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N G Bazan

Publications and source records attributed to N G Bazan.

At least 19 recordsLinked to original sources
PubMed2006

Survival signalling in Alzheimer's disease.

Significant advancements in our understanding of cell-survival signalling in AD (Alzheimer's disease) stem from recent investigations into the metabolism, trafficking and fate of the essential omega-3 fatty acid DHA (docosahexaenoic acid) (C(22:6), n=3). Brain synaptic terminals and neuronal plasma membranes are highly enriched in DHA, and deficiencies in this polyunsaturated fatty acid are characteristic of AD-affected brain. Oxidative stress, targeting phospholipids containing DHA, and age-related DHA depletion are associated with the progressive erosion of normal cognitive function in AD. Current studies support the idea that DHA itself and novel DHA-derived neural synapse- and membrane-derived lipid messengers have considerable potential to modulate cell survival signalling in stressed cultured neural cell models in vitro and in mammalian models of learning, memory and AD in vivo. Key players in this intrinsic rescue system include the alpha-secretase-processed neurotrophin sAPPalpha [soluble APPalpha (amyloid precursor protein alpha)] peptide, the DHA-derived 10,17S-docosatriene NPD1 (neuroprotectin D1), a tandem brain cytosolic phospholipase A(2) and 15-lipoxygenase enzymatic system that biosynthesizes NPD1, and a small family of anti-apoptotic neuroprotective genes that encode Bcl-2, Bcl-X(L) and Bfl-1 (A1). This paper reviews current ideas regarding DHA and the oxygenated DHA derivative NPD1, intrinsically triggered biolipid neuroprotectants that along with their associated rescue pathways, contribute to life-or-death decisions of brain cells during homoeostasis, aging and neurodegenerative disease.

Alzheimer Disease↗
PubMed2002

Regulatory region variability in the human presenilin-2 (PSEN2) gene: potential contribution to the gene activity and risk for AD.

We have analyzed the 5'-upstream promoter region of the presenilin 2 gene (PSEN2) for regulatory elements and examined Alzheimer disease (AD) patients and non-demented individuals for polymorphisms in the 5' upstream promoter region of the PSEN2 gene. Direct sequencing analysis detected a common single adenine (A) nucleotide deletion polymorphism in the upstream promoter region of the PSEN2 gene. Examination of cohorts of AD patients and age-matched control individuals revealed no statistically significant differences in the frequency of this polymorphism when compared with the total sample of AD patients and control individuals. However, subgroup and regression analysis suggested that the relatively rare -A/-A genotype increases risk of AD among subjects lacking apolipoprotein E (APOE) epsilon4 and among persons ages 65 years and younger. DNA sequence and DNA-protein binding analysis demonstrated that this mutation negates binding with putative repressor transcription factor (TF), interferon regulatory factor 2 (IRF2), in nuclear extracts prepared from the aged human brain neocortex. However this mutation creates a potential regulatory element, C/EBPbeta, that is responsive to pro-inflammatory (PI) induction. The expression activity assay with luciferase reporter gene into normal human neural progenitor cells in primary culture shows that the mutant PSEN2 regulatory region exhibits a 1.8-fold higher level of basal expression and is sensitive to IL-1beta and Abeta42, but that it is synergistically induced 3.2-fold over the wild-type PSEN2 by [IL-1beta+Abeta42]. These results suggest that under Pl and oxygen stress conditions relatively minor variations in PSEN2 promoter DNA sequence structure can enhance PSEN2 gene expression and that consequently these may play a role in the induction and/or proliferation of a Pl response in AD brain.

5' Untranslated Regions↗
PubMed2001

Diacylglycerol kinase epsilon regulates seizure susceptibility and long-term potentiation through arachidonoyl- inositol lipid signaling.

