scholarly journals Testing the Neuroprotective Properties of PCSO-524® Using a Neuronal Cell Cycle Suppression Assay

Marine Drugs ◽  
2019 ◽  
Vol 17 (2) ◽  
pp. 79 ◽  
Author(s):  
Beika Zhu ◽  
Yang Zhang ◽  
Karl Herrup
Keyword(s):  
Cell Cycle ◽  
Neurodegenerative Disease ◽  
Neuronal Cell ◽  
Brain Inflammation ◽  
Neuroprotective Effects ◽  
Ht22 Cells ◽  
Cell Cycle Reentry ◽  
The Central Nervous System ◽  
Vitro Model

Cell cycle reentry is a unified mechanism shared by several neurodegenerative diseases, including Alzheimer’s disease (AD) and Ataxia Telangiectasia (A-T). This phenotype is often related to neuroinflammation in the central nervous system. To mimic brain inflammation in vitro, we adopted the previously established method of using conditioned medium collected from activated THP-1 cells and applied it to both differentiated HT22 cells and primary neurons. Unscheduled cell cycle events were observed in both systems, indicating the potential of this approach as an in vitro model of neurodegenerative disease. We used this assay to measure the neuroprotective effects of New Zealand green-lipped mussel extract, PCSO-524®, to protect post-mitotic cells from cell cycle reentry. We found that, both in vitro and in an animal model, PCSO-524® displayed promising neuroprotective effects, and thus has potential to postpone or prevent the onset of neurodegenerative disease.

Abstract 2357: Src Kinase Inhibition Blocks Thrombin-induced Brain Injuries without Cognitive Side Effects

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Da-Zhi Liu ◽  
Bradley P Ander ◽  
Ali Izadi ◽  
Ken Van ◽  
Xinhua Zhan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cognitive Deficits ◽  
Neuronal Cell ◽  
Thrombin Injection ◽  
Cell Cycle Reentry ◽  
Cell Cycle Inhibition ◽  
Mature Neurons ◽  
Cognitive Side Effects

Intracerebral hemorrhage (ICH) activates thrombin, a potent mitogen. Thrombin triggers mitosis by modulating several intracellular mitogenic molecules including Src family kinases. These molecules regulate mitogen-activated protein kinases (MAPKs) and cell cycle proteins such as cyclin-dependent kinases (Cdks); and play critical roles in mitogenic signaling pathways and cell cycle progression. Since aberrant cell cycle reentry results in death of mature neurons, cell cycle inhibition appears to be a candidate strategy for the treatment of neurological diseases including ICH. However, this can also block cell cycle (proliferation) of neural progenitor cells (NPCs) and thus impair brain neurogenesis leading to cognitive deficits. We hypothesized that inhibition of cell cycle by blocking mitogenic signaling molecules (i.e., Src family kinase members) blocks cell cycle reentry of mature neurons without injuring NPCs, which will avoid cognitive side effects during cell cycle inhibition treatment for ICH. Our data shows: (1) Thrombin 30U/ml results in apoptosis of mature neurons via neuronal cell cycle reentry in vitro ; (2) PP2 (Src family kinase inhibitor) 0.3 µM attenuates the thrombin-induced neuronal apoptosis via blocking neuronal cell cycle reentry, but does not affect the viability of NPCs at the same doses in vitro ; (3) Intracerebral ventricular thrombin injection (20U, i.c.v.) results in neuron loss in hippocampus and cognitive deficits 5 weeks after thrombin injection in vivo ; (4) PP2 (1mg/kg, i.p.), given immediately after thrombin injection (i.c.v.), blocks the thrombin-induced neuron loss in hippocampus and cognitive deficits, whereas PP2 on its own at the same doses does not affect normal cognition in vivo . These suggest that Src kinase inhibition prevents hippocampal neuron death via blocking neuronal cell cycle reentry after ICH, but does not affect survival of NPCs.

scholarly journals Xenon Neurotoxicity in Rat Hippocampal Slice Cultures Is Similar to Isoflurane and Sevoflurane

2013 ◽  
Vol 119 (2) ◽  
pp. 335-344 ◽  
Author(s):  
Heather Brosnan ◽  
Philip E. Bickler
Keyword(s):  
Cell Death ◽  
Hippocampal Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuron Death ◽  
Neuroprotective Effects ◽  
Low Concentrations ◽  
Vitro Model ◽  
Developing Neurons

