scholarly journals Valproic Acid Protects Primary Dopamine Neurons from MPP+-Induced Neurotoxicity: Involvement of GSK3βPhosphorylation by Akt and ERK through the Mitochondrial Intrinsic Apoptotic Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Chi Zhang ◽  
Xianrui Yuan ◽  
Zhongliang Hu ◽  
Songlin Liu ◽  
Haoyu Li ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Neurological Diseases ◽  
Neuroprotective Effect ◽  
Dopamine Neurons ◽  
Intrinsic Apoptotic Pathway ◽  
Apoptotic Pathway ◽  
Neuroprotective Effects ◽  
Mitogen Activated Protein

Valproic acid (VPA), a drug widely used to treat manic disorder and epilepsy, has recently shown neuroprotective effects in several neurological diseases, particularly in Parkinson’s disease (PD). The goal of the present study was to confirm VPA’s dose-dependent neuroprotective propensities in the MPP+model of PD in primary dopamine (DA) neurons and to investigate the underlying molecular mechanisms using specific mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase- (PI3K-) Akt signaling inhibitors. VPA reversed MPP+-induced mitochondrial apoptosis and counteracted MPP+-induced extracellular signal-regulated kinase (ERK) and Akt repression and inhibited glycogen synthase kinase 3β(GSK3β) activation through induction of GSK3βphosphorylation. Moreover, inhibitors of the PI3K and MAPK pathways abolished GSK3βphosphorylation and diminished the VPA-induced neuroprotective effect. These findings indicated that VPA’s neuroprotective effect in the MPP+-model of PD is associated with GSK3βphosphorylation via Akt and ERK activation in the mitochondrial intrinsic apoptotic pathway. Thus, VPA may be a promising therapeutic candidate for clinical treatment of PD.

Cordycepin Exerts Neuroprotective Effects via an Anti-Apoptotic Mechanism based on the Mitochondrial Pathway in a Rotenone-Induced Parkinsonism Rat Model

2019 ◽  
Vol 18 (8) ◽  
pp. 609-620 ◽  
Author(s):  
Xin Jiang ◽  
Pei-Chen Tang ◽  
Qin Chen ◽  
Xin Zhang ◽  
Yi-Yun Fan ◽  
...  
Keyword(s):  
Rat Model ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Neuroprotective Effects ◽  
Cyt C

Background: Cordycepin (Cor), one of the major bioactive components of the traditional Chinese medicine Cordyceps militaris, has been used in clinical practice for several years. However, its neuroprotective effect remains unknown. Aim: The purpose of the study was to evaluate the neuroprotective effects of Cor using a rotenoneinduced Parkinson’s Disease (PD) rat model and to delineate the possible associated molecular mechanisms. Methods: In vivo, behavioural tests were performed based on the 10-point scale and grid tests. Levels of dopamine and its metabolites in the striatum and the numbers of TH-positive neurons in the Substantia Nigra pars compacta (SNpc) were investigated by high-performance liquid chromatography with electrochemical detection and immunohistochemical staining, respectively. In vitro, cell apoptosis rates and Mitochondrial Membrane Potential (MMP) were analysed by flow cytometry and the mRNA and protein levels of Bax, Bcl-2, Bcl-xL, Cytochrome c (Cyt-c), and caspase-3 were determined by quantitative real-time PCR and western blotting. Results: Showed that Cor significantly improved dyskinesia, increased the numbers of TH-positive neurons in the SNpc, and maintained levels of dopamine and its metabolites in the striatum in rotenone- induced PD rats. We also found that apoptosis was suppressed and the loss of MMP was reversed with Cor treatment. Furthermore, Cor markedly down-regulated the expression of Bax, upregulated Bcl-2 and Bcl-xL, inhibited the activation of caspase-3, and decreased the release of Cyt-c from the mitochondria to the cytoplasm, as compared to those in the rotenone-treated group. Conclusion: Therefore, Cor protected dopamine neurons against rotenone-induced apoptosis by improving mitochondrial dysfunction in a PD model, demonstrating its therapeutic potential for this disease.