Arachidonoyldiacylglycerol (20:4-DAG) is a second messenger derived from phosphatidylinositol 4,5-bisphosphate and generated by stimulation of glutamate metabotropic receptors linked to G proteins and activation of phospholipase C. 20:4-DAG signaling is terminated by its phosphorylation to phosphatidic acid, catalyzed by diacylglycerol kinase (DGK). We have cloned the murine DGKepsilon gene that showed, when expressed in COS-7 cells, selectivity for 20:4-DAG. The significance of DGKepsilon in synaptic function was investigated in mice with targeted disruption of the DGKepsilon. DGKepsilon(-/-) mice showed a higher resistance to electroconvulsive shock with shorter tonic seizures and faster recovery than DGKepsilon(+/+) mice. The phosphatidylinositol 4,5-bisphosphate-signaling pathway in cerebral cortex was greatly affected, leading to lower accumulation of 20:4-DAG and free 20:4. Also, long-term potentiation was attenuated in perforant path-dentate granular cell synapses. We propose that DGKepsilon contributes to modulate neuronal signaling pathways linked to synaptic activity, neuronal plasticity, and epileptogenesis.

Animals↗
PubMed2001

Presenilin-2 (PS2) expression up-regulation in a model of retinopathy of prematurity and pathoangiogenesis.

Presenilin-2 (PS2; AD4), a regulator of intercellular signaling during CNS development and cell fate determination, appears to be involved in pathogenic processing of beta-amyloid precursor protein (betaAPP) into potentially neurotoxic beta-amyloid (Abeta) peptides. The PS2 gene promoter contains multiple DNA binding sites for the relatively rare hypoxia-inducible transcription factor HIF-1, suggesting that PS2 expression may be a sensitive indicator of decreased oxygen availability. We have used a cycled hypoxia/hyperoxia (10-50% O2) protocol followed by normoxia (20% O2) as a retinal model of retinopathy of prematurity to induce neovascularization (NV) in rat pups. Retinal cell nuclear extracts from pups undergoing hypoxia exhibited a dramatic increase in HIF-1-DNA binding, followed by a delayed (2-7 day) elevation of PS2 RNA message and protein. PS2 gene activation during hypoxia may direct cellular fate towards pathoangiogenesis and intercellular PS2-mediated signaling dysfunction.

Animals↗
PubMed2001

Differential interaction of platelet-activating factor and NMDA receptor function in hippocampal and dorsal striatal memory processes.

The interaction between platelet activating factor (PAF) and NMDA receptor function in hippocampal and dorsal striatal memory processes was examined. In both a hidden and a visible platform water maze task, peripheral post-training injection of MK-801 (0.05 mg/kg) impaired memory. Post-training intrahippocampal infusions of PAF (1.0 microg/0.5 microl) enhanced memory in the hidden platform task, while intradorsal striatal infusion of PAF (1.0 microg/0.5 microl) enhanced memory in the visible platform task. The memory impairing effects of post-training injection of MK-801 was blocked by concurrent intrahippocampal infusion of PAF. In contrast, post-training injection of MK-801 blocked the memory enhancing effects of concurrent intradorsal striatal infusion of PAF. The results suggest that (1) the memory enhancing effects of intracerebral PAF infusion involve an interaction with NMDA receptor function, and (2) the nature of this interaction may represent a differential mechanism mediating the distinct roles of the hippocampus and dorsal striatum in cognitive memory and stimulus-response habit formation, respectively.

Animals↗
PubMed2001

Effects of topical unoprostone and latanoprost on acute and recurrent herpetic keratitis in the rabbit.

