scholarly journals Mystixin-7 Peptide Protects Ionotropic Glutamatergic Mechanisms against Glutamate-Induced Excitotoxicity In Vitro

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Anatoly A. Mokrushin
Keyword(s):  
Glutamate Receptors ◽  
Neurological Diseases ◽  
Glutamate Excitotoxicity ◽  
Protective Effects ◽  
Corticotrophin Releasing Factor ◽  
Toxic Concentration ◽  
Acid Type ◽  
Cortex Slices ◽  
Excessive Activation

Hyperactivation of the N-methyl-D-aspartic acid type glutamate receptors (NMDARs) causes glutamate excitotoxicity, a process potentially important for many neurological diseases. This study aims to investigate protective effects of the synthetic corticotrophin-releasing factor-like peptide, mystixin-7 (MTX), on model glutamate-induced excitotoxicity in vitro. The technique online monitoring of electrophysiological parameters (excitatory glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPAR) and NMDAR-dependent postsynaptic mechanisms) in the olfactory cortex slices was used. Application of L-glutamate in toxic concentration (20 mM) on slices evoked hyperactivation of NMDARs and weaker activation of the AMPARs. Upon further action agonist, the excessive activation of glutamate receptors was replaced by their irreversible blockade. Pretreatment of the slices using MTX in different concentrations (50 and 100 mg/mL) protected both NMDARs and AMPARs from glutamate-induced damage. An enzymatic treatment of MTX reduced hyperactivation of both NMDARs and AMPARs. The present study demonstrated that MTX minipeptide protected the functioning of both NMDARs and AMPARs against glutamate-induced damage. The MTX peptide is a prospective candidate for elaborated medication in treatment of neurological diseases.

Interaction between glutamate signalling and immune attack in damaging oligodendrocytes

2007 ◽  
Vol 3 (4) ◽  
pp. 281-285 ◽  
Author(s):  
Carlos Matute
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Uptake ◽  
Kainate Receptors ◽  
Glutamate Excitotoxicity ◽  
Excitatory Neurotransmitter ◽  
Glutamate Signaling ◽  
Immune Attack ◽  
Glutamate Homeostasis

AbstractGlutamate is the principal excitatory neurotransmitter in the CNS, but it is also a potent neurotoxin that can kill nerve cells. Glutamate damages oligodendrocytes, like neurons, by excitotoxicity which is caused by sustained activation of AMPA, kainate and NMDA receptors. Glutamate excitotoxicity depends entirely on Ca2+ overload of the cytoplasm and can be initiated by disruption of glutamate homeostasis. Thus, inhibition of glutamate uptake in isolated oligodendrocytes in vitro and in the optic nerve in vivo, is sufficient to trigger cell death which is prevented by glutamate receptor antagonists. In turn, activated, but not resting microglia, can compromise glutamate homeostasis and induce oligodendrocyte excitotoxicity, which is attenuated either by AMPA/kainate antagonists or by the blockade of the system xc_ antiporter present in microglia. By contrast, non-lethal, brief, activation of glutamate receptors in oligodendrocytes rapidly sensitizes these cells to complement attack. Intriguingly, these effects are exclusively mediated by kainate receptors which induce Ca2+ overload of the cytosol and the generation of reactive oxygen species. In conjunction, these observations reveal novel mechanisms by which neuroinflammation alters glutamate homeostasis and triggers oligodendrocyte death. Conversely, they also show how glutamate signaling in oligodendrocytes might induce immune attack. In both instances direct activation of glutamate receptors present in oligodendrocytes plays a pivotal role in either initiating or executing death signals, which might be relevant to the pathogenesis of white matter disorders.

scholarly journals Interleukin-1β Protects Neurons against Oxidant-Induced Injury via the Promotion of Astrocyte Glutathione Production

Antioxidants ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 100 ◽  
Author(s):  
Twinkle Chowdhury ◽  
Matthew Allen ◽  
Trista Thorn ◽  
Yan He ◽  
Sandra Hewett
Keyword(s):  
Neurological Diseases ◽  
Oxidant Stress ◽  
Cortical Cell ◽  
Mixed Cultures ◽  
Interleukin 1Β ◽  
Neuronal Cultures ◽  
Dependent Manner ◽  
Protective Effects ◽  
Oxidant Injury

