STING in SNc dampened the effect of WA. Using genetically modified mice (DJ1-KO, Nrf2-KO, STINGgt/gt and STING-KO) and immunolabeling technique, we identified that WA targeted DJ1-Nrf2-STING pathway in dopaminergic neurons; and we demonstrate that STING might be an important factor in PD pathogenesis. In addition, WA alleviated accumulation of phosphorylated α-synuclein (p-α-syn) and insoluble α-syn within SNc in adeno-associated virus (AAV)-mediated human α-syn overexpression PD model. Our comparative analysis on whole-genome transcriptome profiles suggests that STING might be a key target of WA and amantadine in PD treatment. This study highlights a multifaceted role for WA in neuroprotection, and suggests that WA can be a potential candidate for treatment of PD.

scholarly journals The Nrf2-NLRP3-Caspase1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

2020 ◽  
Author(s):  
Chenyu Zhang ◽  
Miao Zhao ◽  
Bingwei Wang ◽  
Zhijie Su ◽  
Bingbing Guo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Motor Deficits ◽  
Inflammasome Activation ◽  
Sequencing Analysis ◽  
Pentacyclic Triterpene ◽  
Neuroprotective Effects ◽  
Neuroprotective Actions

Abstract Background: Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied by chronic neuroinflammation, oxidative stress, and widespread accumulation of α-synuclein. Celastrol (Cel), a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged as a neuroprotective agent. However, the mechanisms by which celastrol is neuroprotective in PD has not yet been elucidated. Methods: The MPTP and AAV-mediated human wild-type α-syn overexpression within SNc induced PD mouse models were employed in this study. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase1-KO), we identified that celastrol effectively inhibited the NLRP3 inflammasome activation, mitigated motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-Caspase1 pathway. Results: Here we show that celastrol protected against the loss of dopaminergic neurons, mitigated the neuroinflammation and motor deficits in both MPTP-induced PD mouse model and AAV-mediated human α-syn overexpression PD model. Whole-genome deep sequencing analysis reveals that Nrf2, NLRP3 and Caspase1 in SNc may be associated with the neuroprotective actions of celastrol in PD. Conclusions: These findings suggest that Nrf2-NLRP3-Caspase1 axis may be a key target of celastrol in PD treatment, and highlight the favorable properties linked to neuroprotection of celastrol, making celastrol as a promising disease-modifying agent for PD.

scholarly journals The potassium channel KCa3.1 represents a valid pharmacological target for microgliosis-induced neuronal impairment in a mouse model of Parkinson’s disease

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Jia Lu ◽  
Fangfang Dou ◽  
Zhihua Yu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Mouse Model ◽  
Gene Deletion ◽  
Substantia Nigra Pars Compacta ◽  
Phenotype Switch ◽  
Pharmacological Blockade ◽  
Locomotor Ability

Abstract Background Recent studies described a critical role for microglia in Parkinson’s disease (PD), where these central nerve system resident immune cells participate in the neuroinflammatory microenvironment that contributes to dopaminergic neurons loss in the substantia nigra. Understanding the phenotype switch of microgliosis in PD could help to identify the molecular mechanism which could attenuate or delay the progressive decline in motor function. KCa3.1 has been reported to regulate the “pro-inflammatory” phenotype switch of microglia in neurodegenerative pathological conditions. Methods We here investigated the effects of gene deletion or pharmacological blockade of KCa3.1 activity in wild-type or KCa3.1−/− mice after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mouse model of PD. MPTP-induced PD mouse model was subjected to the rotarod test to evaluate the locomotor ability. Glia activation and neuron loss were measured by immunostaining. Fluo-4 AM was used to measure cytosolic Ca2+ level in 1-methyl-4-phenylpyridinium (MPP+)-induced microgliosis in vitro. Results We report that treatment of MPTP-induced PD mouse model with gene deletion or pharmacological blockade of KCa3.1 with senicapoc improves the locomotor ability and the tyrosine hydroxylase (TH)-positive neuron number and attenuates the microgliosis and neuroinflammation in the substantia nigra pars compacta (SNpc). KCa3.1 involves in store-operated Ca2+ entry-induced Ca2+ overload and endoplasmic reticulum stress via the protein kinase B (AKT) signaling pathway during microgliosis. Gene deletion or blockade of KCa3.1 restored AKT/mammalian target of rapamycin (mTOR) signaling both in vivo and in vitro. Conclusions Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in PD.