PURPOSE: To determine the effect of the topical ocular hypotensive drug, isopropyl unoprostone, a docosanoid molecule with very weak prostaglandin activity, on herpes keratitis in the rabbit eye. METHODS: For acute disease, rabbit corneas inoculated with the corticosteroid-sensitive F(MP)E strain of herpes simplex virus type 1 were treated with various combinations of 0.12% isopropyl unoprostone, latanoprost, trifluridine, benzalkonium chloride 0.02%, dexamethasone sodium phosphate, ketorolac tromethamine, or saline solution beginning 1 day after infection. Severity of keratitis was evaluated in a masked manner. For recurrent disease, rabbit corneas infected with McKrae strain herpes simplex virus type 1 were treated with unoprostone or saline solution on postinfection days 25 to 42, and the presence or absence of lesions was recorded. RESULTS: Eyes treated with unoprostone showed significantly less severe disease than saline-treated or latanoprost-treated eyes during acute infection. Unoprostone-treated and saline-treated eyes showed no significant difference in the frequency of recurrent lesions. Eyes treated with latanoprost and/or dexamethasone, separately or in combination, showed increased severity of acute herpes simplex virus keratitis, whereas benzalkonium chloride 0.02%--treated eyes showed no significant difference, compared with saline treatment. Trifluridine resulted in rapid healing. CONCLUSIONS: Unoprostone did not increase the severity or recurrence rate of herpes simplex virus keratitis. Unoprostone requires twice-a-day administration, compared with once-a-day for latanoprost, and unoprostone lowers intraocular pressure less than latanoprost. Nevertheless, unoprostone's superior safety profile may make its use advantageous. Benzalkonium chloride alone did not make the keratitis worse.

Acute Disease↗
PubMed2001

Gene expression analyzed by microarrays in HSV-1 latent mouse trigeminal ganglion following heat stress.

An understanding of the cellular genes whose expression is altered during HSV reactivation will enable us to better understand host responses and biochemical pathways involved in the process. Furthermore, this knowledge could allow us to develop gene-targeted inhibitors to prevent viral reactivation. Mice latent with HSV-1 strain McKrae and uninfected control mice were subjected to hyperthermic stress (43 degrees C for 10 min) and their trigeminal ganglia (TG) collected 1 h later. Two additional groups included HSV-1 latently infected and uninfected mice not subjected to hyperthermic stress. Poly A+ mRNA was enriched from total mouse TG RNA and reverse transcribed using MMLV RT. Radioactively labeled cDNAs were analyzed by microarray analysis. A stress/toxicology array of 149 mouse genes on a nylon membrane was used. The labeled cDNAs prepared from latently infected, stressed mice demonstrated 3-fold or greater increases in certain mRNA-early response genes (ERGs) compared to cDNAs from uninfected, stressed control mice. The ERG mRNAs that showed increases included two heat shock proteins (HSP60 and HSP40), a basic transcription factor (BTF T62), a DNA repair enzyme, two kinases [MAP kinase and a stress-induced protein kinase (SADK)], an oxidative stress-induced protein, a manganese superoxide dismutase precursor-2 (SOD-2), and cyclooxygenase 2 (COX-2). The gene expression in unstressed, infected TGs was similar to the gene expression in unstressed, uninfected controls. These results suggest that there is a significant difference in the ERG expression profile in latently infected TGs undergoing stress-induced reactivation compared to uninfected TGs.

Animals↗
PubMed2001

Attenuated LTP in hippocampal dentate gyrus neurons of mice deficient in the PAF receptor.

