Furoxans (Oxadiazole-4 N-oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory.
Journal of medicinal chemistry
2018; 61 (10): 4593?4607
A Bioactive Resveratrol Trimer from the Stem Bark of the Sri Lankan Endemic Plant Vateria copallifera.
Journal of natural products
2018; 81 (8): 1693?1700
Nitric oxide (NO) mimetics and other agents capable of enhancing NO/cGMP signaling have demonstrated efficacy as potential therapies for Alzheimer's disease. A group of thiol-dependent NO mimetics known as furoxans may be designed to exhibit attenuated reactivity to provide slow onset NO effects. The present study describes the design, synthesis, and evaluation of a furoxan library resulting in the identification of a prototype furoxan, 5a, which was profiled for use in the central nervous system. Furoxan 5a demonstrated negligible reactivity toward generic cellular thiols under physiological conditions. Nonetheless, cGMP-dependent neuroprotection was observed, and 5a (20 mg/kg) reversed cholinergic memory deficits in a mouse model of passive avoidance fear memory. Importantly, 5a can be prepared as a pharmaceutically acceptable salt and is observed in the brain 12 h after oral administration, suggesting potential for daily dosing and excellent metabolic stability. Continued investigation into furoxans as attenuated NO mimetics for the CNS is warranted.
View details for DOI 10.1021/acs.jmedchem.8b00389
View details for PubMedID 29683322
Cofilin Knockdown Attenuates Hemorrhagic Brain Injury-induced Oxidative Stress and Microglial Activation in Mice.
2018; 383: 33?45
A new resveratrol trimer, vateriferol (1), having four cis-oriented methine protons and constituting four contiguous stereocenters, was isolated from the bark extract of Vateria copallifera by bioassay-guided fractionation using a combination of normal, reversed phase, and size exclusion column chromatography. The structure was established based on its spectroscopic data. Vateriferol (1) was evaluated in vitro for its antioxidant capacity, enzyme inhibitory activity, growth inhibitory activity on a number of cancer cell lines, neuroprotective activity, and anti-inflammatory activity. Vateriferol (1) exhibited AChE inhibitory activity (IC50 8.4 ▒ 0.2 ?M), ORAC activity (2079 ▒ 0.20 TE/g), and neuroprotective activity at 1.5 ?M using PC12 cells deprived of oxygen and glucose and lowered NO levels in lipopolysaccharide-stimulated SIM-A9 microglial cells at 14.7 and 73.6 ?M. Vateriferol (1) exhibited weak cytotoxic potency (<50% growth inhibition) against the tested cell lines at 147.2 ?M.
View details for DOI 10.1021/acs.jnatprod.7b00892
View details for PubMedID 30040425
Cofilin Mediates LPS-Induced Microglial Cell Activation and Associated Neurotoxicity Through Activation of NF-?B and JAK-STAT Pathway.
Intracerebral hemorrhage (ICH) resulting from the rupture of the blood vessels in the brain is associated with significantly higher mortality and morbidity. Clinical studies focused on alleviating the primary injury, hematoma formation and expansion, were largely ineffective, suggesting that secondary injury-induced inflammation and the formation of reactive species also contribute to the overall injury process. In this study, we explored the effects of cofilin knockdown in a mouse model of ICH. Animals given stereotaxic injections of cofilin siRNA, 72-h prior to induction of ICH by collagenase injection within the area of siRNA administration showed significantly decreased cofilin expression levels and lower hemorrhage volume and edema, and the animals performed significantly better in neurobehavioral tasks i.e., rotarod, grip strength and neurologic deficit scores. Cofilin siRNA knocked-down mice had reduced ICH-induced DNA fragmentation, blood-brain barrier disruption and microglial activation, with a concomitant increase in astrocyte activation. Increased expression of pro-survival proteins and decreased markers of oxidative stress were also observed in cofilin siRNA-treated mice possibly due to the reduced levels of cofilin. Our results suggest that cofilin plays a major role in ICH-induced secondary injury, and could become a potential therapeutic target.
View details for DOI 10.1016/j.neuroscience.2018.04.036
View details for PubMedID 29746992
The Interplay between Cofilin and Phospho-cofilin: Its Role in Maintaining Blood Brain Barrier Integrity.