Abstract Background: Anesthetic neurotoxicity in the developing brain of rodents and primates has raised concern. Xenon may be a nonneurotoxic alternative to halogenated anesthetics, but its toxicity has only been studied at low concentrations, where neuroprotective effects predominate in animal models. An equipotent comparison of xenon and halogenated anesthetics with respect to neurotoxicity in developing neurons has not been made. Methods: Organotypic hippocampal cultures from 7-day-old rats were exposed to 0.75, 1, and 2 minimum alveolar concentrations (MAC) partial pressures (60% xenon at 1.2, 2.67, and 3.67 atm; isoflurane at 1.4, 1.9, and 3.8%; and sevoflurane at 3.4 and 6.8%) for 6 h, at atmospheric pressure or in a pressure chamber. Cell death was assessed 24 h later with fluorojade and fluorescent dye exclusion techniques. Results: Xenon caused death of hippocampal neurons in CA1, CA3, and dentate regions after 1 and 2 MAC exposures, but not at 0.75 MAC. At 1 MAC, xenon increased cell death 40% above baseline (P < 0.01; ANOVA with Dunnett test). Both isoflurane and sevoflurane increased neuron death at 1 but not 2 MAC. At 1 MAC, the increase in cell death compared with controls was 63% with isoflurane and 90% with sevoflurane (both P < 0.001). Pretreatment of cultures with isoflurane (0.75 MAC) reduced neuron death after 1 MAC xenon, isoflurane, and sevoflurane. Conclusion: Xenon causes neuronal cell death in an in vitro model of the developing rodent brain at 1 MAC, as does isoflurane and sevoflurane at similarly potent concentrations. Preconditioning with a subtoxic dose of isoflurane eliminates this toxicity.

scholarly journals Calycosin-7-O-β-D-glucoside Attenuates OGD/R-Induced Damage by Preventing Oxidative Stress and Neuronal Apoptosis via the SIRT1/FOXO1/PGC-1α Pathway in HT22 Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Xiangli Yan ◽  
Aiming Yu ◽  
Haozhen Zheng ◽  
Shengxin Wang ◽  
Yingying He ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neuronal Apoptosis ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Pathological Process ◽  
Neuroprotective Effects ◽  
Ht22 Cells ◽  
Positive Effects ◽  
Antioxidant Stress

Neuronal apoptosis induced by oxidative stress is a major pathological process that occurs after cerebral ischemia-reperfusion. Calycosin-7-O-β-D-glucoside (CG) is a representative component of isoflavones in Radix Astragali (RA). Previous studies have shown that CG has potential neuroprotective effects. However, whether CG alleviates neuronal apoptosis through antioxidant stress after ischemia-reperfusion remains unknown. To investigate the positive effects of CG on oxidative stress and apoptosis of neurons, we simulated the ischemia-reperfusion process in vitro using an immortalized hippocampal neuron cell line (HT22) and oxygen-glucose deprivation/reperfusion (OGD/R) model. CG significantly improved cell viability and reduced oxidative stress and neuronal apoptosis. In addition, CG treatment upregulated the expression of SIRT1, FOXO1, PGC-1α, and Bcl-2 and downregulated the expression of Bax. In summary, our findings indicate that CG alleviates OGD/R-induced damage via the SIRT1/FOXO1/PGC-1α signaling pathway. Thus, CG maybe a promising therapeutic candidate for brain injury associated with ischemic stroke.

scholarly journals Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1616
Author(s):  
Nicoletta di Leo ◽  
Stefania Moscato ◽  
Marco Borso' ◽  
Simona Sestito ◽  
Beatrice Polini ◽  
...  
Keyword(s):  
High Performance ◽  
In Vitro Model ◽  
New Drugs ◽  
Therapeutic Approaches ◽  
Neuroprotective Effects ◽  
Pharmacological Response ◽  
Preliminary Study ◽  
Vitro Model ◽  
The Brain

Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood–brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property.

scholarly journals BK polyomavirus (BKPyV) is a risk factor for bladder cancer through induction of APOBEC3-mediated genomic damage

2021 ◽  
Author(s):  
Simon Charles Baker ◽  
Andrew S Mason ◽  
Raphael G Slip ◽  
Katie T Skinner ◽  
Andrew Macdonald ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Risk Factor ◽  
The Elderly ◽  
T Antigen ◽  
Transplant Patients ◽  
Adult Kidney ◽  
Bk Polyomavirus ◽  
Vitro Model

Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. BK polyomavirus (BKPyV) is a common childhood infection that can be reactivated in the adult kidney leading to viruria. Here we used a mitotically-quiescent, differentiated, normal human urothelial in vitro model to study BKPyV infection. BKPyV infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry into the cell cycle via inhibition of Retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, which combined to push urothelial cells from G0 into an arrested G2 cell cycle state. The single-stranded DNA displacement loops formed during BKPyV-infection, provide a substrate for APOBEC3 enzymes where they interacted with LT-Ag. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations, including transplant patients and the elderly.