Platelet-activating factor (PAF), a bioactive lipid (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) derived from phospholipase A(2) and other pathways, has been implicated in neural plasticity and memory formation. Long-term potentiation (LTP) can be induced by the application of PAF and blocked by a PAF receptor (PAF-R) inhibitor in the hippocampal CA1 and dentate gyrus. To further investigate the role of PAF in synaptic plasticity, we compared LTP in dentate granule cells from hippocampal slices of adult mice deficient in the PAF-R and their age-matched wild-type littermates. Whole cell patch-clamp recordings were made in the current-clamp mode. LTP in the perforant path was induced by a high-frequency stimulation (HFS) and defined as >20% increase above baseline of the amplitude of excitatory postsynaptic potentials (EPSPs) from 26 to 30 min after HFS. HFS-induced enhancement of the EPSP amplitude was attenuated in cells from the PAF-R-deficient mice (163 +/- 14%, mean +/- SE; n = 32) when compared with that in wild-type mice (219 +/- 17%, n = 32). The incidence of LTP induction was also lower in the cells from the deficient mice (72%, 23 of 32 cells) than in the wild-type mice (91%, 29 of 32 cells). Using paired-pulse facilitation as a synaptic pathway discrimination, it appeared that there were differences in LTP magnitudes in the lateral perforant path but not in the medial perforant path between the two groups. BN52021 (5 microM), a PAF synaptosomal receptor antagonist, reduced LTP in the lateral path in the wild-type mice. However, neither BN52021, nor BN50730 (5 microM), a microsomal PAF-R antagonist, reduced LTP in the lateral perforant path in the receptor-deficient mice. These data provide evidence that PAF-R-deficient mice are a useful model to study LTP in the dentate gyrus and support the notion that PAF actively participates in hippocampal synaptic plasticity.

Animals↗
PubMed2000

Photoreceptor phagocytosis selectively activates PPARgamma expression in retinal pigment epithelial cells.

Phagocytosis of tips of rod outer segments (ROS) by retinal pigment epithelial (RPE) cells is vitally important for maintaining structural and functional integrity of the retina. We previously reported that receptor-mediated specific phagocytosis of ROS induces expression of early response genes coding for transcription factors. Here we study the expression of peroxisome proliferator-activated receptors (PPAR) -alpha, -delta (beta) and -gamma during ROS phagocytosis of rat RPE cells in primary cell culture, using competitive quantitative RT-PCR. During phagocytosis of ROS (but not of latex particles) by RPE cells, RT-PCR revealed a transient increase in PPARgamma mRNA expression, that peaked at 4-6 hr. We sequenced and described two alternatively spliced variants of rat PPARgamma: rPPARgamma1a and rPPARgamma1b. Both of these, along with the recently described rPPARgamma2 were induced by ROS phagocytosis. PPARalpha and PPARdelta mRNA expression was also detected in RPE cells, but the level of expression did not change during ROS phagocytosis. All-trans-retinoic acid and prostaglandin E(2) (PGE(2)) selectively potentiated both basal and ROS-phagocytosis-induced PPARgamma expression. All-trans-retinoic acid had the opposite inhibitory effect on PPARalpha and PPARdelta expression. Cycloheximide had a dual action on PPARgamma expression in RPE cells: it enhanced expression under basal conditions but repressed expression induced by ROS phagocytosis. It also stimulated expression of PPARalpha but had no effect on PPARdelta. Selective activation of PPARgamma may play an important role in regulating the expression of target genes that are involved in lipid and fatty acid metabolism in the photoreceptor renewal process.

Animals↗
PubMed2000

Cortical impact injury in rats promotes a rapid and sustained increase in polyunsaturated free fatty acids and diacylglycerols.

Neurotrauma activates the release of membrane phospholipid-derived second messengers, such as free arachidonic acid (20:4n-6, AA) and diacylglycerols (DAGs). In the present study, we analyze the effect of cortical impact injury of low-grade severity applied to the rat frontal right sensory-motor cortex (FRC) on the accumulation of free fatty acids (FFAs) and DAGs in eight brain areas 30 min and 24 hours after the insult. At these times, accumulation of FFAs and DAGs occurred mainly in the damaged FRC. The cerebellum was the only other brain area that displayed a significant accumulation of DAGs by day one post-injury. By 30 min, accumulation of free AA in the FRC displayed the greatest relative increase (300% over sham value), followed by free docosahexaenoic acid (22:6n-3, DHA, 150%), while both 20:4-DAGs and 22:6-DAGs were increased 100% over sham values. At day one, free 22:6 and 22:6-DAGs showed the greatest increase (590% and 230%, respectively). These results suggest that TBI elicits the hydrolysis of phospholipids enriched in excitable membranes, targeting early on 20:4-phospholipids (by 30 min post- trauma) and followed 24 hours later by preferential hydrolysis of DHA-phospholipids. These lipid metabolic changes may contribute to the initiation and maturation of neuronal and fiber track degeneration observed following cortical impact injury.

