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 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 The Thioredoxin Family Proteins: Histopathological Time Course Study in the Asphyctic Male Rat Brain

2020 ◽  
Vol 26 (S1) ◽  
pp. 183-184
Author(s):  
Ma. Laura Aón Bertolino ◽  
Christopher Horst Lillig ◽  
Capani Francisco
Keyword(s):  
Structural Damage ◽  
Cellular Localization ◽  
Time Course ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Cell Types ◽  
Initial Time ◽  
Male Rat ◽  
Morphological Evidence

Summary:Thioredoxin Family of proteins as Thioredoxin (Trxs), Glutaredoxins (Grxs) and Peroxiredoxins (Prxs) are one of the most important agents in the defense of oxidative  stress  and  redox regulation. Perinatal asphyxia (AP) a disorder generated at the expense of the deficit of oxygen associated or not to ischemia, affects 5 to 10 of every 1,000 live births in developing country and is a serious health problem worldwide. Alterations in antioxidant protection systems are involved in the pathogenesis of hypoxic-ischemic insult and neuronal death. For these reasons it is proposed that the  AP can cause changes in the distribution and expression of antioxidant proteins and enhance their deleterious or neuroprotective effects on the CNS. Methods: to determine the implication of the  proteins role induced in the hypoxic brain injury, an animal model in vivo of PA was used in this    work. In the first instance, the identification of the distribution of Trxs family proteins Trx1, Trx2, TrxR1, TrxR2, Txnip, Grx1, Grx2, Grx3, Grx5, γ-GCS, Prx1, Prx2, Prx3, Prx4, Prx5 and Prx6 was performed by immunohistochemistry on areas most sensitive to a  hypoxia-ischemia  insult:  cerebellum, striatum, hippocampus, spinal cord, sustantia nigra, cortex and retina. Previous studies suggest that these proteins have an extensive and characteristic distribution in various cell types and regions of the CNS, although we observed significant differences in labeling intensity and distribution with conventional and fluorescence optical microscopy. After determining the cellular localization of Trxs, their behavior was studied by during a hypoxic- ischemic event by setting a time course at different times (2, 4, 6, 12, 24 and 72 hours post AP). Results: Trx1, Trx2, Grx1 and Grx2 proteins constitutes the main oxidoreductases in the cytosol and mitochondria, both in physiological and pathological conditions. Thus, for the short asphyxia times in which they were studied, Trx1 was detected with increased expression at 2 hours and up to 4 hours post-AP, arguing a probable neuroprotective effect, although not enough, if taken  into account tissue liability and high levels  of  free radicals detected at initial hours and the presence of structural damage at 7 days post-AP. Trx2 shows its increase at 6 and 12 hours and Grx1 at 24 hours. For Grx2, values elicited with the ELISA technique in the initial time curve were not representative in their expression in the hippocampus, contrary to the findings in the distribution in the striatum, where Grx2 was observed to be increased. Although at 7 hours post-AP levels begin to decline, these  redoxins appears to be essential  in the  initial response to injury. Conclusions: by demonstrating of the presence of these enzymes in different cell types and specific regions of the brain in rats subjected to AP provided us with important morphological evidence base to study later some of the molecular mechanisms involved in the pathogenesis of cerebral ischemia that will help to generate new therapeutic tools to mitigate a disease whose neurological complications have no definitive  solution.

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 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.

scholarly journals The neuroprotective effect of nicotine in Parkinson’s disease models is associated with inhibiting PARP-1 and caspase-3 cleavage

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3933 ◽  
Author(s):  
Justin Y.D. Lu ◽  
Ping Su ◽  
James E.M. Barber ◽  
Joanne E. Nash ◽  
Anh D. Le ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Neuroprotective Effect ◽  
Future Research ◽  
Neuroprotective Effects ◽  
Α7 Nachr ◽  
Parp 1