scholarly journals Tetramethylpyrazine Analogue T-006 Exerts Neuroprotective Effects against 6-Hydroxydopamine-Induced Parkinson’s Disease In Vitro and In Vivo

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hefeng Zhou ◽  
Min Shao ◽  
Xuanjun Yang ◽  
Chuwen Li ◽  
Guozhen Cui ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Motor Coordination ◽  
Neurodegenerative Disorder ◽  
Nerve Fibers ◽  
Substantia Nigra Pars Compacta ◽  
Neuroprotective Effects ◽  
6 Hydroxydopamine

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer’s disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3β and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.

scholarly journals Tubeimoside I Protects Dopaminergic Neurons Against Inflammation-Mediated Damage in Lipopolysaccharide (LPS)-Evoked Model of Parkinson’s Disease in Rats

2018 ◽  
Vol 19 (8) ◽  
pp. 2242 ◽  
Author(s):  
Dewei He ◽  
Bingxu Huang ◽  
Shoupeng Fu ◽  
Yuhang Li ◽  
Xin Ran ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Dopaminergic Neurons ◽  
Inflammatory Responses ◽  
Substantia Nigra Pars Compacta ◽  
Peripheral Tissues ◽  
Tubeimoside I

Parkinson’s disease (PD), a frequent degenerative disease in the elderly, is characterized by dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc). Neuroinflammation caused by over-activated microglia plays a crucial role in the pathogenesis of PD. Tubeimoside I (TBMS1) has a broad anti-inflammatory effect in peripheral tissues, but the effect on neuroinflammation has not been reported. Therefore, we explored whether TBMS1 could protect dopaminergic neurons by inhibiting the activation of microglia in lipopolysaccharide (LPS)-induced PD rat model. In addition, then, the effect and mechanism of TBMS1 on neuroinflammation were assessed in LPS-exposed murine microglial BV-2 cells. The results in vivo showed that TBMS1 suppressed microglial activation and dopaminergic neurons’ reduction in LPS-injected PD rat model. In vitro study found that TBMS1 could inhibit LPS-induced inflammatory responses in BV-2 cells, and this effect was mediated by suppressing the phosphorylation of protein kinase B (AKT), nuclear factor-kappa B (NF-κB p65), p38 and extracellular regulated protein kinases (ERK1/2). Taken together, these results demonstrated for the first time that TBMS1 played a role in protecting dopaminergic neurons by inhibiting neuroinflammation mediated by microglia.

scholarly journals Neuroprotective Effects of San-Huang-Xie-Xin-Tang in the MPP+/MPTP Models of Parkinson’s DiseaseIn VitroandIn Vivo

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Yi-Ching Lo ◽  
Yu-Tzu Shih ◽  
Yu-Ting Tseng ◽  
Hung-Te Hsu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alternative Therapy ◽  
Disease Model ◽  
Substantia Nigra Pars Compacta ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Complementary And Alternative Therapy

San-Huang-Xie-Xin-Tang (SHXT), composed ofCoptidis rhizoma, Scutellariae radix, andRhei rhizoma, is a traditional Chinese medicine used for complementary and alternative therapy of cardiovascular and neurodegenerative diseases via its anti-inflammatory and antioxidative effects. The aim of this study is to investigate the protective effects of SHXT in the 1–methyl–4–phenylpyridinium (MPP+)/1–methyl–4–phenyl–1,2,3,6–tetrahydropyridine (MPTP) models of Parkinson’s disease. Rat primary mesencephalic neurons and mouse Parkinson disease model were used in this study. Oxidative stress was induced by MPP+in vitroand MPTPin vivo. In MPP+-treated mesencephalic neuron cultures, SHXT significantly increased the numbers of TH-positive neurons. SHXT reduced apoptotic signals (cytochrome and caspase) and apoptotic death. MPP+-inducedgp91phoxactivation and ROS production were attenuated by SHXT. In addition, SHXT increased the levels of GSH and SOD in MPP+-treated neurons. In MPTP animal model, SHXT markedly increased TH-positive neurons in the substantia nigra pars compacta (SNpc) and improved motor activity of mice. In conclusion, the present results reveal the evidence that SHXT possesses beneficial protection against MPTP-induced neurotoxicity in this model of Parkinson’s disease via its antioxidative and antiapoptotic effects. SHXT might be a potentially alternative and complementary medicine for neuroprotection.

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