Biomedical subjects

J D Geiger

Publications and source records attributed to J D Geiger.

At least 19 recordsLinked to original sources

PubMed2001

Endoplasmic reticulum D-myo-inositol 1,4,5-trisphosphate-sensitive stores regulate nuclear factor-kappaB binding activity in a calcium-independent manner.

The transcription factor nuclear factor-kappaB (NF-kappaB) plays critical roles in neuronal survival and plasticity and in activation of immune responses. The activation of NF-kappaB has been closely associated with changes in intracellular calcium levels, but the relationship between the two remains unclear. Here we report that inhibition of endoplasmic reticulum (ER) d-myo-inositol 1,4,5-trisphosphate (IP(3))-gated calcium release caused decreased basal NF-kappaB DNA-binding activity in cultured rat cortical neurons. Activation of NF-kappaB in response to tumor necrosis factor-alpha and glutamate was completely abolished when IP(3) receptors were blocked, and NF-kappaB activation in response to depletion of ER calcium by thapsigargin treatment was also decreased by IP(3) receptor blockade. We further investigated the relationship between IP(3) receptor activation and NF-kappaB activity using a cell-free system. Microsomes enriched in the ER were isolated from adult rat cerebral cortex, resuspended, and treated with agents that induce or inhibit ER calcium release. They were then recentrifuged, and the supernatant was added to cytoplasmic extract isolated from the same source tissue. We found that microsomes released an NF-kappaB-stimulating signal in response to activation of IP(3) receptors or inhibition of the ER Ca(2+)-ATPase, but not in response to ryanodine. Studies of intact cells and cell-free preparations indicated that the signal released from the ER was not calcium and was heat- and trypsin-sensitive. Our data suggest that activation of IP(3) receptors is required for a major component of both constitutive and inducible NF-kappaB binding activity in neurons and that decreasing ER intraluminal calcium levels triggers release of a diffusible NF-kappaB-activating signal from the ER.

Animals↗

PubMed2001

Profiling changes in gene expression during differentiation and maturation of monocyte-derived dendritic cells using both oligonucleotide microarrays and proteomics.

Dendritic cells (DCs) are antigen-presenting cells that play a major role in initiating primary immune responses. We have utilized two independent approaches, DNA microarrays and proteomics, to analyze the expression profile of human CD14(+) blood monocytes and their derived DCs. Analysis of gene expression changes at the RNA level using oligonucleotide microarrays complementary to 6300 human genes showed that approximately 40% of the genes were expressed in DCs. A total of 255 genes (4%) were found to be regulated during DC differentiation or maturation. Most of these genes were not previously associated with DCs and included genes encoding secreted proteins as well as genes involved in cell adhesion, signaling, and lipid metabolism. Protein analysis of the same cell populations was done using two-dimensional gel electrophoresis. A total of 900 distinct protein spots were included, and 4% of them exhibited quantitative changes during DC differentiation and maturation. Differentially expressed proteins were identified by mass spectrometry and found to represent proteins with Ca(2+) binding, fatty acid binding, or chaperone activities as well as proteins involved in cell motility. In addition, proteomic analysis provided an assessment of post-translational modifications. The chaperone protein, calreticulin, was found to undergo cleavage, yielding a novel form. The combined oligonucleotide microarray and proteomic approaches have uncovered novel genes associated with DC differentiation and maturation and has allowed analysis of post-translational modifications of specific proteins as part of these processes.

Amino Acid Sequence↗

PubMed2001

Car surfing: an underreported mechanism of serious injury in children and adolescents.

