C Kaur

National University of Singapore, Singapore, Singapore

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Publications (138)425.8 Total impact

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    ABSTRACT: This study was carried out to investigate the roles of tight junction proteins and other vascular factors in the increased permeability of the blood retinal barrier (BRB) affecting the immature neonatal retina following a hypoxic insult. The expression of endothelial tight junction proteins such as claudin-5, occludin and zonula occludens-1 (ZO-1) and endothelial cell specific molecule-1 (ESM-1), and associated structural changes in the blood vessels were analyzed in the retinas of 1-day-old wistar rats subjected to hypoxia for 2 h and subsequently sacrificed at different time points ranging from 3 h to 14 d. The mRNA and protein expression of claudin-5, occludin & ZO-1 was found to be reduced in the hypoxic retina, although, at the ultrastructural level, the tight junctions between the endothelial cells and retinal pigment epithelial cells appeared to be intact. Following a hypoxic insult vascular endothelial cells frequently showed presence of cytoplasmic vacuoles, vacuolated mitochondria and multivesicular aggregations projecting into the capillary lumen. The expression of ESM-1 in the immature retinas was found to be increased following hypoxic exposure. The structural and molecular changes in the hypoxic neonatal retinas were consistent with a hypoxia induced impairment of the BRB. Hypoxia reduced the expression of TJ proteins in the neonatal retina, but the role of increased ESM-1 expression in this process warrants further investigation. Copyright © 2014. Published by Elsevier Ltd.
    Experimental Eye Research 11/2014; · 3.03 Impact Factor
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    ABSTRACT: Purpose:Hypoxic insult to the developing retina results in apoptosis of retinal ganglion cells (RGCs) through production of inflammatory mediators, nitric oxide (NO) and free radicals. The present study was aimed at elucidating the pathway through which hypoxia results in overproduction of NO in the immature retina, and its role in causing apoptosis of RGCs. Methods:One-day-old Wistar rats were exposed to hypoxia and their retinas were studied at 3h to 14 days after exposure. The protein expression of nuclear factor-κB (NF-κB) and neuronal nitric oxide synthase (nNOS) in the retina and primary cultures of RGCs was analysed using western blotting and double-immunofluorescence; whereas, the concentration of NO was determined calorimetrically. In cultured RGCs, hypoxia-induced apoptosis was evaluated by caspase-3 immunolabelling. Results:Following hypoxic exposure, NF-κB mediated expression of nNOS, which was localized to the RGCs, and subsequent NO production was significantly increased in the developing retina. In primary cultures of RGCs subjected to hypoxia, the up-regulation of nNOS and NO was significantly suppressed when treated with 7-nitroindazole (7-NINA), a nNOS inhibitor or BAY, a NF-κB inhibitor. Hypoxia-induced apoptosis of RGCs, which was evident with caspase-3 labelling, was also suppressed when these cells were treated with 7-NINA or BAY. Conclusions:Our results suggest that in RGCs, hypoxic induction of nNOS is mediated by NF-κB and the resulting increased release of NO by RGCs, results in their apoptosis through caspase-3 activation. It is speculated that targeting nNOS could be a potential neuroprotective strategy against hypoxia-induced RGCs death in the developing retina.
    Investigative ophthalmology & visual science. 08/2014;
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    ABSTRACT: Cerebral edema/brain edema refers to the accumulation of fluid in the brain and is one of the fatal conditions that require immediate medical attention. Cerebral edema develops as a consequence of cerebral trauma, cerebral infarction, hemorrhages, abscess, tumor, hypoxia, and other toxic or metabolic factors. Based on the causative factors cerebral edema is differentiated into cytotoxic cerebral edema, vasogenic cerebral edema, osmotic and interstitial cerebral edema. Treatment of cerebral edema depends on timely diagnosis and medical assistance. Pragmatic treatment strategies such as antihypertensive medications, nonsteroidal anti-inflammatory drugs, barbiturates, steroids, glutamate and N-methyl-D-aspartate receptor antagonists and trometamol are used in clinical practice. Although the above mentioned treatment approaches are being used, owing to the complexity of the mechanisms involved in cerebral edema, a single therapeutic strategy which could ameliorate cerebral edema is yet to be identified. However, recent experimental studies have suggested that melatonin, a neurohormone produced by the pineal gland, could be an effective alternative for treating cerebral edema. In animal models of stroke, melatonin was not only shown to reduce cerebral edema but also preserved the blood brain barrier. Melatonin's beneficial effects were attributed to its properties, such as being a potent anti-oxidant, and its ability to cross the blood brain barrier within minutes after its administration. This review summarizes the beneficial effects of melatonin when used for treating cerebral edema.