Clinical evidence points to neuroprotective effects of smoking in Parkinson’s disease (PD), but the molecular mechanisms remain unclear. We investigated the pharmacological pathways involved in these neuroprotective effects, which could provide novel ideas for developing targeted neuroprotective treatments for PD. We used the ETC complex I inhibitor methylpyridinium ion (MPP+) to induce cell death in SH-SY5Y cells as a cellular model for PD and found that nicotine inhibits cell death. Using choline as a nicotinic acetylcholine receptor (nAChR) agonist, we found that nAChR stimulation was sufficient to protect SH-SY5Y cells against cell death from MPP+. Blocking α7 nAChR with methyllycaconitine (MLA) prevented the protective effects of nicotine, demonstrating that these receptors are necessary for the neuroprotective effects of nicotine. The neuroprotective effect of nicotine involves other pathways relevant to PD. Cleaved Poly (ADP-ribose) polymerase-1 (PARP-1) and cleaved caspase-3 were decreased by nicotine in 6-hydroxydopamine (6-OHDA) lesioned mice and in MPP+-treated SH-SY5Y cells. In conclusion, our data indicate that nicotine likely exerts neuroprotective effects in PD through the α7 nAChR and downstream pathways including PARP-1 and caspase-3. This knowledge could be pursued in future research to develop neuroprotective treatments for PD.

scholarly journals Unraveling the Neuroprotective Effect of Tinospora Cordifolia in Parkinsonian Mouse Model Through Proteomics Approach.

2021 ◽  
Author(s):  
Hareram Birla ◽  
Chetan Keswani ◽  
Saumitra Sen Singh ◽  
Walia Zahra ◽  
Hagera Dilnashin ◽  
...  
Keyword(s):  
Treatment Group ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Mitochondrial Gene ◽  
Tinospora Cordifolia ◽  
Therapeutic Effects ◽  
Label Free ◽  
Neuroprotective Effects ◽  
Multiple Drugs

Abstract BackgroundStress-induced dopaminergic (DAergic) neuronal death in the midbrain region is the primary cause of Parkinson’s disease (PD). Approximately 2% of the global population aged above 65 years is affected with PD. Various factors are responsible for the death of DAergic neurons, among which mitochondrial dysfunction, oxidative stress, misfolded protein aggregation and neuroinflammation are the primary factors. From the discovery of L-dopa, multiple drugs were discovered to improve lifestyle of PD patients, but they failed due to their multiple side effects. Tinospora cordifolia (Tc), a medicinal herb has been used in traditional medicines to treat neurodegenerative diseases. In our previous study, the neuroprotective role of Tc against MPTP-intoxicated Parkinsonian mice was reported. Here, we further explore the neuroprotective molecular mechanisms of Tc in Rotenone (ROT) intoxicated mouse model through proteomics approach.MethodsMice were pretreated with Tc extract by oral administration, followed by ROT-intoxication (2mg/kg body wt. for 35 days, subcutaneous). Rotarod, catalepsy, footprint and pole tests were carried out at 35th day to observe the neuroprotective effects of Tc on motor impairment caused by ROT in PD mice. Protein from nigrostriatal region of the mid brain was isolated, and label free quantification (LFQ) was carried out to identify differentially expressed protein (DEPs) in control vs. PD and PD vs. treatment group. Bioinformatics analysis of DEPs was carried out to explore the molecular pathway, cellular location, molecular function of proteins.ResultsIn this study, we report 800 DEPs in control vs. PD and 133 in PD vs. Treatment group. In silico tools clearly demonstrate significant enrichment of biochemical and molecular pathways with DEPs which are known to be important for PD progression, including, mitochondrial gene expression, hypothetical network for drug addiction, PD pathways, TGF-β signaling, Alzheimer’s disease, Odorant GPCRs and chemokine signaling pathway.ConclusionThis study provides a novel insight for the disease progression in PD mouse. More importantly, it demonstrates that Tc exerts the therapeutic effects through the regulation of multiple pathways to protect DAergic neurons.

scholarly journals Zn2+ influx activates ERK and Akt signaling pathways

2021 ◽  
Vol 118 (11) ◽  
pp. e2015786118
Author(s):  
Kelsie J. Anson ◽  
Giulia A. Corbet ◽  
Amy E. Palmer
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Single Cells ◽  
Cell Types ◽  
Cell Physiology ◽  
Kinase Signaling ◽  
Experimental Conditions ◽  
Kinase Activation ◽  
Fluorescent Biosensors ◽  
Stress Dependent

