James A HewettSyracuse University | SU · Department of Biology
James A Hewett
Doctorate in Pharmacology and Toxicology
About
62
Publications
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2,062
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Introduction
In general, the research in my laboratory explores the function of endogenous neuromodulatory mechanisms activated within the brain under pathological conditions, with a particular interest in epilepsy. We reason that a better understanding of the function of endogenous neuromodulatory mechanism in epilepsy may facilitate development of novel therapeutic targets for new antiepileptic drug development. For more details, see https://jameshewettlab.syr.edu/
Additional affiliations
January 2013 - present
August 2012 - present
July 2011 - present
Education
August 1986 - May 1991
August 1983 - May 1986
Publications
Publications (62)
The function of endogenous interleukin-1β (IL-1β) signaling in acute seizure activity was examined using transgenic mice harboring targeted deletions in the genes for either IL-1β (Il1b) or its signaling receptor (Il1r1). Acute epileptic seizure activity was modeled using two mechanistically distinct chemoconvulsants, kainic acid (KA) and pentylene...
The goal of this study was to determine whether prophylactic prandial administration of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, could alter seizure generation, kindling acquisition, and/or kindling maintenance in the mouse pentylenetetrazole (PTZ) epilepsy model.
Male CD-1 mice were fed ad libitum with control chow or chow formul...
Astrocytes are a major component of the resident non-neuronal glial cell population of the CNS. They are ubiquitously distributed throughout the brain and spinal cord, where they were initially thought to function in both structural and homeostatic capacities, providing the framework and environment in which neurons performed their parenchymal duti...
Cyclooxygenase (COX) enzymes, or prostaglandin-endoperoxide synthases (PTGS), are heme-containing bis-oxygenases that catalyze the first committed reaction in metabolism of arachidonic acid (AA) to the potent lipid mediators, prostanoids and thromboxanes. Two isozymes of COX enzymes (COX-1 and COX-2) have been identified to date. This review will f...
Both transforming growth factor-beta1 (TGF-beta1) and nitric oxide synthase-2 (NOS-2) are upregulated under various neuropathological states. Evidence suggests that TGF-beta1 can either attenuate or augment NOS-2 expression, with the prevailing effect dependent on the experimental paradigm employed and the cell-type under study. The purpose of the...
Disruption of Interleukin-1β (IL-1β) signaling sensitized mice to convulsant stimuli, suggesting that this quintessential cytokine of the innate immune system contributes to maintenance of the innate seizure threshold (ST). However, little is known about where and how IL-1β secretion occurs in the normal brain. This study examined the possibility t...
Objective
Although the cystine/glutamate antiporter System xc‐ (Sxc‐) plays a permissive role in glioma‐associated seizures, its contribution to other acquired epilepsies has not been determined. As such, the present study investigates whether and how Sxc‐ contributes to the pentylenetetrazole (PTZ) chemical kindling model of epileptogenesis.
Meth...
Objective
Studies have addressed the potential involvement of L‐12/15 Lipoxygenases (LO), a polyunsaturated fatty acid metabolizing enzyme, in experimental models of acute stroke and chronic neurodegeneration; however, none to our knowledge have explored its role in epilepsy development. Thus, this study characterizes the cell‐specific expression o...
Activity of neuronal cyclooxygenase-2 (COX-2), a primary source of PG synthesis in the normal brain, is enhanced by excitatory neurotransmission and this is thought to be involved in seizure suppression. Results herein showing that the incidence of pentylenetetrazole (PTZ)-induced convulsions is suppressed in transgenic mice overexpressing COX-2 in...
Burgeoning evidence supports a role for cyclooxygenase metabolites in regulating membrane excitability in various forms of synaptic plasticity. Two cyclooxygenases, COX-1 and COX-2, catalyze the initial step in the metabolism of arachidonic acid to prostaglandins. COX-2 is generally considered inducible, but in glutamatergic neurons in some brain r...
Abstract (2 leaves) bound with copy. Thesis (Ph. D.)--University of Connecticut, 2007. Includes bibliographical references. Advisor: Sandra J. Hewett, Dept. of Biomedical Sciences.
System xc (-) is a heteromeric amino acid cystine/glutamate antiporter that is constitutively expressed by cells of the central nervous system (CNS), where it functions in the maintenance of intracellular glutathione and extracellular glutamate levels. We recently determined that the cytokine, IL-1β, increases the activity of system xc (-) in CNS a...
The astrocyte cystine/glutamate antiporter (system xc-) contributes substantially to the excitotoxic neuronal cell death facilitated by glucose deprivation. The purpose of this study was to determine the mechanism by which this occurred. Using pure astrocyte cultures, as well as, mixed cortical cell cultures containing both neurons and astrocytes,...