    Histology and histopathology 05/2014; · 2.28 Impact Factor
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    ABSTRACT: Iron accumulation occurs in tissues such as periventricular white matter (PWM) in response to hypoxic injuries, and microglial cells sequester excess iron following hypoxic exposure. As hypoxia has a role in altering the expression of proteins involved in iron regulation, this study was aimed at examining the interaction between hypoxia inducible factor (HIF)-1α and proteins involved in iron transport in microglial cells, and evaluating the mechanistic action of deferoxamine and KC7F2 (a HIF-1α inhibitor) in iron mediated hypoxic injury. Treating the microglial cultures with KC7F2, led to decreased expression of transferrin receptor and divalent metal transporter-1. Administration of deferoxamine or KC7F2 to hypoxic microglial cells enhanced extracellular signal-regulated kinase (ERK) phosphorylation (p-ERK), but decreased the phosphorylation of p38 (p-p38). The increased p-ERK further phosphorylated the cAMP response element-binding protein (p-CREB) which in turn may have resulted in the increased mitogen activated protein kinase (MAPK) phosphatase 1 (MKP1), known to dephosphorylate MAPKs. Consistent with the decrease in p-p38, the production of pro-inflammatory cytokines TNF-α and IL-1β was reduced in hypoxic microglia treated with deferoxamine and SB 202190, an inhibitor for p38. This suggests that the anti-inflammatory effect exhibited by deferoxamine is by inhibition of p-p38 induced inflammation through the pERK-pCREB-MKP1 pathway, whereas that of KC7F2 requires further investigation. The present results suggest that HIF-1α may mediate iron accumulation in hypoxic microglia and KC7F2, similar to deferoxamine, might provide limited protection against iron induced PWMD.
    Neuropharmacology 10/2013; · 4.11 Impact Factor
  • L Yao, Q Cao, C Wu, C Kaur, E A Ling
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    ABSTRACT: Notch signaling pathway is a major player in normal development in neurons, oligodendrocytes and astrocytes as well as neurological disorders of the central nervous system (CNS). Microglia, one of the major types of glial cells in the CNS, partakes in diverse roles within the CNS mainly related to normal brain development and inflammatory diseases, yet the involvement of Notch signaling pathway in microglia has remained elusive and has only recently been recognized suggesting its putative role in microglial maturation and activation. Notch ligands and receptors are constitutively expressed by microglia in developing brain. Notch signaling pathway is important for the maintenance of microglial population during early development as in other glial cells in normal development. Remarkably, Notch signaling pathway is also involved in microglial activation and inflammation process in neuroinflammatory diseases in both postnatal and adult rats. Targeting Notch signaling is therefore a promising strategy for prevention of neurodevelopmental diseases and development of future therapies for the treatment of neuroinflammatory disorders. This review highlights some recent findings of Notch signaling in microglia, both in normal development and pathological conditions.
    CNS & neurological disorders drug targets 09/2013; · 3.57 Impact Factor
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    ABSTRACT: Iron is a vital element required by almost all cells for their normal functioning. The well-established role of iron in oxidative metabolism, myelination and synthesis of neurotransmitter makes it an indispensable nutrient required by the brain. Both iron deficiency and excess have been associated with numerous patho-physiologies of the brain, suggesting a need for iron homeostasis. Various studies have reported that the immune effector cells of the brain, the microglial cells, are involved in iron homeostasis in the brain. Microglial cells, which accumulate iron during the developmental period, have a role in myelination process. Along with the increased iron accumulation documented in neurodegenerative diseases, the striking finding is the presence of iron positive microglial cells at the foci of lesion. Though excess iron within activated microglia is demonstrated to enhance the release of pro-inflammatory cytokines and free radicals, a complete understanding of the role of iron in microglia is lacking. The present knowledge on iron mediated changes, in the functions of microglia is summarized in this review.