Zinc (Zn2+) is an essential metal in biology, and its bioavailability is highly regulated. Many cell types exhibit fluctuations in Zn2+ that appear to play an important role in cellular function. However, the detailed molecular mechanisms by which Zn2+ dynamics influence cell physiology remain enigmatic. Here, we use a combination of fluorescent biosensors and cell perturbations to define how changes in intracellular Zn2+ impact kinase signaling pathways. By simultaneously monitoring Zn2+ dynamics and kinase activity in individual cells, we quantify changes in labile Zn2+ and directly correlate changes in Zn2+ with ERK and Akt activity. Under our experimental conditions, Zn2+ fluctuations are not toxic and do not activate stress-dependent kinase signaling. We demonstrate that while Zn2+ can nonspecifically inhibit phosphatases leading to sustained kinase activation, ERK and Akt are predominantly activated via upstream signaling and through a common node via Ras. We provide a framework for quantification of Zn2+ fluctuations and correlate these fluctuations with signaling events in single cells to shed light on the role that Zn2+ dynamics play in healthy cell signaling.

scholarly journals Protection of Tong-Sai-Mai Decoction against Apoptosis Induced by H2O2in PC12 Cells: Mechanisms via Bcl-2-Mitochondria-ROS-INOS Pathway

2014 ◽  
Vol 2014 ◽  
pp. 1-18 ◽  
Author(s):  
Maxwell Kim Kit Lee ◽  
Yin Lu ◽  
Liu-qing Di ◽  
Hui-qin Xu
Keyword(s):  
Oxidative Stress ◽  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
In Vivo Studies ◽  
Marker Genes ◽  
Mitochondria Membrane Potential ◽  
Stress Dependent

Tong-Sai-Mai decoction (TSM) is a Chinese materia medica polyherbal formulation that has been applied in treating brain ischemia for hundreds of years. Because it could repress the oxidative stress in in vivo studies, now we focus on the in vitro studies to investigate the mechanism by targeting the oxidative stress dependent signaling. The relation between the neurogenesis and the reactive oxygen species (ROS) production remains largely unexamined. PC12 cells are excitable cell types widely used as in vitro model for neuronal cells. Most marker genes that are related to neurotoxicity, apoptosis, and cell cycles are expressed at high levels in these cells. The aim of the present study is to explore the cytoprotection of TSM against hydrogen peroxide- (H2O2-) induced apoptosis and the molecular mechanisms underlying PC12 cells. Our findings revealed that TSM cotreatment with H2O2restores the expression of bcl-2, inducible nitric oxide synthase (INOS), and mitochondria membrane potential. Meanwhile, it reduces intracellular [Ca2+] concentration, lactate dehydrogenase (LDH) release, and the expression of caspase-3 and bax. The results of the present study suggested that the cytoprotective effects of the TSM might be mediated, at least in part, by the bcl-2-mitochondria-ROS-INOS pathway. Due to its nontoxic characteristics, TSM could be further developed to treat the neurodegenerative diseases which are closely associated with the oxidative stress.

scholarly journals Neuroprotective Effect of Carotenoid-Rich Enteromorpha prolifera Extract via TrkB/Akt Pathway against Oxidative Stress in Hippocampal Neuronal Cells

Marine Drugs ◽  
2020 ◽  
Vol 18 (7) ◽  
pp. 372 ◽  
Author(s):  
Seung Yeon Baek ◽  
Mee Ree Kim
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Neuroprotective Effect ◽  
Neuronal Cells ◽  
Food Supplement ◽  
Akt Pathway ◽  
Heme Oxygenase 1 ◽  
Neuroprotective Effects ◽  
Glutamate Cysteine Ligase ◽  
Induced Apoptosis

In this study, we found that E. prolifera extract (EAEP) exhibits neuroprotective effects in oxidative stress-induced neuronal cells. EAEP improved cell viability as well as attenuated the formation of intracellular reactive oxygen species (ROS) and apoptotic bodies in glutamate-treated hippocampal neuronal cells (HT-22). Furthermore, EAEP improved the expression of brain-derived neurotrophic factor (BDNF) and antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H quinine oxidoreductase-1 (NQO-1), and glutamate–cysteine ligase catalytic subunit (GCLC) via the tropomyosin-related kinase receptor B/ protein kinase B (TrkB/Akt) signaling pathway. In contrast, the pre-incubation of K252a, a TrkB inhibitor, or MK-2206, an Akt-selective inhibitor, ameliorated the neuroprotective effects of EAEP in oxidative stress-induced neuronal cells. These results suggest that EAEP protects neuronal cells against oxidative stress-induced apoptosis by upregulating the expression of BDNF and antioxidant enzymes via the activation of the TrkB/Akt pathway. In conclusion, such an effect of EAEP, which is rich in carotenoid-derived compounds, may justify its application as a food supplement in the prevention and treatment of neurodegenerative disorders.

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