Animals↗
PubMed2000

Neuroinflammatory signaling upregulation in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive, neurodestructive process of the human neocortex, characterized by the deterioration of memory and higher cognitive function. A progressive and irreversible brain disorder, AD is characterized by three major pathogenic episodes involving (a) an aberrant processing and deposition of beta-amyloid precursor protein (betaAPP) to form neurotoxic beta-amyloid (betaA) peptides and an aggregated insoluble polymer of betaA that forms the senile plaque, (b) the establishment of intraneuronal neuritic tau pathology yielding widespread deposits of agyrophilic neurofibrillary tangles (NFT) and (c) the initiation and proliferation of a brain-specific inflammatory response. These three seemingly disperse attributes of AD etiopathogenesis are linked by the fact that proinflammatory microglia, reactive astrocytes and their associated cytokines and chemokines are associated with the biology of the microtubule associated protein tau, betaA speciation and aggregation. Missense mutations in the presenilin genes PS1 and PS2, implicated in early onset familial AD, cause abnormal betaAPP processing with resultant overproduction of betaA42 and related neurotoxic peptides. Specific betaA fragments such as betaA42 can further potentiate proinflammatory mechanisms. Expression of the inducible oxidoreductase cyclooxygenase-2 and cytosolic phospholipase A2 (cPLA2) are strongly activated during cerebral ischemia and trauma, epilepsy and AD, indicating the induction of proinflammatory gene pathways as a response to brain injury. Neurotoxic metals such as aluminum and zinc, both implicated in AD etiopathogenesis, and arachidonic acid, a major metabolite of brain cPLA2 activity, each polymerize hyperphosphorylated tau to form NFT-like bundles. Further, epidemiological and longitudinal studies have identified a reduced risk for AD in patients (<70 yrs) previously treated with non-steroidal anti-inflammatory drugs for non-CNS afflictions that include arthritis. This review will focus on the interrelationships between the mechanisms of PS1, PS2 and betaAPP gene expression, tau and betaA deposition and the induction, regulation and proliferation in AD of the neuroinflammatory response. Novel therapeutic interventions in AD are discussed.

Aluminum↗
PubMed2000

Alterations in lipid and calcium metabolism associated with seizure activity in the postischemic brain.

Transient ischemia is known to lead to a long-lasting depression of cerebral metabolic rate and blood flow and to an attenuated metabolic and circulatory response to physiological stimuli. However, the corresponding responses to induced seizures are retained, demonstrating preserved metabolic and circulatory capacity. The objective of the present study was to explore how a preceding period of ischemia (15 min) alters the release of free fatty acids (FFAs) and diacylglycerides (DAGs), the formation of cyclic nucleotides, and the influx/efflux of Ca(2+), following intense neuronal stimulation. For that purpose, seizure activity was induced with bicuculline for 30 s or 5 min at 6 h after the ischemia. Extracellular Ca(2+) concentration (Ca(2+)(e)) was recorded, and the tissue was frozen in situ for measurements of levels of FFAs, DAGs, and cyclic nucleotides. Six hours after ischemia, the FFA concentrations were normalized, but there was a lowering of the content of 20:4 in the DAG fraction. Cyclic AMP levels returned to normal values, but cyclic GMP content was reduced. Seizures induced in postischemic animals showed similar changes in Ca(2+)(e), as well as in levels of FFAs, DAGs, and cyclic nucleotides, as did seizures induced in nonischemic control animals, with the exception of an attenuated rise in 20:4 content in the DAG fraction. We conclude that, at least in the neocortex, seizure-induced phospholipid hydrolysis and cyclic cAMP/cyclic GMP formation are not altered by a preceding period of ischemia, nor is there a change in the influx/efflux of Ca(2+) during seizure discharge or in associated spreading depression.