    CNS & neurological disorders drug targets 09/2013; · 3.57 Impact Factor
  • C Kaur, E A Ling
    CNS & neurological disorders drug targets 09/2013; · 3.57 Impact Factor
  • M Murugan, E A Ling, C Kaur
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    ABSTRACT: Expression of functional glutamate receptors (GluR) on glial cells in the developing and mature brain has been recently established. Over the last decade there has been physiological, molecular and biochemical evidence suggesting the presence of GluR on microglia. However, the significance of GluR activation in microglia remains largely unknown. In this review, we discuss the expression of GluR on microglia and the effect of GluR activation on microglial function. Microglia are the resident immune cells of the central nervous system, and activation of GluR in them has been shown to regulate their immunological response which may be either neuroprotective or neurotoxic. Microglial activation is known to initiate a myriad of molecular events such as nitric oxide production, free radicals generation, disruption of calcium regulation and release of proinflammatory cytokines, proteases, neurotransmitters, and excitatory amino acids, primarily glutamate. Since microglial activation has been implicated in several neuropathologies, an understanding of the pathway coupled to the various microglial GluR will help to develop therapeutic interventions for ameliorating microglia-mediated damage.
    CNS & neurological disorders drug targets 09/2013; · 3.57 Impact Factor
  • Madhuvika Murugan, Eng-Ang Ling, Charanjit Kaur
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    ABSTRACT: Excess glutamate mediates damage to oligodendroglia, resulting in myelination disturbances characteristic of hypoxic periventricular white matter (PWM) damage. We sought to examine if hypoxia altered the expression of astroglial excitatory amino acid transporters (EAAT1, EAAT2 and EAAT3) in the PWM, and, if so, whether it activated astroglial N-methyl D-aspartate receptors (NMDAR) leading to apoptosis of oligodendroglia. EAATs expression in the PWM of neonatal rats was measured at different time points after hypoxic exposure; it was attenuated at 7 and 14 d following hypoxia. Hypoxia prevented uptake of glutamate by astroglial EAATs causing increased levels of extracellular glutamate. Excess glutamate augmented the expression of functional astroglial NMDAR. Following hypoxia, an increase in gap junction proteins between astroglia and oligodendroglia aided in spreading of NMDAR-mediated excitotoxic calcium signals into the latter cell type triggering its apoptosis. Hence, dysregulated glutamate homeostasis is believed to contribute to hypoxia-induced death of oligodendroglia leading to neonatal PWM damage.
    Molecular and Cellular Neuroscience 07/2013; · 3.84 Impact Factor
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    ABSTRACT: The pineal product melatonin has remarkable antioxidant properties. It is secreted during darkness and plays a key role in various physiological responses including regulation of circadian rhythms, sleep homeostasis, retinal neuromodulation, and vasomotor responses. It scavenges hydroxyl, carbonate, and various organic radicals as well as a number of reactive nitrogen species. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase, and by augmenting glutathione levels. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases. The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD. In the case of other neurological conditions, like PD, the evidence is less compelling. Melatonin's efficacy in combating free radical damage in the brain suggests that it can be a valuable therapeutic agent in the treatment of cerebral edema following traumatic brain injury or stroke. Clinical trials employing melatonin doses in the range of 50-100 mg/day are warranted before its relative merits as a neuroprotective agent is definitively established.