Interleukin-1β (IL-1β), a key cytokine that drives neuroinflammation in the Central Nervous System (CNS), is enhanced in many neurological diseases/disorders. Although IL-1β contributes to and/or sustains pathophysiological processes in the CNS, we recently demonstrated that IL-1β can protect cortical astrocytes from oxidant injury in a glutathione (GSH)-dependent manner. To test whether IL-1β could similarly protect neurons against oxidant stress, near pure neuronal cultures or mixed cortical cell cultures containing neurons and astrocytes were exposed to the organic peroxide, tert-butyl hydroperoxide (t-BOOH), following treatment with IL-1β or its vehicle. Neurons and astrocytes in mixed cultures, but not pure neurons, were significantly protected from the toxicity of t-BOOH following treatment with IL-1β in association with enhanced GSH production/release. IL-1β failed to increase the GSH levels or to provide protection against t-BOOH toxicity in chimeric mixed cultures consisting of IL-1R1+/+ neurons plated on top of IL-1R1−/− astrocytes. The attenuation of GSH release via block of multidrug resistance-associated protein 1 (MRP1) transport also abrogated the protective effect of IL-1β. These protective effects were not strictly an in vitro phenomenon as we found an increased striatal vulnerability to 3-nitropropionic acid-mediated oxidative stress in IL-1R1 null mice. Overall, our data indicate that IL-1β protects neurons against oxidant injury and that this likely occurs in a non-cell-autonomous manner that relies on an increase in astrocyte GSH production and release.

scholarly journals Protective Effects and Mechanism of Radix Polygalae Against Neurological Diseases as Well as Effective Substance

2021 ◽  
Vol 12 ◽  
Author(s):  
Ning Jiang ◽  
Shanshan Wei ◽  
Yiwen Zhang ◽  
Wenlu He ◽  
Haiyue Pei ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Chinese Herb ◽  
Receptor Activation ◽  
Mechanisms Of Action ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Apoptotic Effects

Radix Polygalae (also known as Yuanzhi in China) is the dried rhizome of Polygala tenuifolia Willd. or Polygala sibirica L., which is a famous Chinese herb and has been widely used for centuries in traditional medicines including expectorants, tonics, tranquilizers, antipsychotic, and so on. This article reviews the neuroprotective effects of Radix Polygalae in preclinical models of central nervous system (CNS) disorders, especially anxiety, depression, declining cognition, Alzheimer's disease (AD), and Parkinson's disease (PD). The chemical composition of Radix Polygalae as well as the underlying mechanisms of action were also reviewed. We found that Radix Polygalae possesses a broad range of beneficial effects on the abovementioned conditions. The multifold mechanisms of action include several properties such as antioxidant and associated apoptotic effects; anti-inflammatory and associated apoptotic effects; neurogenesis, regeneration, differentiation, and neuronal plasticity improvement; hypothalamic–pituitary–adrenal axis (HPA) regulation; neurotransmitter release; and receptor activation (A2AR, NMDA-R, and GluR). Nevertheless, the detailed mechanisms underlying this array of pharmacological effects observed in vitro and in vivo still need further investigation to attain a coherent neuroprotective profile.

scholarly journals Anxiety Therapeutic Interventions of β-Caryophyllene: A Laboratory-Based Study

2020 ◽  
Vol 15 (10) ◽  
pp. 1934578X2096222
Author(s):  
Keylla da Conceição Machado ◽  
Márcia Fernanda Correia Jardim Paz ◽  
José Victor de Oliveira Santos ◽  
Felipe Cavalcanti Carneiro da Silva ◽  
Jana Dimitrova Tchekalarova ◽  
...  
Keyword(s):  
Biological Activities ◽  
Neurological Diseases ◽  
Radical Scavenging ◽  
Artemia Salina ◽  
Therapeutic Interventions ◽  
Test Model ◽  
Protective Effects ◽  
In Vivo Test