Prostaglandin E 2 (PGE 2) is a potent prostanoid metabolite of the cyclooxygenase (COX) pathway of arachidonic acid. It is generated by neurons in response to excitatory neuronal activity and, as such, is considered to be an important neuromodulator in the brain. PGE 2 is produced from free arachidonic acid by the sequential actions of COX and pros...
Despite longstanding evidence that hypoglycaemic neuronal injury is mediated by glutamate excitotoxicity, the cellular and molecular mechanisms involved remain incompletely defined. Here, we demonstrate that the excitotoxic neuronal death that follows GD (glucose deprivation) is initiated by glutamate extruded from astrocytes via system xc---an ami...
Microglia, resident phagocytic cells of the central nervous system, are frequent contaminants of astrocyte cultures. Unfortunately and not always fully appreciated, contamination by microglia can confound results of studies designed to elucidate the molecular mechanisms underlying astrocyte-specific responses. The paradigm described herein employs...
Astrocytes produce numerous mediators under conditions of inflammation in the central nervous system. One such mediator is nitric oxide (NO) derived from nitric oxide synthase-2 (NOS-2), the high output, inducible NOS isoform. Expression of NOS-2 and production of NO can be stimulated in astrocyte cultures by combinations of cytokines and lipopolys...
We recently demonstrated that interleukin-1β (IL-1β) increases system x(c)(-) (cystine/glutamate antiporter) activity in mixed cortical cell cultures, resulting in an increase in hypoxic neuronal injury when glutamate clearance is impaired. Herein, we demonstrate that neurons, astrocytes, and microglia all express system x(c)(-) subunits (xCT, 4F2h...
We previously demonstrated that transforming growth factor-beta1 (TGF-beta1), while having no effect alone, enhances nitric oxide (NO) production in primary, purified mouse astrocytes induced by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma), by recruiting a latent population of astrocytes to respond, thereby enhancing the total number...
Phospholipase A(2) (PLA(2)) enzymes encompass a superfamily of at least 13 extracellular and intracellular esterases that hydrolyze the sn-2 fatty acyl bonds of phospholipids to yield fatty acids and lysophospholipids. The purpose of this study was to characterize which phospholipase paralog regulates NMDA receptor-mediated arachidonic acid (AA) re...
Nitric oxide (NO) synthase-2 (NOS-2), a key source of NO at sites of neuroinflammation, is induced in astrocyte cultures treated with lipopolysaccharide (LPS) plus interferon-gamma (IFN gamma). A recent study examining the regulation of astrocytic NOS-2 expression demonstrated that transforming growth factor-beta1 (TGF beta 1) potentiated LPS plus...
Transforming growth factor-beta1 (TGF-beta1) is upregulated by inflammatory mediators in several neurological diseases/disorders where it either participates in the pathology or provides protection. Often, the biological outcome of TGF-beta1 is dependent upon changes in gene expression. Recently, we demonstrated that TGF-beta1 enhances astrocytic n...
The purpose of this study was to determine whether the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib [4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone] could effectively prevent hippocampal neuronal injury in an animal model of excitotoxic neurodegeneration. COX-2 protein levels increased between 3 and 6 h, peaked at 12 h, and declined...
Cultures of astrocytes can be readily established and are widely used to study the biological functions of these glial cells in isolation. Unfortunately, contamination by microglia can confound results from such studies. Herein, a simple and highly effective modification of a common procedure to remove microglia from astrocyte cultures is described...
A splice variant of cyclooxygenase-1 (COX-1), COX-1b (previously termed as COX-3), has been identified in canine tissues as an acetaminophen-sensitive isoform, but the sequence of COX-1b mRNA and the encoded protein are not known in rats. We cloned and sequenced rat COX-1b mRNA from cerebral endothelial cells. Sequence analysis indicated that the 9...
The purpose of this study was to develop a suitable in vitro model system to study the biochemical pathway(s) by which interleukin-1beta (IL-1beta) contributes to the pathogenesis of cerebral ischemia. Thus, the effect of IL-1beta on a number of injury paradigms associated with energy deprivation was investigated using murine mixed cortical cell cu...
The purpose of this study was to examine the optimal dose and therapeutic window of opportunity of the nonsteroidal anti-inflammatory drug naproxen in an animal model of excitotoxic neuronal injury. Injection of N-methyl-D-aspartate (NMDA; 18-20 nmol) into the CA1 region of the left hippocampus resulted in significant brain edema as measured by the...
Nitrogen monoxide (NO) has been reported to both activate and inhibit prostaglandin (PG) biosynthesis. This apparent paradox might be explained by the production/action of distinct NO-related species formed as a result of the prevailing redox states of different cellular systems. As such, the effect of NO donors with different redox characteristics...