    Neurotoxicity Research 06/2013; 23(3):267-300. · 2.87 Impact Factor
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    ABSTRACT: BACKGROUND: Hypoxia induces microglial activation which causes damage to the developing brain. Microglia derived inflammatory mediators may contribute to this process. Toll-like receptor 4 (TLR4) has been reported to induce microglial activation and cytokines production in brain injuries; however, its role in hypoxic injury remains uncertain. We investigate here TLR4 expression and its roles in neuroinflammation in neonatal rats following hypoxic injury. METHODS: One day old Wistar rats were subjected to hypoxia for 2 h. Primary cultured microglia and BV-2 cells were subjected to hypoxia for different durations. TLR4 expression in microglia was determined by RT-PCR, western blot and immunofluorescence staining. Small interfering RNA (siRNA) transfection and antibody neutralization were employed to downregulate TLR4 in BV-2 and primary culture. mRNA and protein expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and inducible nitric oxide synthase (iNOS) was assessed. Reactive oxygen species (ROS), nitric oxide (NO) and NF-kappaB levels were determined by flow cytometry, colorimetric and ELISA assays respectively. Hypoxia-inducible factor-1 alpha (HIF-1alpha) mRNA and protein expression was quantified and where necessary, the protein expression was depleted by antibody neutralization. In vivo inhibition of TLR4 with CLI-095 injection was carried out followed by investigation of inflammatory mediators expression via double immunofluorescence staining. RESULTS: TLR4 immunofluorescence and protein expression in the corpus callosum and cerebellum in neonatal microglia were markedly enhanced post-hypoxia. In vitro, TLR4 protein expression was significantly increased in both primary microglia and BV-2 cells post-hypoxia. TLR4 neutralization in primary cultured microglia attenuated the hypoxia-induced expression of TNF-alpha, IL-1beta and iNOS. siRNA knockdown of TLR4 reduced hypoxia-induced upregulation of TNF-alpha, IL-1beta, iNOS, ROS and NO in BV-2 cells. TLR4 downregulation-mediated inhibition of inflammatory cytokines in primary microglia and BV-2 cells was accompanied by the suppression of NF-kappaB activation. Furthermore, HIF-1alpha antibody neutralization attenuated the increase of TLR4 expression in hypoxic BV-2 cells. TLR4 inhibition in vivo attenuated the immunoexpression of TNF-alpha, IL-1beta and iNOS on microglia post-hypoxia. CONCLUSION: Activated microglia TLR4 expression mediated neuroinflammation via a NF-kappaB signaling pathway in response to hypoxia. Hence, microglia TLR4 presents as a potential therapeutic target for neonatal hypoxia brain injuries.
    Journal of Neuroinflammation 02/2013; 10(1):23. · 4.35 Impact Factor
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    ABSTRACT: Hypoxia-induced glutamate accumulation in neural tissues results in damage to neurons through excitotoxic mechanisms via activation of glutamate receptors. Here we examine whether hypoxia in the developing retina would cause activation of the ionotropic α-amino-3-hydroxy-5-methylisoxazole-4-propioate (AMPA) glutamate receptors (GluRs) and increase in Ca(2+) influx into retinal ganglion cells (RGCs) that might ultimately lead to their death. Neonatal Wistar rats were subjected to hypoxia for 2 h and then sacrificed at various time points after the exposure together with normal age matched control rats. Primary cultures of RGCs were also prepared and subjected to hypoxia. Expression of AMPA glutamate receptor (GluR) 1-4 was examined in the retina. Additionally, expression of GluRs, intracellular Ca(2+) influx, reactive oxygen species (ROS) generation and cell death were investigated in cultured RGCs. GluR1-4 mRNA and protein expression showed a significant increase (P < 0.01) over control values after the hypoxic exposure both in vivo and in vitro. Cells expressing GluR1-4 in the retina were identified as RGCs by double immunofluorescence labeling with Thy1.1. Increased intracellular Ca(2+) in cultured RGCs following hypoxic exposure was reduced (P < 0.01) by 10 μM AMPA antagonist 6, 7-dinitroquinoxaline-2,3-dione (DNQX). Our results suggest that following a hypoxic insult, an increased amount of glutamate accumulates in the neonatal retina. This would then activate AMPA receptors which may damage RGCs through increased Ca(2+) accumulation and ROS generation. The involvement of AMPA receptors in damaging the RGCs is evidenced by suppression of intracellular Ca(2+) influx by DNQX which also decreases of ROS generation and cell death by 50%.