CNS & neurological disorders drug targets
Microglial cells are activated in response to different types of injuries or stress in the CNS. Such activation is necessary to get rid of the injurious agents and restore tissue homeostasis. However, excessive activation of microglial cells is harmful and contributes to secondary injury. Pertinently, microglial cell activity was targeted in many preclinical and clinical studies but such strategy failed in clinical trials. The main reason behind the failed attempts is the complexity of the injury mechanisms which needs either a combination therapy or targeting a process that is involved in multiple pathways. Cofilin is a cytoskeleton-associated protein involved in actin dynamics. In our previous study, we demonstrated the role of cofilin in mediating neuronal apoptosis during OGD conditions. Previous studies on microglia have shown the involvement of cofilin in ROS formation and phagocytosis. However, additional studies are needed to delineate the role of cofilin in microglial cell activation. Therefore, in the current study, we investigated the role of cofilin in LPS-induced microglial cell activation using cofilin siRNA knockdown paradigms. The viability of differentiated PC12 cells was used as a measure of the neurotoxic potential of conditioned medium derived from cofilin siRNA-transfected and LPS-activated microglial cells. Cofilin knockdown significantly inhibited LPS-induced microglial cell activation through NF-?B and JAK-STAT pathways. The release of proinflammatory mediators (NO, TNF-?, iNOS, and COX2) as well as microglial proliferation and migration rates were significantly reduced by cofilin knockdown. Furthermore, differentiated PC12 cells were protected from the neurotoxicity induced by conditioned medium derived from cofilin-transfected and LPS-activated microglial cells. In conclusion, we demonstrated that cofilin is involved in the cascade of microglial cell activation and further validates our previous study on cofilin's role in mediating neuronal apoptosis. Together, our results suggest that cofilin could present a common target in neurons and microglial cells and might prove to be a promising therapy for different brain injury mechanisms including stroke.
View details for DOI 10.1007/s12035-017-0432-7
View details for PubMedID 28194647
View details for PubMedCentralID PMC5554748
Tanshinone IIA Inhibits VEGF Secretion and HIF-1? Expression in Cultured Human Retinal Pigment Epithelial Cells under Hypoxia.
Current eye research
2017; 42 (12): 1667?73
The blood brain barrier (BBB) is a continuous, non-fenestrated vessel system that tightly regulates the movement of molecules, ions, and cells between the blood and the central nervous system. Endothelial cells are the major constituents of the BBB and these cells are linked to each other through intercellular contact points composed of tight junctions, adherent junctions and gap junctions. These three types of junctions are connected to the intracellular actin cytoskeleton via various adaptor proteins. Thus, the actin cytoskeleton plays a crucial role in regulating the stability of endothelial cell contacts and vascular permeability. Shear stress, growth factors, and Wnt/?-catenin pathway modulators contribute to maintaining endothelial cell integrity by controlling actin dynamics under homeostatic conditions. Interestingly, the downstream signaling of the aforementioned factors converges at Rac1, which mediates cortical actin stabilization, stress fiber destabilization and junctional complex stabilization by controlling subcellular cofilin dynamics. However, Rac1 is not the only modulator of cofilin activity; many other agents activated during inflammatory, ischemic, and excitotoxic conditions can disturb homeostatic cofilin dynamics and induce BBB disruption. Therefore, in this review, we discuss organization of the actin cytoskeleton in BBB endothelial cells and how interactions between the actin cytoskeleton and junctional complexes are maintained during homeostatic conditions. Furthermore, we discuss how an imbalance in subcellular cofilin dynamics can contribute to BBB disruption and highlight Rac1 as a potential target that can be exploited to preserve BBB stability.
View details for PubMedID 28124604
Cofilin signaling in hemin-induced microglial activation and inflammation.