Cyclooxygenase isozymes (COX-1 and COX-2) are found to be constitutively expressed in brain, with neuronal expression of COX-2 being rapidly induced after numerous insults, including cerebral ischemia. Because overactivation of N-methyl-D-aspartate (NMDA) receptors has been implicated in the cell loss associated with ischemia, we characterized the...
Hewett JA, Hewett SJ, Winkler S, Pfeiffer SE. 1999. Inducible nitric oxide synthase expression in cultures enriched for mature oligodendrocytes is due to microglia. J Neurosci Res 56:189-198. In the article referenced above, the LPS concentration employed in all studies was 1 &mgr;g/ml, not 1 mg/ml as published. This correction appears: in the Mate...
Expression of inducible nitric oxide (NO) synthase (NOS-2) occurs during inflammation in the central nervous system (CNS) and has been linked to demyelination accompanying certain CNS inflammatory diseases. Although astrocytes and microglia are thought to be the major sources of NOS-2 expression in the CNS in vivo, recent evidence suggested that th...
Evidence suggests that components of the coagulation system contribute to the pathogenesis of liver injury after exposure to lipopolysaccharide (LPS) from gram-negative bacteria. Although the mechanism by which the coagulation system mediates liver injury remains unknown, it has been proposed that the conversion of fibrinogen to insoluble fibrin an...
Methylene dianiline (DDM) causes a dose- and time-dependent cholestasis, bile ductular epithelial injury, and hepatic parenchymal insult in rats. The mechanism of toxicity is unknown. Since hepatic leukocyte infiltration is a prominent feature of DDM-induced liver injury, and because leukocytes play a causal role in hepatic and extrahepatic tissue...
Tumor necrosis factor-alpha (TNF-alpha) and blood neutrophils (polymorphonuclear leukocytes; PMNs) have been implicated in the pathogenesis of endotoxin (lipopolysaccharide, LPS) hepatotoxicity. However, the mechanism by which these factors mediate liver injury during LPS exposure is uncertain. The objective of this study was to test the hypothesis...
Figure 6 summarizes a proposed model for the role of multiple mediators in the pathogenesis of LPS hepatotoxicity. This model is based on evidence reviewed above but is not meant to be exclusive. Exposure to LPS is associated with the accumulation of PMNs in the liver and increased levels of circulating TNF-α, which is probably derived, at least in...
Neutrophil (PMN) infiltration is an early occurrence in the liver after exposure to hepatotoxic doses of endotoxin lipopolysaccharide (LPS). The purpose of this study was to test the hypothesis that PMNs contribute to the pathogenesis of LPS hepatotoxicity. The immunoglobulin fraction from serum of rabbits immunized with rat PMNs (anti-PMN Ig) was...
Studies in rats indicate that neutrophils (polymorphonuclear leukocytes (PMNs] are associated with areas of tissue damage after treatment with the hepatotoxicant, alpha-naphthylisothiocyanate (ANIT). Several synthetic and naturally occurring substances stimulate PMNs to release cytotoxic mediators, such as superoxide (O2-). The purpose of the prese...
Suppression of phagocytic cell function has been proposed as a possible mechanism for the enhanced sensitivity to certain infectious agents exhibited by animals exposed to the organochloride insecticide, dieldrin. In the present study, we examined the effects of dieldrin on superoxide production by glycogen-elicited peritoneal neutrophils (PMNs) fr...
Certain bile salts cause hepatotoxicity as well as injury to extrahepatic organs when administered to animals. Activated neutrophils (PMNs) may cause tissue injury by releasing reactive oxygen species and other products. Since PMNs may come in contact with biliary components, such as bile salts, following chemical insult to the liver or during chol...
cap alpha..-Naphthylisothiocyanate (ANIT) is an hepatotoxicant that produces cholestasis and hyperbilirubinemia in rats. Its mechanism of action is unknown. The observation that polymorphonuclear leukocytes (PMNs) accumulate in the bile ductular region of the liver following ANIT administration prompted us to examine the ability of ANIT to stimulat...
Projects
Projects (6)
TIA-1 is an mRNA binding protein that suppresses translation of target mRNAs. We have shown that it is distributed widely in neurons throughout the normal brain. However, little is known about its function. Our results suggest that TIA-1 suppresses the progressive changes in neuroplasticity that lead to a progressive and persistent reduction in the innate seizure threshold, a characteristic of the epileptic brain. Our current research explores the molecular mechanisms by which TIA-1 suppresses the process of epileptogenesis. A better understanding of its role could lead to novel therapies to suppress epilepsy in at risk individuals (e.g., following brain trauma, cancer, or infection).
Investigation of the role of Cyclooxygenase-2 (COX-2) as an endogenous neuromodulatory pathway in the maintenance of the innate seizure threshold of the brain.
Investigation of the role of interleukin-1 signaling, including its possible interaction with COX-2, as an endogenous neuromodulatory pathway in the maintenance of the innate seizure threshold of the brain.