scholarly journals Hederagenin Protects PC12 Cells Against Corticosterone-Induced Injury by the Activation of the PI3K/AKT Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruohong Lin ◽  
Linlin Liu ◽  
Marta Silva ◽  
Jiankang Fang ◽  
Zhiwei Zhou ◽  
...  
Keyword(s):  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Biological Activities ◽  
Neuroprotective Effect ◽  
Akt Pathway ◽  
Triterpenoid Saponin ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Concentration Dependent Manner

Depression is a prevalent psychiatric disorder and a leading cause of disability worldwide. Despite a variety of available treatments currently being used in the clinic, a substantial proportion of patients is unresponsive to these treatments, urging the development of more effective therapeutic approaches. Hederagenin (Hed), a triterpenoid saponin extracted from Fructus Akebiae, has several biological activities including anti-apoptosis, anti-hyperlipidemic and anti-inflammatory properties. Over the years, its potential therapeutic effect in depression has also been proposed, but the information is limited and the mechanisms underlying its antidepressant-like effects are unclear. The present study explored the neuroprotective effects and the potential molecular mechanisms of Hederagenin action in corticosterone (CORT)-injured PC12 cells. Obtained results show that Hederagenin protected PC12 cells against CORT-induced damage in a concentration dependent manner. In adittion, Hederagenin prevented the decline of mitochondrial membrane potential, reduced the production of intracellular reactive oxygen species (ROS) and decreased the apoptosis induced by CORT. The protective effect of Hederagenin was reversed by a specific phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and AKT (also known as protein kinase B) inhibitor MK2206, suggesting that the effect of Hederagenin is mediated by the PI3K/AKT pathway. In line with this, western blot analysis results showed that Hederagenin stimulated the phosphorylation of AKT and its downstream target Forkhead box class O 3a (FoxO3a) and Glycogen synthase kinase-3-beta (GSK3β) in a concentration dependent manner. Taken together, these results indicate that the neuroprotective effect of Hederagenin is likely to occur via stimulation of the PI3K/AKT pathway.

scholarly journals Isorhynchophylline Protects PC12 Cells Against Beta-Amyloid-Induced Apoptosis via PI3K/Akt Signaling Pathway

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yan-Fang Xian ◽  
Zhi-Xiu Lin ◽  
Qing-Qiu Mao ◽  
Jian-Nan Chen ◽  
Zi-Ren Su ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Neuroprotective Effect ◽  
Protective Action ◽  
Protective Effects ◽  
Phosphorylated Akt ◽  
Induced Apoptosis

The neurotoxicity of amyloid-β(Aβ) has been implicated as a critical cause of Alzheimer’s disease. Isorhynchophylline (IRN), an oxindole alkaloid isolated fromUncaria rhynchophylla,exerts neuroprotective effect againstAβ25–35-induced neurotoxicityin vitro. However, the exact mechanism for its neuroprotective effect is not well understood. The present study aimed to investigate the molecular mechanisms underlying the protective action of IRN againstAβ25–35-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Pretreatment with IRN significantly increased the cell viability, inhibited the release of lactate dehydrogenase and the extent of DNA fragmentation inAβ25–35-treated cells. IRN treatment was able to enhance the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase-3β(p-GSK-3β). Lithium chloride blockedAβ25–35-induced cellular apoptosis in a similar manner as IRN, suggesting that GSK-3βinhibition was involved in neuroprotective action of IRN. Pretreatment with LY294002 completely abolished the protective effects of IRN. Furthermore, IRN reversedAβ25–35-induced attenuation in the level of phosphorylated cyclic AMP response element binding protein (p-CREB) and the effect of IRN could be blocked by the PI3K inhibitor. These experimental findings unambiguously suggested that the protective effect of IRN againstAβ25–35-induced apoptosis in PC12 cells was associated with the enhancement of p-CREB expression via PI3K/Akt/GSK-3βsignaling pathway.