Journal of neuroimmunology
2017; 313: 46?55
The current work intends to study the activity of tanshinone IIA on secretion of vascular endothelial growth factor (VEGF) and expression of hypoxia inducible factor 1? (HIF-1?) in human retinal pigment epithelial cells (ARPE-19 cells) under hypoxic condition.The cytotoxicity of tanshinone IIA was tested in ARPE-19 cells by MTT assay. ARPE-19 cells were incubated with different concentrations of cobalt chloride (100, 150, and 200 ÁM) for 12 h, and levels of expressed HIF-1? and secreted VEGF were quantified through Western blot and ELISA, respectively. Further, ARPE-19 cells were pretreated for 1 h with different concentrations of tanshinone IIA (5, 10, 15, and 18 ÁM). After 1 h, the cells were subjected to hypoxic condition using 150 ÁM cobalt chloride for 12 h in the presence and absence of tanshinone IIA. The cells were then harvested, and the secreted VEGF and expressed HIF-1? was studied.Tanshinone IIA at concentrations of 5, 10, 15, and 18 ?M did not show cytotoxicity in ARPE-19 cells. Chemical hypoxia induced by cobalt chloride caused a significant increase in VEGF level in a dose-dependent manner, and HIF-1? expression peaked at 150 ÁM. Based on the data, cobalt chloride concentration was maintained at 150 ?M for further studies. Tanshinone IIA decreased the level of HIF-1? and VEGF secretion in a dose-dependent manner under hypoxic condition.Tanshinone IIA could be explored as a new potential candidate for treating wet AMD.
View details for DOI 10.1080/02713683.2017.1355467
View details for PubMedID 28937825
Cofilin Inhibition Restores Neuronal Cell Death in Oxygen-Glucose Deprivation Model of Ischemia
2016; 53 (2): 867?78
Intracerebral hemorrhage (ICH) is the most severe form of stroke and is further exacerbated by the secondary injury involving inflammatory response due to the activation of microglia. This secondary injury is partly due to the toxic effects of hemin, an endogenous breakdown product of hemoglobin. Cofilin, an actin depolymerizing factor, controls actin dynamics and has been previously shown to be involved in mediating neuronal cell death in ischemic conditions and during bacterial lipopolysaccharide induced microglial activation. There are limited studies regarding the deleterious effects of extremely high concentrations of hemin released during ICH and its effects on microglia and subsequent cofilin response. Therefore, investigations were conducted to study the effects of hemin on microglial activation induced inflammation and the critical role of cofilin in mediating the response. We observed that hemin treated microglia had a concentration dependent increase in cofilin expression and NO production. There were increased levels of iNOS, TNF-?, HO1, Nrf2, Wfs-1, XBP-1 and spliced XBP-1 observed in response to hemin treatment and the signaling was found to be partly mediated by cofilin. Acute hemin treatment did not evoke Ca2+ signaling and long-term treatment of hemin also resulted in the failure of microglial response to acetylcholine-evoked Ca2+ signaling. Knockdown of cofilin by siRNA also reduced acetylcholine-evoked Ca2+ signaling. These studies demonstrate that cofilin signaling is important in hemin-induced inflammation, oxidative stress, ER stress, microglial migration, and the ability to evoke Ca2+ signaling. Therefore, cofilin inhibition could be a potential therapy in brain injuries triggered by hemin toxicity in conditions like ICH.
View details for DOI 10.1016/j.jneuroim.2017.10.007
View details for PubMedID 29153608
Cofilin as a Promising Therapeutic Target for Ischemic and Hemorrhagic Stroke
TRANSLATIONAL STROKE RESEARCH
2016; 7 (1): 33-41
Ischemia is a condition associated with decreased blood supply to the brain, eventually leading to death of neurons. It is associated with a diverse cascade of responses involving both degenerative and regenerative mechanisms. At the cellular level, the changes are initiated prominently in the neuronal cytoskeleton. Cofilin, a cytoskeletal actin severing protein, is known to be involved in the early stages of apoptotic cell death. Evidence supports its intervention in the progression of disease states like Alzheimer's and ischemic kidney disease. In the present study, we have hypothesized the possible involvement of cofilin in ischemia. Using PC12 cells and mouse primary cultures of cortical neurons, we investigated the potential role of cofilin in ischemia in two different in vitro ischemic models: chemical induced oxidative stress and oxygen-glucose deprivation/reperfusion (OGD/R). The expression profile studies demonstrated a decrease in phosphocofilin levels in all models of ischemia, implying stress-induced cofilin activation. Furthermore, calcineurin and slingshot 1L (SSH) phosphatases were found to be the signaling mediators of the cofilin activation. In primary cultures of cortical neurons, cofilin was found to be significantly activated after 1 h of OGD. To delineate the role of activated cofilin in ischemia, we knocked down cofilin by small interfering RNA (siRNA) technique and tested the impact of cofilin silencing on neuronal viability. Cofilin siRNA-treated neurons showed a significant reduction of cofilin levels in all treatment groups (control, OGD, and OGD/R). Additionally, cofilin siRNA-reduced cofilin mitochondrial translocation and caspase 3 cleavage, with a concomitant increase in neuronal viability. These results strongly support the active role of cofilin in ischemia-induced neuronal degeneration and apoptosis. We believe that targeting this protein mediator has a potential for therapeutic intervention in ischemic brain injury and stroke.