BACKGROUND: Car surfing, in which participants stand on top of a moving vehicle as though it were a surfboard, has been reported as a cause of traumatic injury in only 5 cases in the literature. Over the last 8 years, however, the authors have treated 26 children, primarily adolescents, for injuries resulting from car surfing. This report describes the injuries and outcomes of this potentially underreported mechanism of injury. METHODS: Medical records of 26 patients treated for car surfing injuries between 1991 and 1999 were reviewed. Demographics, hospital course, and type and severity of injuries were analyzed. RESULTS: Eighteen boys (69%) and 8 girls (31%) with an average age of 15.7+/-3.4 years (range, 6 to 22) have presented with injuries related to car surfing. All patients had fallen from the hood, roof, or trunk of a moving motor vehicle, the majority falling from the hood (n = 13; 50%). Injury severity was evaluated using the Injury Severity Scores (ISS; 12.4+/-6.5), Revised Trauma Score (RTS; 7.5+/- 1.1) and Glasgow Coma Score (GCS; 13.5+/-3.2). Injury severity was equivalent between boys and girls (P>.05). Central nervous system injuries predominated, with closed head injuries occurring in 22 (85%) and loss of consciousness in 10 (39%). Skull fractures occurred in 11 (42%) and intracranial bleeding in 9 (35%). Long-term cognitive rehabilitation was necessary in 22 (85%) patients. Three patients (12%) had spinal column fractures, with 2 (8%) suffering permanent paralysis. Two extremity (8%) and 3 (11.7%) pelvic fractures occurred. Most patients (73%) suffered significant skin and soft tissue injuries. Two patients (8%) presented with solid visceral injuries, and 1 child died. CONCLUSIONS: Car surfing is an extremely high-risk behavior in children and adolescents that leads to significant morbidity, long-term disability, and is potentially fatal. The incidence of car surfing may be greater than has been reported previously; therefore, prevention programs aimed at discouraging this high-risk behavior in children and adolescents should be considered.

Accidents, Traffic↗

PubMed2000

Simultaneous assessment of ecto- and cytosolic-5'-nucleotidase activities in brain micropunches.

We propose a new methodology for simultaneous assessment of ecto- and cytosolic-5'-nucleotidase that can be utilized in brain to measure the activity of these enzymes in micropunches of tissues. It is based on the differential sensitivity of both enzymes to alpha,beta-methyleneadenosine 5'-diphosphate (AMP-CP) and the requirements for magnesium as a co-factor. The design of assay protocol contains an internal validation by allowing comparisons between total level of 5'-nucleotidase activity with that calculated from the sum of individual activities of the ecto- and cytosolic-5'-nucleotidases. We have applied this new approach to assess the activity of ecto- and cytosolic-5'-nucleotidase in the brain regions relevant to sleep regulation. The level of both enzymes was significantly lower in the cerebral cortex than other brain regions tested.

5'-Nucleotidase↗

PubMed2000

Activity of adenosine deaminase in the sleep regulatory areas of the rat CNS.

There are data to support the notion that adenosine (ADO), a neuromodulator in the CNS, is an important regulator of sleep homeostasis. It has been demonstrated that ADO agonists and antagonists strongly impact upon sleep. In addition, the level of adenosine varies across the sleep/wake cycle and increases following sleep deprivation. Adenosine deaminase (ADA) is a key enzyme involved in the metabolism of ADO. We questioned, therefore, whether there are differences in adenosine deaminase activity in brain regions relevant to sleep regulation. We found that ADA exhibits a characteristic spatial pattern of activity in the rat CNS with the lowest activity in the parietal cortex and highest in the region of the tuberomammillary nucleus (15.0+/-4.8 and 63.4+/-28.0 nmoles/mg protein/15 min, mean+/-S.D., respectively). There were significant differences among the brain regions by one-way ANOVA (F=31.33, df=6, 123, P=0.0001). The regional differences in ADA activity correlate with variations in the level of its mRNA. This suggests that spatial differences in ADA activity are the result of changes in the expression of the ADA gene. We postulate that adenosine deaminase plays an important role in the mechanism that controls regional concentration of adenosine in the brain and thus, it is a part of the sleep-wake regulatory mechanism.

Adenosine Deaminase↗

PubMed2000

Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons.

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. PS1 mutations may perturb cellular Ca(2+) homeostasis and thereby render neurons vulnerable to excitotoxicity and apoptosis. We now report that PC12 cells expressing PS1 mutations and primary hippocampal neurons from PS1 mutant knockin mice exhibit greatly increased levels of ryanodine receptors (RyR) and enhanced Ca(2+) release following stimulation with caffeine. Double-labeling immunostaining and co-immunoprecipitation analyses indicate that PS1 and RyR are colocalized and interact physically. Caffeine treatment sensitizes neurons expressing mutant PS1 to apoptosis induced by amyloid beta-peptide, a neurotic peptide linked to the pathogenesis of AD. When taken together with recent evidence for alterations in RyR in brains of AD patients, our data suggest that PS1 mutations may promote neuronal degeneration in AD by increasing transcription and translation of RyR and altering functional properties of ryanodine-sensitive Ca(2+) pools.

Animals↗

PubMed2000

Release of calcium from inositol 1,4,5-trisphosphate receptor-regulated stores by HIV-1 Tat regulates TNF-alpha production in human macrophages.