    Experimental Eye Research 01/2013; · 3.03 Impact Factor
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    ABSTRACT: Neuroinflammation mediated by the activated microglia is suggested to play a pivotal role in the pathogenesis of hypoxic brain injury; however, the underlying mechanism of microglia activation remains unclear. Here, we show that the canonical Notch signaling orchestrates microglia activation after hypoxic exposure which is closely associated with multiple pathological situations of the brain. Notch-1 and Delta-1 expression in primary microglia and BV-2 microglial cells was significantly elevated after hypoxia. Hypoxia-induced activation of Notch signaling was further confirmed by the concomitant increase in the expression and translocation of intracellular Notch receptor domain (NICD), together with RBP-Jκ and target gene Hes-1 expression. Chemical inhibition of Notch signaling with N-[N-(3,5-difluorophenacetyl)-1-alany1- S-phenyglycine t-butyl ester (DAPT), a γ-secretase inhibitor, effectively reduced hypoxia-induced upregulated expression of most inflammatory mediators. Notch inhibition also reduced NF-κB/p65 expression and translocation. Remarkably, Notch inhibition suppressed expression of TLR4/MyD88/TRAF6 pathways. In vivo, Notch signaling expression and activation in microglia were observed in the cerebrum of postnatal rats after hypoxic injury. Most interestingly, hypoxia-induced upregulation of NF-κB immunoexpression in microglia was prevented when the rats were given DAPT pretreatment underscoring the interrelationship between Notch signaling and NF-κB pathways. Taken together, we conclude that Notch signaling is involved in regulating microglia activation after hypoxia partly through the cross talk between TLR4/MyD88/TRAF6/NF-κB pathways. Therefore, Notch signaling may serve as a prospective target for inhibition of microglia activation known to be implicated in brain damage in the developing brain.
    PLoS ONE 01/2013; 8(11):e78439. · 3.53 Impact Factor
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    ABSTRACT: The developing cerebellum is extremely vulnerable to hypoxia which can damage the Purkinje neurons. We hypothesized that this might be mediated by tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) derived from activated microglia as in other brain areas. One-day-old rats were subjected to hypoxia following, which the expression changes of various proteins in the cerebellum including hypoxia inducible factor-1α, TNF-α, IL-1β, TNF-R(1) and IL-1R(1) were analyzed. Following hypoxic exposure, TNF-α and IL-1β immunoexpression in microglia was enhanced coupled by that of TNF-R(1) and IL-1R(1) in the Purkinje neurons. Along with this, hypoxic microglia in vitro showed enhanced release of TNF-α and IL-1β whose receptor expression was concomitantly increased in the Purkinje neurons. In addition, nitric oxide (NO) level was significantly increased in the cerebellum and cultured microglia subjected to hypoxic exposure. Moreover, cultured Purkinje neurons treated with conditioned medium derived from hypoxic microglia underwent apoptosis but the incidence was significantly reduced when the cells were treated with the same medium that was neutralized with TNF-α/IL-1β antibody. We conclude that hypoxic microglia in the neonatal cerebellum produce increased amounts of NO, TNF-α and IL-1β which when acting via their respective receptors could induce Purkinje neuron death.
    Brain Structure and Function 12/2012; · 7.84 Impact Factor
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    ABSTRACT: The purpose of this study was to determine whether melatonin treatment would mitigate retinal ganglion cell (RGC) death in the developing retina following a hypoxic insult. Lipid peroxidation (LPO), glutathione (GSH), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) concentrations, expression of vascular endothelial growth factor receptors, Flt-1 and Flk-1, release of cytochrome c from mitochondria, and caspase-3 expression were examined in the retinas of 1-day-old rats at 3 hr to 14 days after a hypoxic exposure. The mRNA and protein expression of Flt-1 and Flk-1 and the tissue concentration of LPO, TNF-α, and IL-1β were upregulated significantly after the hypoxic exposure, whereas the content of GSH was decreased significantly. RGC cultures also showed increased LPO and decreased GSH levels after hypoxic exposure but these effects were reversed in cells treated with melatonin. TNF-α and IL-1β expression was specifically located on microglial cells, whereas Flt-1 and Flk-1 was limited to RGCs as confirmed by double immunofluorescence labeling. Cultures of hypoxic microglial cells treated with melatonin showed a significant reduction in the release of these cytokines as compared to untreated hypoxic cells. Hypoxia induced increase in the cytosolic cytochrome c and caspase-3 in RGCs was attenuated with melatonin treatment. The results suggest that, in hypoxic injuries, melatonin is neuroprotective to RGCs in the developing retina through its antioxidative, anti-inflammatory, and anti-apoptotic effects. Melatonin suppressed Flt-1 and Flk-1 expression in retinal blood vessels, which may result in reduced retinal vascular permeability and it also preserved mitochondrial function as shown by a reduction in cytochrome c leakage into the cytosol. The results may have therapeutic implications for the management of retinopathy of prematurity.