The bicyclic sesquiterpene β-caryophyllene (BCP) has diverse biological activities, including antioxidant, anti-inflammatory, antidiabetic, and analgesic effects. This study evaluates anxiolytic, toxicity, and antioxidant effects of BCP using in vitro and in vivo test models. The anxiolytic effects were tested in Swiss albino mice ( Mus musculus) by applying the elevated plus-maze, rota-rod, light and dark, and hiding sphere models, while the toxicity was evaluated by brine shrimp ( Artemia salina) lethality bioassay. Additionally, the antioxidant capacity was tested by using 2,2-diphenyl-1-picrylhydrazyl radical, 2,2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid hydroxyl radical scavenging, and the Saccharomyces cerevisiae test model. The results suggest that BCP exerted a dose-dependent anxiolytic-like effect on the experimental animals. It did not show toxicity in A. salina at 24 hours. BCP showed a concentration-dependent free-radical-scavenging capacity, similar to the standard antioxidant Trolox. It also showed protective and repair capacities against hydrogen peroxide-induced damaging effects in isogenic and wild-type S. cerevisiae strains. Taken together, BCP exerted antioxidant and protective effects, which can be targeted to treat neurological diseases and disorders such as anxiety.

scholarly journals GPR68 Is a Neuroprotective Proton Receptor in Brain Ischemia

Stroke ◽  
2020 ◽  
Vol 51 (12) ◽  
pp. 3690-3700
Author(s):  
Tao Wang ◽  
Guokun Zhou ◽  
Mindi He ◽  
Yuanyuan Xu ◽  
W.G. Rusyniak ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Neuronal Injury ◽  
Artery Occlusion ◽  
Dependent Manner ◽  
Protective Effects ◽  
Pkc Protein Kinase C ◽  
Neuroprotective Function ◽  
Cerebral Artery Occlusion

Background and Purpose: Brain acidosis is prevalent in stroke and other neurological diseases. Acidosis can have paradoxical injurious and protective effects. The purpose of this study is to determine whether a proton receptor exists in neurons to counteract acidosis-induced injury. Methods: We analyzed the expression of proton-sensitive GPCRs (G protein-coupled receptors) in the brain, examined acidosis-induced signaling in vitro, and studied neuronal injury using in vitro and in vivo mouse models. Results: GPR68, a proton-sensitive GPCR, was present in both mouse and human brain, and elicited neuroprotection in acidotic and ischemic conditions. GPR68 exhibited wide expression in brain neurons and mediated acidosis-induced PKC (protein kinase C) activation. PKC inhibition exacerbated pH 6-induced neuronal injury in a GPR68-dependent manner. Consistent with its neuroprotective function, GPR68 overexpression alleviated middle cerebral artery occlusion–induced brain injury. Conclusions: These data expand our knowledge on neuronal acid signaling to include a neuroprotective metabotropic dimension and offer GPR68 as a novel therapeutic target to alleviate neuronal injuries in ischemia and multiple other neurological diseases.

scholarly journals Calcitriol Alleviates MPP+- and MPTP-Induced Parthanatos Through the VDR/PARP1 Pathway in the Model of Parkinson’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Junjie Hu ◽  
Jiawei Wu ◽  
Fang Wan ◽  
Liang Kou ◽  
Sijia Yin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Vitamin D ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Cell Model ◽  
Dopamine Neurons ◽  
Protective Effects ◽  
Excessive Activation

The pathogenesis of Parkinson’s disease (PD) is currently unclear. Recent studies have suggested a correlation between vitamin D and PD. Vitamin D and its analogs have protective effects in animal models of PD, but these studies have not clarified the mechanism. Parthanatos is a distinct type of cell death caused by excessive activation of poly (ADP-ribose) polymerase-1 (PARP1), and the activation of PARP1 in PD models suggests that parthanatos may exist in PD pathophysiology. 1,25-Dihydroxyvitamin D3 (calcitriol) is a potential inhibitor of PARP1 in macrophages. This study aimed to investigate whether calcitriol treatment improves PD models and its effects on the parthanatos pathway. A 1-methyl-4-phenylpyridinium (MPP+)-induced cell model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) subacute animal model were selected as the in vitro and in vivo PD models, and calcitriol was applied in these models. Results showed that parthanatos existed in the MPP+-induced cell model and pretreatment with calcitriol improved cell viability, reduced the excessive activation of PARP1, and relieved parthanatos. The application of calcitriol in the MPTP subacute animal model also improved behavioral tests, restored the damage to dopamine neurons, and reduced the activation of PARP1-related signaling pathways. To verify whether calcitriol interacts with PARP1 through its vitamin D receptor (VDR), siRNA, and overexpression plasmids were used to downregulate or overexpress VDR. Following the downregulation of VDR, the expression and activation of PARP1 increased and PARP1 was inhibited when VDR was overexpressed. Coimmunoprecipitation verified the combination of VDR and PARP1. In short, calcitriol can substantially improve parthanatos in the MPP+-induced cell model and MPTP model, and the protective effect might be partly through the VDR/PARP1 pathway, which provides a new possibility for the treatment of PD.