HIV-1 protein Tat is neurotoxic and increases macrophage and microglia production of TNF-alpha, a cytopathic cytokine linked to the neuropathogenesis of HIV dementia. Others have shown that intracellular calcium regulates TNF-alpha production in macrophages, and we have shown that Tat releases calcium from inositol 1,4, 5-trisphosphate (IP3) receptor-regulated stores in neurons and astrocytes. Accordingly, we tested the hypothesis that Tat-induced TNF-alpha production was dependent on the release of intracellular calcium from IP3-regulated calcium stores in primary macrophages. We found that Tat transiently and dose-dependently increased levels of intracellular calcium and that this increase was blocked by xestospongin C, pertussis toxin, and by phospholipase C and type 1 protein kinase C inhibitors but not by protein kinase A or phospholipase A2 inhibitors. Xestospongin C, BAPTA-AM, U73122, and bisindolylmalemide significantly inhibited Tat-induced TNF-alpha production. These results demonstrate that in macrophages, Tat-induced release of calcium from IP3-sensitive intracellular stores and activation of nonconventional PKC isoforms play an important role in Tat-induced TNF-alpha production.

Calcium↗

PubMed2000

Stimulation of nucleoside efflux and inhibition of adenosine kinase by A1 adenosine receptor activation.

Adenosine is produced intracellularly during conditions of metabolic stress and is an endogenous agonist for four subtypes of G-protein linked receptors. Nucleoside transporters are membrane-bound carrier proteins that transfer adenosine, and other nucleosides, across biological membranes. We investigated whether adenosine receptor activation could modulate transporter-mediated adenosine efflux from metabolically stressed cells. DDT1 MF-2 smooth muscle cells were incubated with 10 microM [3H]adenine to label adenine nucleotide pools. Metabolic stress with the glycolytic inhibitor iodoacetic acid (1AA, 5 mM) increased tritium release by 63% (P < 0.01), relative to cells treated with buffer alone. The IAA-induced increase was blocked by the nucleoside transport inhibitor nitrobenzylthioinosine (1 microM), indicating that the increased tritium release was primarily a purine nucleoside. HPLC verified this to be [3H]adenosine. The adenosine A1 receptor selective agonist N6-cyclohexyladenosine (CHA, 300 nM) increased the release of [3H]purine nucleoside induced by IAA treatment by 39% (P < 0.05). This increase was blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (10 microM). Treatment of cells with UTP (100 microM), histamine (100 microM), or phorbol-12-myristate-13-acetate (PMA, 10 microM) also increased [3H]purine nucleoside release. The protein kinase C inhibitor chelerythrine chloride (500 nM) inhibited the increase in [3H]purine nucleoside efflux induced by CHA or PMA treatment. The adenosine kinase activity of cells treated with CHA or PMA was found to be decreased significantly compared with buffer-treated cells. These data indicated that adenosine A1 receptor activation increased nucleoside efflux from metabolically stressed DDT1 MF-2 cells by a PKC-dependent inhibition of adenosine kinase activity.

Adenosine↗

PubMed2000

Diadenosine pentaphosphate increases levels of intracellular calcium in astrocytes by a mechanism involving release from caffeine/ryanodine- and IP3-sensitive stores.

Diadenosine polyphosphates (ApnAs, n = 2 to 6 phosphate groups) activate P2-type cell-surface adenine nucleotide purinoreceptors, increase the influx of calcium into neural cells, and modulate the binding of ryanodine to ryanodine receptor-regulated intracellular calcium release channels. In this study, we tested the hypothesis, using single cell fluorescence techniques and cultured human fetal astrocytes, that p1, P5-di(adenosine-5') pentaphosphate (Ap5A)-induced increases in levels of intracellular calcium ([Ca2+]i) resulted from release of calcium from intracellular pools. Basal [Ca2+]i were 141+/-12 nM and Ap5A increased [Ca2+]i to 980+/-150 nM. The effect of Ap5A on [Ca2+]i was mediated in part through activation of purinoceptors and influx of extracellular calcium because the purinoceptor antagonist pyridoxal-phosphate-6-azophenel-2', 4'-disuphonic acid blocked by 52%, and chelation of extracellular calcium with EGTA prevented, almost completely, Ap5A-induced increases in [Ca2+]i. Implicating calcium release from IP3- and ryanodine-regulated pools of intracellular calcium were findings that Ap5A-induced increases in [Ca2+]i were blocked, at least in part, by thapsigargin, ryanodine, caffeine, and xestospongin, and Ap5A increased by 2-fold the production of IP3. Release of calcium from IP3- and ryanodine-regulated intracellular pools may be an important signaling event in neural cells that are exposed to Ap5A.