    Journal of Pineal Research 09/2012; · 7.30 Impact Factor
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    ABSTRACT: It is well established that hypoxia causes excess accumulation of glutamate in developing neural tissues. This study aimed to elucidate the mechanism by which glutamate can cause retinal ganglion cell (RGC) death through the N-methyl-D-aspartate (NMDA) receptors (NR) in the developing retina. One-day-old Wistar rats were exposed to hypoxia for 2 hours and then killed at different time points. Normal age-matched rats were used as controls. NR1, NR2A-D, and NR3A messenger RNA and protein expression showed significant increases over control values, notably at early time points (3 hours to 7 days) after the hypoxic exposure, and immunoexpression of NR1, NR2A-D and NR3A on retinal ganglion cells (RGCs) was enhanced in hypoxic rats and this was confirmed in cultured hypoxic RGCs. Ca(2+) influx in cultured RGCs was increased after hypoxic exposure, and the intracellular Ca(2+) concentration was suppressed by MK-801. Mitochondrial permeability transition pore opening, mitochondrial/cytosolic cytochrome c, and cytosolic caspase-3 expression levels were significantly increased in the hypoxic RGCs. These increases were reversed by MK-801, suggesting that the NMDA receptor subunits in the retina respond rapidly to the hypoxia-induced glutamate overload that leads to the cascade of events that result in RGC death.
    Journal of Neuropathology and Experimental Neurology 04/2012; 71(4):330-47. · 4.35 Impact Factor
  • Chi D Luu, Wallace S Foulds, Charanjit Kaur
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    ABSTRACT: To determine the effects on the electroretinogram (ERG) of retinal capillary closure induced in the pig by embolization with microspheres. Fourteen Yorkshine Landrace pigs of 25- to 45-kg body weight were used. With a customized cannula introduced into the external carotid artery, 10-μm diameter microspheres were delivered to the origin of the vessel that supplies blood to the eye in the pig. Fundus fluorescein angiography and electroretinography were performed between days 7 and 28 post injection. The ERG responses of embolized eyes were compared with those of the contralateral nonembolized eyes. The amplitudes of the scotopic b-wave (P = 0.002), the maximal b-wave (P < 0.010), the photopic a-wave (P < 0.001) and b-wave (P < 0.001), and the scotopic oscillatory potentials (OPs) (P = 0.025) and photopic OPs (P = 0.036) were significantly reduced in embolized eyes. The reduction of these ERG amplitudes was significantly correlated with the number of microspheres in the retina. There was no significant difference in the combined rod-cone bright flash (maximal) ERG a-wave amplitude between eyes with and without microspheres. Implicit times, however, were similar in embolized and control eyes. In eyes embolized with microspheres, the amplitudes of most ERG components were significantly reduced without alteration of their implicit times. The magnitude of ERG amplitude reduction correlated with the number of microspheres in the retina.