scholarly journals Anti-Inflammatory Effects of Dimethyl Fumarate in Microglia via an Autophagy Dependent Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Young-Sun Lee ◽  
Deepak Prasad Gupta ◽  
Sung Hee Park ◽  
Hyun-Jeong Yang ◽  
Gyun Jee Song
Keyword(s):  
Cytokine Production ◽  
Dimethyl Fumarate ◽  
Neuroprotective Effects ◽  
Autophagy Induction ◽  
The Central Nervous System ◽  
Anti Inflammatory ◽  
Lc3 Puncta ◽  
Relationship Of ◽  
Dependent Pathway

Dimethyl fumarate (DMF), which has been approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis, is considered to exert anti-inflammatory and antioxidant effects. Microglia maintain homeostasis in the central nervous system and play a key role in neuroinflammation, while autophagy controls numerous fundamental biological processes, including pathogen removal, cytokine production, and clearance of toxic aggregates. However, the role of DMF in autophagy induction and the relationship of this effect with its anti-inflammatory functions in microglia are not well known. In the present study, we investigated whether DMF inhibited neuroinflammation and induced autophagy in microglia. First, we confirmed the anti-neuroinflammatory effect of DMF in mice with streptozotocin-induced diabetic neuropathy. Next, we used in vitro models including microglial cell lines and primary microglial cells to examine the anti-inflammatory and neuroprotective effects of DMF. We found that DMF significantly inhibited nitric oxide and proinflammatory cytokine production in lipopolysaccharide-stimulated microglia and induced the switch of microglia to the M2 state. In addition, DMF treatment increased the expression levels of autophagy markers including microtubule-associated protein light chain 3 (LC3) and autophagy-related protein 7 (ATG7) and the formation of LC3 puncta in microglia. The anti-inflammatory effect of DMF in microglia was significantly reduced by pretreatment with autophagy inhibitors. These data suggest that DMF leads to the induction of autophagy in microglia and that its anti-inflammatory effects are partially mediated through an autophagy-dependent pathway.

The LPA-CDK5-Tau Pathway Mediates Neuronal Injury in an In Vitro Model of Ischemia-Reperfusion Insult

2021 ◽  
Author(s):  
Yaya Wang ◽  
Jie Zhang ◽  
Liqin Huang ◽  
Yanhong Mo ◽  
Changyu Wang ◽  
...  
Keyword(s):  
Brain Injury ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Ischemia Reperfusion ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ischemic Brain ◽  
Pathophysiological Process ◽  
Vitro Model

Abstract Lysophosphatidic acid (LPA) is a common glycerol phospholipid and an important extracellular signaling molecule. LPA binds to its receptors and mediates a variety of biological effects, including the pathophysiological process underlying ischemic brain damage and traumatic brain injury. However, the molecular mechanisms mediating the pathological role of LPA are not clear. Here, we found that LPA activates cyclin-dependent kinase 5 (CDK5). CDK5 phosphorylates tau, which leads to neuronal cell death. Inhibition of LPA production or blocking its receptors reduced the abnormal activation of CDK5 and phosphorylation of tau, thus reversing the death of neurons. Our data indicate that the LPA-CDK5-Tau pathway plays an important role in the pathophysiological process after ischemic stroke. Inhibiting the LPA pathway may be a potential therapeutic target for treating ischemic brain injury.

scholarly journals Peroxiredoxin 5 Inhibits Glutamate-Induced Neuronal Cell Death through the Regulation of Calcineurin-Dependent Mitochondrial Dynamics in HT22 Cells

2019 ◽  
Vol 39 (20) ◽  
Author(s):  
Mi Hye Kim ◽  
Hong Jun Lee ◽  
Sang-Rae Lee ◽  
Hyun-Shik Lee ◽  
Jae-Won Huh ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Glutamate Toxicity ◽  
Ht22 Cells ◽  
Peroxidase Enzyme ◽  
The Central Nervous System

ABSTRACT Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca2+ influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca2+/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca2+/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca2+/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.

The Blockade of K+‐ATP Channels has Neuroprotective Effects in an In Vitro Model of Brain Ischemia

2007 ◽  
pp. 383-395 ◽  
Author(s):  
Robert Nisticò ◽  
Silvia Piccirilli ◽  
L. Sebastianelli ◽  
Giuseppe Nisticò ◽  
G. Bernardi ◽  
...  
Keyword(s):  
Brain Ischemia ◽  
In Vitro Model ◽  
Neuroprotective Effects ◽  
Vitro Model
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