Adenosine Triphosphate↗

PubMed2000

Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders.

Endoplasmic reticulum (ER) is a multifaceted organelle that regulates protein synthesis and trafficking, cellular responses to stress, and intracellular Ca2+ levels. In neurons, it is distributed between the cellular compartments that regulate plasticity and survival, which include axons, dendrites, growth cones and synaptic terminals. Intriguing communication networks between ER, mitochondria and plasma membrane are being revealed that provide mechanisms for the precise regulation of temporal and spatial aspects of Ca2+ signaling. Alterations in Ca2+ homeostasis in ER contribute to neuronal apoptosis and excitotoxicity, and are being linked to the pathogenesis of several different neurodegenerative disorders, including Alzheimer's disease and stroke.

Animals↗

PubMed2000

Effects of nitrobenzylthioinosine on neuronal injury, adenosine levels, and adenosine receptor activity in rat forebrain ischemia.

Adenosine levels increase in brain during cerebral ischemia, and adenosine has receptor-mediated neuroprotective effects. This study was performed to test the hypothesis that nitrobenzylthioinosine (NBMPR), a selective and potent inhibitor of one adenosine transporter subtype termed ENT1, or es, can protect against ischemic neuronal injury by enhancing adenosine levels and potentiating adenosine receptor-mediated effects, including attenuation of the cellular production and release of tumor necrosis factor-alpha (TNF-alpha). In rats, the phosphorylated prodrug form of NBMPR, NBMPR-phosphate, or saline was administered by intracerebroventricular injection 30 min before forebrain ischemia. Seven days following the ischemic episode, rats were killed, and neuronal damage in the CA1 region of the hippocampus was assessed. The number of pyramidal neurons was significantly (p < 0.001) greater in the NBMPR-P treatment group. A trend toward protection was still evident at 28 days postreperfusion. Adenosine increased significantly during ischemia to levels eight- to 85-fold above basal. NBMPR-P treatment did not cause statistically significant increases in ischemic adenosine levels; however, this treatment tended to increase adenosine levels in all brain regions at 7 min postreperfusion. Ischemia-induced expression of TNF-alpha was not altered by NBMPR-P treatment, and the nonselective adenosine receptor antagonist 8-(p-sulfophenyl) theophylline did not abolish the neuroprotective effects of NBMPR-P treatment. These data indicate that NBMPR can protect CA1 pyramidal neurons from ischemic death without statistically significant effects on adenosine levels or adenosine receptor-mediated inhibition of the proinflammatory cytokine TNF-alpha.

Adenosine↗

PubMed2000

Selective laparoscopic probing for a contralateral patent processus vaginalis reduces the need for contralateral exploration in inconclusive cases.

BACKGROUND/PURPOSE: Repair of an indirect inguinal hernia is the most common procedure performed by pediatric surgeons, yet the need for contralateral exploration remains controversial. This prospective study evaluated the use of laparoscopy combined with the selective use of probing to determine the presence or absence of a contralateral patent processus vaginalis (CPPV). METHODS: A consecutive series of 75 of the author's patients presenting with a unilateral inguinal hernia were studied. Laparoscopy was performed through the known hernia sac with CO2 insufflation utilizing a 4-mm 70 degrees telescope to inspect the contralateral inguinal region. A patent processus was diagnosed when an obvious opening through the internal ring was identified. In some patients this evaluation was found to be inconclusive because of the inability to determine accurately the length of the patent processus or to rule out a patent processus obscured by a veil of peritoneum. This group of patients was then evaluated selectively with a silver probe placed under direct vision through a 14-gauge intravenous catheter placed through the abdominal wall on the side in question to manipulate the peritoneum and directly measure the length of the potentially patent processus. A patent processus greater then 1.5 cm was considered positive. RESULTS: A total of 54 patients (72%) had a conclusive laparoscopic evaluation of the contralateral inguinal region with a CPPV clearly absent in 38 and an obvious CPPV present in 16. A total of 21 patients (28%) had inconclusive laparoscopy finding and were evaluated further with probing. The probing technique changed the determination of a CPPV in 15 patients (12 positive to negative and 3 negative to positive; P = .029, Fisher's Exact test). Probing resulted in a decrease in the overall rate of identification of a CPPV from 45% to 32%. CONCLUSION: In inconclusive cases, the addition of selective probing to the laparoscopic evaluation for a CPPV reduces the number of patent processus vaginalis found and the need for contralateral inguinal exploration.