scholarly journals Ganglioside GM1 Targets Astrocytes to Stimulate Cerebral Energy Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Charles Finsterwald ◽  
Sara Dias ◽  
Pierre J. Magistretti ◽  
Sylvain Lengacher
Keyword(s):  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Brain Diseases ◽  
Mitochondrial Activity ◽  
Ganglioside Gm1 ◽  
Neuroprotective Effects ◽  
Wide Range ◽  
Cord Injury ◽  
Clinical Benefits ◽  
The Brain

Gangliosides are major constituents of the plasma membrane and are known to promote a number of physiological actions in the brain, including synaptic plasticity and neuroprotection. In particular, the ganglioside GM1 was found to have a wide range of preclinical and clinical benefits in brain diseases such as spinal cord injury, Huntington’s disease and Parkinson’s disease. However, little is known about the underlying cellular and molecular mechanisms of GM1 in the brain. In the present study, we show that GM1 exerts its actions through the promotion of glycolysis in astrocytes, which leads to glucose uptake and lactate release by these cells. In astrocytes, GM1 stimulates the expression of several genes involved in the regulation of glucose metabolism. GM1 also enhances neuronal mitochondrial activity and triggers the expression of neuroprotection genes when neurons are cultured in the presence of astrocytes. Finally, GM1 leads to a neuroprotective effect in astrocyte-neuron co-culture. Together, these data identify a previously unrecognized mechanism mediated by astrocytes by which GM1 exerts its metabolic and neuroprotective effects.

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 Nimodipine-Dependent Protection of Schwann Cells, Astrocytes and Neuronal Cells from Osmotic, Oxidative and Heat Stress Is Associated with the Activation of AKT and CREB

2019 ◽  
Vol 20 (18) ◽  
pp. 4578 ◽  
Author(s):  
Sandra Leisz ◽  
Sebastian Simmermacher ◽  
Julian Prell ◽  
Christian Strauss ◽  
Christian Scheller
Keyword(s):  
Heat Stress ◽  
Schwann Cells ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Neuronal Cells ◽  
Cell Types ◽  
Stress Conditions ◽  
Cell Culture Supernatant ◽  
Neuroprotective Effects ◽  
Stress Dependent

Clinical and experimental data assumed a neuroprotective effect of the calcium channel blocker nimodipine. However, it has not been proven which neuronal or glial cell types are affected by nimodipine and which mechanisms underlie these neuroprotective effects. Therefore, the aim of this study was to investigate the influence of nimodipine treatment on the in vitro neurotoxicity of different cell types in various stress models and to identify the associated molecular mechanisms. Therefore, cell lines from Schwann cells, neuronal cells and astrocytes were pretreated for 24 h with nimodipine and incubated under stress conditions such as osmotic, oxidative and heat stress. The cytotoxicity was measured via the lactate dehydrogenase (LDH) activity of cell culture supernatant. As a result, the nimodipine treatment led to a statistically significantly reduced cytotoxicity in Schwann cells and neurons during osmotic (p ≤ 0.01), oxidative (p ≤ 0.001) and heat stress (p ≤ 0.05), when compared to the vehicle. The cytotoxicity of astrocytes was nimodipine-dependently reduced during osmotic (p ≤ 0.01), oxidative (p ≤ 0.001) and heat stress (not significant). Moreover, a decreased caspase activity as well as an increased proteinkinase B (AKT) and cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation could be observed after the nimodipine treatment under different stress conditions. These results demonstrate a cell type-independent neuroprotective effect of the prophylactic nimodipine treatment, which is associated with the prevention of stress-dependent apoptosis through the activation of CREB and AKT signaling pathways and the reduction of caspase 3 activity.

scholarly journals Molecular Targets of Cannabidiol in Experimental Models of Neurological Disease

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5186 ◽  
Author(s):  
Serena Silvestro ◽  
Giovanni Schepici ◽  
Placido Bramanti ◽  
Emanuela Mazzon
Keyword(s):  
G Protein ◽  
Serotonin Receptor ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Neurological Diseases ◽  
In Vivo Studies ◽  
Receptor Subtype ◽  
Transient Receptor Potential Vanilloid ◽  
Neuroprotective Effects ◽  
G Protein Coupled