Protective effects of Dioscorea membranacea rhizome ethanolic extract against doxorubicin-induced genotoxicity in human lymphocytes in vitro

Planta Medica ◽  
2015 ◽  
Vol 81 (16) ◽  
Author(s):  
T Ratanavalachai ◽  
S Thitiorul ◽  
A Itharat ◽  
N Runraksa ◽  
S Ruangnoo
Keyword(s):  
Human Lymphocytes ◽  
Ethanolic Extract ◽  
Protective Effects

Probing the 14-3-3 Isoform-Specificity Profile of Interactions Stabilized by Fusicoccin A

2020 ◽  
Author(s):  
James Frederich ◽  
Ananya Sengupta ◽  
Josue Liriano ◽  
Ewa A. Bienkiewicz ◽  
Brian G. Miller
Keyword(s):  
Protein Interactions ◽  
Neurological Diseases ◽  
Adapter Proteins ◽  
Protein Protein Interactions ◽  
Specific Expression ◽  
Individual Client ◽  
Isoform Specificity ◽  
Fusicoccin A

Fusicoccin A (FC) is a fungal phytotoxin that stabilizes protein–protein interactions (PPIs) between 14-3-3 adapter proteins and their phosphoprotein interaction partners. In recent years, FC has emerged as an important chemical probe of human 14-3-3 PPIs implicated in cancer and neurological diseases. These previous studies have established the structural requirements for FC-induced stabilization of 14-3-3·client phosphoprotein complexes; however, the effect of different 14-3-3 isoforms on FC activity has not been systematically explored. This is a relevant question for the continued development of FC variants because there are seven distinct isoforms of 14-3-3 in humans. Despite their remarkable sequence and structural similarities, a growing body of experimental evidence supports both tissue-specific expression of 14-3-3 isoforms and isoform-specific functions <i>in vivo</i>. Herein, we report the isoform-specificity profile of FC <i>in vitro</i>using recombinant human 14-3-3 isoforms and a focused library of fluorescein-labeled hexaphosphopeptides mimicking the C-terminal 14-3-3 recognition domains of client phosphoproteins targeted by FC in cell culture. Our results reveal modest isoform preferences for individual client phospholigands and demonstrate that FC differentially stabilizes PPIs involving 14-3-3s. Together, these data provide strong motivation for the development of non-natural FC variants with enhanced selectivity for individual 14-3-3 isoforms.

Antioxidant Activity, Phenolic Content and Hematoprotective Effects of Cleome arabica Polyphenolic Leaf Extract

2019 ◽  
Author(s):  
C. Tigrine ◽  
A. Kameli
Keyword(s):  
Antioxidant Activity ◽  
Biological Effects ◽  
Reducing Power ◽  
Hematological Toxicity ◽  
Protective Effects ◽  
Ferrous Ions ◽  
Polyphenolic Extract ◽  
Cleome Arabica

In this study a polyphenolic extract from Cleome arabica leaves (CALE) was investigated for its antioxidant activity in vitro using DPPH•, metal chelating and reducing power methods and for its protective effects against AraC-induced hematological toxicity in vivo using Balb C mice. Results indicated that CALE exhibited a strong and dose-dependent scavenging activity against the DPPH• free radical (IC50 = 4.88 μg/ml) and a high reducing power activity (EC50 = 4.85 μg/ml). Furthermore, it showed a good chelating effects against ferrous ions (IC50 = 377.75 μg/ml). The analysis of blood showed that subcutaneous injection of AraC (50 mg/kg) to mice during three consecutive days caused a significant myelosupression (P < 0.05). The combination of CALE and AraC protected blood cells from a veritable toxicity. Where, the number of the red cells, the amount of hemoglobin and the percentage of the hematocrite were significantly high. On the other hand, AraC cause an elevation of body temperature (39 °C) in mice. However, the temperature of the group treated with CALE and AraC remained normal and did not exceed 37.5 °C. The observed biological effects of CALE, in vitro as well as in vivo, could be due to the high polyphenol and flavonoid contents. In addition, the antioxidant activity of CALE suggested to be responsible for its hematoprotective effect.

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