    Investigative ophthalmology & visual science 03/2012; 53(4):2218-25. · 3.43 Impact Factor
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    ABSTRACT: Amoeboid microglial cells (AMCs) in the developing brain display surface receptors and antigens shared by the monocyte-derived tissue macrophages. Activation of AMCs in the perinatal brain has been associated with periventricular white matter damage in hypoxic-ischemic conditions. The periventricular white matter, where the AMCs preponderate, is selectively vulnerable to hypoxia as manifested by death of premyelinating oligodendrocytes and degeneration of axons leading to neonatal mortality and long-term neurodevelopmental deficits. AMCs respond vigorously to hypoxia by producing excess amounts of inflammatory cytokines e.g. the tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) along with glutamate, nitric oxide (NO) and reactive oxygen species which collectively cause oligodendrocyte death, axonal degeneration as well as disruption of the immature blood brain barrier. A similar phenomenon is observed in the hypoxic developing cerebellum in which activated AMCs induced Purkinje neuronal death through production of TNF-α and IL-1β via their respective receptors. Hypoxia is also implicated in retinopathy of prematurity in which activation of AMCs has been shown to cause retinal ganglion cell death through production of TNF-α and IL-1β and NO. Because AMCs play a pivotal role in hypoxic injuries in the developing brain affecting both neurons and oligodendrocytes, a fuller understanding of the underlying molecular mechanisms of microglial activation under such conditions would be desirable for designing of a novel therapeutic strategy for management of hypoxic damage.
    Journal of Neuroimmune Pharmacology 02/2012; · 3.80 Impact Factor
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    ABSTRACT: The review aims to elucidate the potential of microglia as a therapeutic target in alleviating Alzheimer's Disease (AD). Microglia are the resident immune cells in the brain which respond to the presence of the hallmarks of AD, amyloid-beta (A beta) plaques and neurofibrillary tangles (NFT). Activated microglia are able to phagocytose and secrete pro-inflammatory and anti-inflammatory cytokines. However, the eventual accumulation of excess A beta peptides and NFT in AD means that microglial clearance of pathogens has been impaired. Pro-inflammatory cytokines may also contribute to the neurodegeneration. Based on the amyloid cascade hypothesis, A beta-activated microglia can produce pro-inflammatory cytokines which may exacerbate the hyperphosporylation of tau proteins that forms NFT in AD pathology. Microglial activation can thus be manipulated to prevent neurodegeneration and promote neuroprotection through several therapeutic agents and methods. Further studies regarding comprehensive microglial response towards A beta and NFT are required to develop an effective treatment of AD involving microglia.
    Frontiers in bioscience (Scholar edition) 01/2012; 4:1402-12.
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    ABSTRACT: This study was aimed to examine the role of iron in causing periventricular white matter (PWM) damage following a hypoxic injury in the developing brain. Along with iron, the expression of iron regulatory proteins (IRPs) and transferrin receptor (TfR), which are involved in iron acquisition, was also examined in the PWM by subjecting 1-d-old Wistar rats to hypoxia. Apart from an increase in iron levels in PWM, Perls' iron staining showed an increase of intracellular iron in the preponderant amoeboid microglial cells (AMCs) in the tissue. In response to hypoxia, the protein levels of IRP1, IRP2, and TfR in PWM and AMCs were significantly increased. In primary microglial cultures, administration of iron chelator deferoxamine reduced the generation of iron-induced reactive oxygen and nitrogen species and proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. Primary oligodendrocytes treated with conditioned medium from hypoxic microglia exhibited reduced glutathione levels, increased lipid peroxidation, upregulated caspase-3 expression, and reduced proliferation. This was reversed to control levels on treatment with conditioned medium from deferoxamine treated hypoxic microglia; also, there was reduction in apoptosis of oligodendrocytes. The present results suggest that excess iron derived primarily from AMCs might be a mediator of oligodendrocyte cell death in PWM following hypoxia in the neonatal brain.
    Journal of Neuroscience 12/2011; 31(49):17982-95. · 6.91 Impact Factor

Publication Stats

2k Citations
425.80 Total Impact Points


  • 1987–2013
    • National University of Singapore
      • Department of Anatomy
      Singapore, Singapore
  • 2012
    • Royal Victorian Eye and Ear Hospital
      Melbourne, Victoria, Australia
  • 2010
    • Singapore National Eye Centre
      Tumasik, Singapore
  • 2008–2009
    • Kunming Medical College
      Yün-nan, Yunnan, China