Female↗

PubMed2000

A longitudinal analysis of the pediatric surgeon workforce.

OBJECTIVE: To describe the trends in the pediatric surgeon workforce during the last 25 years and to provide objective data useful for planning graduate medical education requirements. SUMMARY BACKGROUND DATA: In 1975, the Study on U.S. Surgical Services (SOSSUS) was published, including a model to survey staffing. A pediatric surgeon workforce study was initiated in conjunction with SOSSUS as a population, supply, and need-based study. The study has been updated every 5 years using the same study model, with the goals of determining the number and distribution of pediatric surgeons in the United States, the number needed and where, and the number of training programs and trainee output required to fill estimated staffing needs. This is the only such longitudinal workforce analysis of a surgical specialty. METHODS: Questionnaires were sent to 100 pediatric surgeons representing the 62 standard metropolitan statistical areas (SMSAs) in the United States with a population of 200,000 or more to verify the names and locations of all active pediatric surgeons and to gain information about the 5-year need for new pediatric surgeons by region. A program was developed to predict the number of pediatric surgeons relative to the total population and the 0-to-17-year-old population in the subsequent 30 years using updated data on the present number and ages of pediatric surgeons, age-specific death and retirement rates, projections of U.S. population by age group, and varying numbers of trainees graduated per year. As each 5-year update was done, previous projections were compared with actual numbers of pediatric surgeons found. The trends during the last 25 years were analyzed and compared and additional information regarding the demographics of practice, trends in reimbursement, and volume and scope of surgery was obtained. RESULTS: The birth rate has been stable since 1994. The 0-to-17-year-old population has been increasing at 0.65% per year; a 0.64% annual rate is projected to 2040. At present, 661 pediatric surgeons are distributed in every SMSA of 200,000 or more population, with an average age of 45 and an average age of retirement 65. The actual number of pediatric surgeons in each 5-year survey has consistently validated previous projections. Trainee output has increased markedly in the past 10 years. The rate of growth of the pediatric surgeon workforce at present is 50% greater than the forecasted rate of increase in the pediatric age group, and during the past 25 years the rate of growth of the pediatric surgeon workforce has been double that of the pediatric population growth. Nationally, significant changes in reimbursement, volume of surgery, and demographics of practice have occurred.

Adolescent↗

PubMed2000

Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine.

Human immunodeficiency virus type 1 (HIV-1) proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection. Recently, we showed the presence of Tat protein in brains of patients with HIV-1 encephalitis as well as macaques with encephalitis caused by a chimeric strain of HIV and simian immunodeficiency virus, and that even transient exposure of cells to Tat leads to release of cytopathic cytokines. Now, we report the first demonstration of gp120 protein in brain of patients with HIV encephalitis. We tested the hypothesis that Tat and gp120 would act synergistically to potentiate each protein's neurotoxic effects and determined the extent to which pharmacological antagonists against processes implicated in HIV-1 neuropathogenesis could block HIV-1 protein-induced neurotoxicity. Subtoxic concentrations of Tat and gp120, when incubated together, caused neuronal cell death and prolonged increases in levels of intracellular calcium. A transient exposure of neurons to Tat and gp120 for seconds initiated neuronal cell death, but maximal levels of neuronal cell death were observed with exposures lasting 30 minutes. The neurotoxicity caused by Tat and gp120 applied in combination was blocked completely by memantine, partially by amiloride, and not at all by dipyridamole or vigabatrin.

AIDS Dementia Complex↗

PubMed2000

Caffeine use in sports. A pharmacological review.

Caffeine is the most widely ingested psychoactive drug in the world. As many know, chronic use of caffeine leads to dependence, tolerance, drug craving, and upon abrupt cessation unpleasant withdrawal symptoms. Thus, caffeine fulfills pharmacological criteria by which agents are classified as drugs of abuse. Nevertheless, its use is legal and only at high, but readily attainable, levels is it banned from sport. Its use is widespread by athletes as young as 11 years of age who are seeking athletic advantage over fellow competitors. It is likely that its use will not decline any time soon because it is inexpensive, readily available, medically quite safe, socially acceptable, and by most measures legal. However, at levels allowed in sport, caffeine through its wide-ranging physiological and psychological effects increases endurance in well-trained athletes. If the goal of drug-testing and education programs in sport is to protect the health of athletes, prevent unfair advantage (cheating) and encourage ethical behavior then it seems obvious that the allowable levels of caffeine ingestion should be decreased. The alternative is to continue with policies designed largely to punish only those that get caught.