Animals↗
PubMed2000

Modulation of early response gene expression by prostaglandins in cultured rat retinal pigment epithelium cells.

PURPOSE: To explore the role of prostaglandins (PGs) as modulators of retinal pigment epithelium (RPE) rod outer segment (ROS)-phagocytosis and ROS-phagocytosis-induced gene expression. METHODS: RPE cells in primary cell culture were pre-incubated with PGE( 2), PGD(2), PGF(2)alpha, PGJ(2), 15-deoxy-Delta( 12,14)-PGJ(2) or U-46619 (stable analog of thromboxane A(2)), and fed with a suspension of ROS. Expression of zif-268 and tis-1 mRNA was determined by Northern blotting. DNA-binding activity of TIS-1 protein was assessed by electrophoretic mobility shift assay. Concentration of PGE (2) and PGD (2) in the tissue culture medium was measured by enzyme immuno-assay. Phagocytis-tosis was quantified by counting of double-immunostained bound and ingested ROS. RESULTS: PGE 2, the most potent of PGs, strongly elevated both basal and ROS-phagocytosis-induced levels of tis-1 mRNA, while significantly inhibiting both basal and phagocytosis-induced expression of zif-268 mRNA. PGD(2), PGJ(2) and 15-deoxy-Delta(12,14)-PGJ( 2) elevated ROS-phagocytosis-induced, but not basal, expression of tis-1 mRNA expression. PGF(2alpha) super-induced both phagocytosis-induced and basal tis-1 mRNA expression. U-46619 and carbaprostacyclin had no effect on expression of tis-1 mRNA. PGE(2) was the only PG to affect zif-268 expression. Exogenous PGE(2), PGD( 2) and PGF(2alpha), when added to the medium at 1-microM concentrations, significantly inhibited ingestion of ROS, with PGE(2) being the most potent PG affecting ROS-phagocytosis. CONCLUSIONS: PGs act as selective regulators of phagocytosis-induced transcription factor gene expression in RPE cells, as well as of ROS-phagocytosis itself. This modulation may help to ensure specificity in the differential activation of target genes by ROS-phagocytosis receptor-mediated signal transduction in RPE cells.

Animals↗
PubMed1999

Platelet-activating factor inhibits ionotropic GABA receptor activity in cultured hippocampal neurons.

Platelet-activating factor (PAF), one of the most potent bioactive lipids, has been implicated in modulating long-term potentiation (LTP) and neurotoxicity. In the CNS, glutamate and GABA are the major excitatory and inhibitory neurotransmitters, respectively. Previous work has focused on the effects of PAF on glutamatergic receptor responses. The purpose of the present study was to investigate the possible actions of PAF on ionotropic GABA receptor responses in primary cultured hippocampal neurons using the whole-cell and single channel patch clamp techniques. Extracellular application of PAF induced a reduction of the GABA gated Cl- current in a majority of cells (29 of 44 cells), while it caused an enhancement in 10 of 44 cells. A similar heterogeneous modulation of PAF on the GABA receptor activities was also observed in outside-out patch recordings. Moreover, the cell-attached single channel recordings showed that PAF decreased the GABA channel activity. Therefore, PAF may modulate synaptic activity by inhibiting GABA receptor channels. During seizures and neural injury, when enhanced synthesis of this lipid mediator takes place, the actions of PAF on inhibitory GABA receptors may contribute to synaptic dysfunction.

Animals↗
PubMed1999

Interleukin-1 beta activates expression of cyclooxygenase-2 and inducible nitric oxide synthase in primary hippocampal neuronal culture: platelet-activating factor as a preferential mediator of cyclooxygenase-2 expression.