View details for DOI 10.1007/s12035-014-9056-3
View details for Web of Science ID 000370187100007
View details for PubMedID 25526862
View details for PubMedCentralID PMC4475502
Natural polyphenols: Influence on membrane transporters.
Journal of intercultural ethnopharmacology
2016; 5 (1): 97-104
Neurovascular unit (NVU) is considered as a conceptual framework for investigating the mechanisms as well as developing therapeutic targets for ischemic and hemorrhagic stroke. From a molecular perspective, oxidative stress, excitotoxicity, inflammation, and disruption of the blood brain barrier are broad pathophysiological frameworks on the basis on which potential therapeutic candidates for ischemic and hemorrhagic stroke could be discussed. Cofilin is a potent actin-binding protein that severs and depolymerizes actin filaments in order to generate the dynamics of the actin cytoskeleton. Although studies of the molecular mechanisms of cofilin-induced reorganization of the actin cytoskeleton have been ongoing for decades, the multicellular functions of cofilin and its regulation in different molecular pathways are expanding beyond its primary role in actin cytoskeleton. This review focuses on the role of cofilin in oxidative stress, excitotoxicity, inflammation, and disruption of the blood brain barrier in the context of NVU as well as how and why cofilin could be studied further as a potential target for ischemic and hemorrhagic stroke.
View details for DOI 10.1007/s12975-015-0438-2
View details for Web of Science ID 000371426400005
View details for PubMedID 26670926
Natural Polyphenols in Cancer Chemoresistance
NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL
2016; 68 (6): 879-891
Accumulated evidence has focused on the use of natural polyphenolic compounds as nutraceuticals since they showed a wide range of bioactivities and exhibited protection against variety of age-related disorders. Polyphenols have variable potencies to interact, and hence alter the activities of various transporter proteins, many of them classified as anion transporting polypeptide-binding cassette transporters like multidrug resistance protein and p-glycoprotein. Some of the efflux transporters are, generally, linked with anticancer and antiviral drug resistance; in this context, polyphenols may be beneficial in modulating drug resistance by increasing the efficacy of anticancer and antiviral drugs. In addition, these effects were implicated to explain the influence of dietary polyphenols on drug efficacy as result of food-drug interactions. However, limited data are available about the influence of these components on uptake transporters. Therefore, the objective of this article is to review the potential efficacies of polyphenols in modulating the functional integrity of uptake transporter proteins, including those terminated the effect of neurotransmitters, and their possible influence in neuropharmacology.
View details for DOI 10.5455/jice.20160118062127
View details for PubMedID 27069731
View details for PubMedCentralID PMC4805155
Resistance to chemotherapy remains a major impediment to the management of most types of cancer. Both intrinsic and acquired drug resistance are mediated by several cellular and molecular mechanisms, including alternative growth-signaling pathways unaffected by specific therapies, alterations in the tumor microenvironment (e.g., hypoxia and angiogenesis), and active transport of drugs out of the cell. Epidemiological studies have validated an inverse correlation between the consumption of dietary polyphenols and the risk of cancer, which has been attributed to polyphenol antioxidant capacity and their potential to inhibit activation of procarcinogens, cancer cell proliferation, metastasis, and angiogenesis, and inhibition or downregulation of active drug efflux transporters. Moreover, polyphenols can induce apoptosis in cancer cells and modulate immune responses and inflammatory cascades. Augmentation of the efficacy of chemotherapy and prevention of multidrug resistance are other important effects of dietary polyphenols that deserve further research, especially after the discovery of tight "crosstalk" between aberrant growth signaling and metabolic dysfunction in cancer cells. In this review, we cover what is currently known about the role of natural polyphenolic compounds in overcoming cancer drug resistance mediated by diverse primary and secondary resistance mechanisms.
View details for DOI 10.1080/01635581.2016.1192201
View details for Web of Science ID 000381276500001
View details for PubMedID 27366999