Cannabidiol (CBD) is a non-psychoactive phytocannabinoid known for its beneficial effects including antioxidant and anti-inflammatory properties. Moreover, CBD is a compound with antidepressant, anxiolytic, anticonvulsant and antipsychotic effects. Thanks to all these properties, the interest of the scientific community for it has grown. Indeed, CBD is a great candidate for the management of neurological diseases. The purpose of our review is to summarize the in vitro and in vivo studies published in the last 15 years that describe the biochemical and molecular mechanisms underlying the effects of CBD and its therapeutic application in neurological diseases. CBD exerts its neuroprotective effects through three G protein coupled-receptors (adenosine receptor subtype 2A, serotonin receptor subtype 1A and G protein-coupled receptor 55), one ligand-gated ion channel (transient receptor potential vanilloid channel-1) and one nuclear factor (peroxisome proliferator-activated receptor γ). Moreover, the therapeutical properties of CBD are also due to GABAergic modulation. In conclusion, CBD, through multi-target mechanisms, represents a valid therapeutic tool for the management of epilepsy, Alzheimer’s disease, multiple sclerosis and Parkinson’s disease.

scholarly journals Effects of multiple sclerosis in pregnant and post-birth: particularities of the disease activity

2021 ◽  
Author(s):  
Bianca Barbosa Araldi ◽  
Victor Hugo Gomes ◽  
Bruno Ludvig Vieira ◽  
Klesia Adayani Rodrigues ◽  
Andressa Gabrieli da Silva ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Neurological Diseases ◽  
Neuroprotective Effect ◽  
Cumulative Effect ◽  
Demyelinating Diseases ◽  
Hormonal Changes ◽  
Neuroprotective Effects ◽  
Maternal Immune System ◽  
The Central Nervous System

Introduction: Demyelinating diseases are a heterogeneous group of neurological diseases related to autoimmunity whose representative is Multiple Sclerosis (MS). It is characterized by an immune-mediated demyelination of the central nervous system, with a typical outbreak and remission clinic. During pregnancy, a reduction in disease activity was noted due to immunomodulatory effects, and an increase in outbreaks in the puerperium. Thus, our goal is to demonstrate the relationship between pregnancy and MS. Methods: This is a systematic bibliographic review based on searching the SCIELO, PUBMED and UPTODATE databases using the words “Multiple Sclerosis”, “Pregnancy”, “Demyelinating diseases” and “Neurological Disorders”. Discussion: Pregnancy is responsible for numerous changes in the maternal body resulting from hormonal changes with an immunological and neuroprotective effect. Until the beginning of the 20th century, it was considered a risk factor or precipitator of outbreaks in these patients. In 1950, Tillmann et al. questioned him and concluded that pregnancy reduces the risk of outbreaks of the disease and that relapses were more associated with postpartum. The question is still raised by several authors, due to their interest in the search for intricate protective factors in the genesis and cure of the disease. It is believed that immunological changes in pregnancy tend to suppress the maternal immune system preventing fetal rejection, and together with gestational hormones, they are able to make neuronal tissue more resistant to inflammatory aggression and greater capacity for cell repair. In the puerperium, there was an increase in outbreaks of the disease, probably associated with a reduction in hormone levels, the effects of which are lost after the elimination of the fetus. Breastfeeding is not associated with the prevention or risk of new MS outbreaks. The frequency of outbreaks before conception is the only independent predictor of new post-term episodes. There is no consensus regarding the therapeutic approach in these pregnant women. Conclusion: Evidence supports the association between pregnancy, reduced activity of MS and increased activity in the 3 months postpartum, due to the probable loss of neuroprotective effects associated with hormones. Recommendations regarding the use of immunomodulator are suspended before conception (“washout”) until term. New evidence did not associate the use of interferon-β with abortion, cesarean section or low birth weight. There was a benefit of long-term parity with a cumulative effect on the patient’s immunohumor modulation.

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.

Sign in / Sign up

Export Citation Format

Share Document