Animals↗

PubMed2000

Identification of beta-tubulin isoforms as tumor antigens in neuroblastoma.

There is currently substantial interest in the identification of human tumor antigens for diagnosis and immunotherapy of cancer. We have implemented a proteomic approach for the identification of tumor proteins that elicit a humoral response in cancer patients, which we have applied to neuroblastoma. Proteins from neuroblastoma tumors and cell lines were separated by two-dimensional PAGE and transferred to poly(vinylidene difluoride) membranes. Sera from 23 newly diagnosed patients with neuroblastoma, from 12 newly diagnosed children with other solid tumors, and from 13 normal individuals were screened for IgG and IgM autoantibodies against neuroblastoma proteins by means of Western blot analysis. Sera from 11 patients with neuroblastoma and from 1 patient with a primitive neuroectodermal tumor, but none of the other controls exhibited IgG-based reactivity against a protein constellation with an estimated Mr 50,000. NH2-terminal sequence and mass spectrometric analysis identified the major constituents of this constellation as beta-tubulin isoforms I and III. The IgG antibodies were additionally characterized to be of the subclass IgG1. Neuroblastoma patient sera that contained anti-beta-tubulin IgG antibodies also contained IgM antibodies specific against the full-length beta-tubulin molecule and against COOH-terminal beta-tubulin cleavage products. Neuroblastoma patient sera that reacted with beta-tubulin I and III isoforms in neuroblastoma tissues did not react with beta-tubulin I and III isoforms found in normal brain tissue. Our findings indicate the occurrence of beta-tubulin peptides in neuroblastoma, which are immunogenic. The occurrence of immunogenic peptides in neuroblastoma may have utility in diagnosis and in immunotherapy of this aggressive childhood tumor.

Adolescent↗

PubMed2000

Dietary supplement creatine protects against traumatic brain injury.

Creatine, one of the most common food supplements used by individuals at almost every level of athleticism, promote gains in performance, strength, and fat-free mass. Recent experimental findings have demonstrated that creatine affords significant neuroprotection against ischemic and oxidative insults. The present experiments investigated the possible effect of creatine dietary supplementation on brain tissue damage after experimental traumatic brain injury. Results demonstrate that chronic administration of creatine ameliorated the extent of cortical damage by as much as 36% in mice and 50% in rats. Protection seems to be related to creatine-induced maintenance of mitochondrial bioenergetics. Mitochondrial membrane potential was significantly increased, intramitochondrial levels of reactive oxygen species and calcium were significantly decreased, and adenosine triphosphate levels were maintained. Induction of mitochondrial permeability transition was significantly inhibited in animals fed creatine. This food supplement may provide clues to the mechanisms responsible for neuronal loss after traumatic brain injury and may find use as a neuroprotective agent against acute and delayed neurodegenerative processes.

Animals↗

PubMed1999

Dysregulation of adenosine A1 receptor-mediated cytokine expression in peripheral blood mononuclear cells from multiple sclerosis patients.

Cytokines, including tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6), have been implicated in the pathogenesis of multiple sclerosis (MS). The production and release of these cytokines are regulated in part by specific purinergic (adenosine) cell surface receptors. To determine the extent to which the adenosine A1 receptor influenced cytokine expression in peripheral blood mononuclear cells (PBMCs) from MS and control patients, we measured plasma adenosine and TNF alpha levels, A1 receptor messenger RNA (mRNA) and protein amounts, and the effects of activation of A1 receptors on TNF alpha and IL-6 production by PBMCs. Plasma levels of TNF alpha were significantly higher and adenosine levels were significantly lower in MS patients compared with control subjects. Levels of TNF alpha and IL-6 in mitogen-stimulated PBMC culture supernatants from MS patients or control patients were similar. Conversely, treatment of PBMCs with the adenosine A1 receptor agonist R-phenylisopropyladenosine (R-PIA) (1 microM) significantly inhibited mitogen-stimulated production of TNF alpha but not IL-6 in control subjects and significantly inhibited production of IL-6 but not TNF alpha in MS patients. The effects of R-PIA were selectively blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). A1 receptor protein levels were decreased significantly in PBMCs from MS patients. Taken together, these results suggest that decreased levels of adenosine and its A1 receptor modulate TNF alpha and IL-6 levels and may contribute to the pathogenesis of MS.

Adenosine↗