Interleukin-1 beta (IL-1beta) is an inflammatory cytokine whose expression is elevated in brain during seizures, ischemia, and injury. Expression of IL-1beta and its receptor can also be observed in normal brain. Platelet-activating factor (PAF) is also a dual mediator that promotes neuronal plasticity responses as well as inflammation. We have determined the role of PAF in the regulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes by IL-1beta in rat primary hippocampal cultures. As assessed by reverse transcriptase/polymerase chain reaction (RT/PCR), recombinant mouse IL-1beta (1 nM) led to an induction of COX-2 mRNA which peaked at 2 hours, declined to baseline levels by 4 hours, began to rise again by 6 hours, and remained elevated at 24 hours post-treatment. iNOS mRNA was also induced, but unlike COX-2, its abundance peaked at 4 hours and decreased by 6 hours to a plateau lasting through 24 hours. Pretreatment with PAF antagonist BN50730 blocked induction of COX-2 mRNA by 2-hour IL-1beta treatment, and 2-hour treatment with the PAF analog mcPAF mimicked the effects of IL-1beta on COX-2 mRNA levels. Following injury, synaptic plasticity changes may be affected by IL-1beta-PAF-COX-2 neuronal signaling.

Animals↗
PubMed1999

Secretory phospholipase A2 potentiates glutamate-induced rat striatal neuronal cell death in vivo.

The secretory phospholipases A2 (sPLA2) OS2 (10, 20 and 50 pmol) or OS1, (50 pmol) purified from taipan snake Oxyuranus scutellatus scutellatus venom, and the excitatory amino acid glutamate (Glu) (2.5 and 5.0 micromol) were injected into the right striatum of male Wistar rats. Injection of 10 and 20 pmol OS2 caused no neurological abnormalities or tissue damage. OS2 (50 pmol) caused apathy and circling towards the injection side. Histology revealed an infarct at the injection site. Injection of 50 pmol OS1 showed very little or no signs of neurotoxicity. Injection of 2.5 micromol Glu caused no tissue damage or neurological abnormality. After injection of 5.0 micromol Glu, the animals initially circled towards the side of injection, and gradually developed generalized clonic convulsions. These animals showed a well demarcated striatal infarct. When non-toxic concentrations of 20 pmol OS2 and 2.5 micromol Glu were co-injected, a synergistic neurotoxicity was observed. Extensive histological damage occurred in the entire right hemisphere, and in several rats comprising part of the contralateral hemisphere. These animals were apathetic in the immediate hours following injection, with circling towards the side of injection in the following days. Thus, OS2 greatly potentiates glutamate excitoxicity in vivo.

Animals↗
PubMed1999

Induction of cyclooxygenase-2 gene expression in retinal pigment epithelium cells by photoreceptor rod outer segment phagocytosis and growth factors.

Retinal pigment epithelium (RPE) cells in culture display selective induction of certain early response transcription factors at the onset of photoreceptor rod outer segment (ROS)-specific phagocytosis (Ershov et al., 1996a). Moreover, this response is modulated by prostaglandins. The purpose of this study is to examine the expression of the key enzymes in prostaglandin synthesis: cyclooxygenase-1 (COX-1, constitutive) and cyclooxygenase-2 (COX-2, inducible), during phagocytosis of ROS by RPE cells. Rat RPE cells in primary cell culture were fed with a suspension of freshly isolated rat ROS. COX-1 and COX-2 mRNA expression was studied by quantitative competitive reverse transcriptase-polymerase chain reaction (RT-PCR). During phagocytosis of ROS by RPE cells, RT-PCR revealed an increase in mRNA expression of COX-2, but not of COX-1. COX-2 was also induced by the phospholipid growth factor lyso-phosphatidic acid (LPA) and by the peptide growth factors platelet derived growth factor (PDGF), basic fibroblast growth factor (FGF), and transforming growth factor (TGFbeta), but not nerve growth factor (NGF). Induction of COX-2 by ROS phagocytosis and growth factors through the modulation of prostanoid synthesis may play an important role in the regulation of cell functions associated with photoreceptor cell renewal.

Animals↗