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Biomedical subjects

E Shohami

Publications and source records attributed to E Shohami.

At least 19 recordsLinked to original sources
PubMed1992

Changes in brain polyamine levels following head injury.

The changes in polyamines levels in the brain after closed head injury were studied in rats. At 1 and 15 min, 24 and 48 h after closed head injury cortical tissue from the site of injury, from the contralateral region, and from remote areas were taken. The levels of the diamine putrescine and the polyamines spermine and spermidine were assayed by thin layer liquid chromatography of their dansyl derivatives. Head injury induced a significant increase in putrescine at 48 h at the site of injury and in the frontal lobe of the injured hemisphere, respectively. In the contralateral hemisphere only minor changes in putrescine were found. Spermine and spermidine showed minor changes at that time course. We have previously shown that at 24-48 h after injury, severe edema is found at the site injury. In order to study the role of putrescine in edema formation in this model we treated the traumatized rats with alpha-difluoromethyl-ornithine (DFMO), an inhibitor of ornithine-decarboxylase, the rate limiting enzyme in putrescine biosynthesis. This drug did not affect the level of edema 4 or 48 h after injury although it abolished the increase in putrescine. The effect of DFMO on blood-brain barrier function was studied, using Evans blue extravasation, at the early post-traumatic period (15 min-4 h), where a massive amount of dye is taken up by traumatized brain. No changes in the amount of dye extracted was found after DFMO treatment. On the other hand, DFMO had a beneficial effect on the neurological outcome, as evaluated by a set of clinical criteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Glucocorticoid regulation of eicosanoid production by glial cells under basal and stimulated conditions.

We measured the production of two eicosanoids, prostaglandin E2 and thromboxane-B2, by rat glial cell cultures under basal conditions, following stimulation with phorbol-12-myristate-13-acetate and the bacterial endotoxin lipopolysaccharide, and following treatment with synthetic glucocorticoids. Stimulation of rat glial cells in culture with either phorbol-12-myristate-13-acetate or lipopolysaccharide caused a 1.5-5.0-fold increase in prostaglandin E2 production, but did not affect thromboxane production. Pretreatment of the cultures with dexamethasone markedly inhibited the stimulated production of prostaglandin E2 but had only a modest effect on basal production. Dexamethasone did not affect the activity of the enzyme protein kinase C, a putative regulator of eicosanoid synthesis. Our findings show that glucocorticoids have the potential to modulate central nervous system eicosanoid production particularly under conditions of stimulated production, such as inflammatory and demyelinating disorders. This mechanism may explain, at least in part, the therapeutic benefit of glucocorticoids in patients with multiple sclerosis.

Animals↗
PubMed1992

Mechanical injury increases eicosanoid production in cultured cardiomyocytes.

The release of three stable metabolites of the arachidonic acid cascade was determined in cultures of cardiac myocytes and of non-muscle cells. In both cell types, the main product was 6-keto-PGF1 alpha much less PGE2 was released, while TXB2 was only detected in muscle cells. Preincubation with arachidonic acid increased the release of all the PGs in both types of culture. Mechanical injury had a synergistic effect on the increased PG release in AA-preincubated cells. However, TXB2 was not detected in F-cells in any experimental conditions. These results suggest that PG production serves a functional role in heart preservation during injury.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Role of the central adrenergic system in the regulation of prostaglandin biosynthesis in rat brain.

The role of endogenous catecholamines in the regulation of brain prostaglandin (PG) synthesis was studied in the rat. Male rats were injected in the brain lateral ventricle or in the ventral noradrenergic bundle with either the catecholaminergic neurotoxin 6-hydroxydopamine or vehicle. Other groups of rats were injected intraperitoneally with the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine, or with the inhibitor of dopamine-beta-hydroxylase, FLA-63. All these drugs produced a significant depletion of norepinephrine (NE) content in the cortex and hypothalamus. The rats that had lower levels of NE exhibited reduced capacity to synthesize PGE2 but not thromboxane B2 and 6-keto-PGE1 alpha in the cortex and hypothalamus. However, induced production of PG, stimulated by the bacterial endotoxin lipopolysaccharide (LPS), remained unchanged, namely, a similar (2- to 2.5-fold) increase of PG synthesis was noted in control and in NE-depleted rats. We suggest that the regulation of PG synthesis under basal condition requires intact adrenergic input, whereas LPS-induced production of PG is independent of the adrenergic innervation.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Methylprednisolone does not decrease eicosanoid concentrations or edema in brain tissue or improve neurologic outcome after head trauma in rats.

Methylprednisolone was recently reported to significantly improve motor and sensory function after acute spinal cord injury in patients. Our study was designed to determine whether methylprednisolone exerts a beneficial effect after head injury. Diethyl ether-anesthetized rats were assigned to receive surgery with no cranial impact and no methylprednisolone (group A, n = 13); surgery with no cranial impact and intraperitoneal methylprednisolone (greater than or equal to 60 mg/kg) (group B, n = 8); surgery with cranial impact and no methylprednisolone (group C, n = 8, and group E, n = 8); or surgery with cranial impact and methylprednisolone (greater than or equal to 60 mg/kg) (group D, n = 15, and group F, n = 13). Neurologic severity score was determined at 1, 2, 4, and 24 h (when appropriate) after injury, and brain tissue eicosanoid levels and cerebral edema were determined when the animals were killed (4 h after injury in groups C and D and 24 h after injury in groups E and F). Treatment with methylprednisolone did not improve neurologic severity score or edema formation and did not alter brain tissue levels of prostaglandin E2, thromboxane B2, or 6-keto-prostaglandin F1 alpha at any time period. The authors conclude that methylprednisolone does not exert a beneficial effect on brain tissue edema or functional activity after cranial impact in rats.

Animals↗
PubMed1990

Lethal hypoglycemia and hypothermia induced by administration of low doses of tumor necrosis factor to adrenalectomized rats.

An increased sensitivity of adrenalectomized (Adex) rats to intravenous (IV) injection of recombinant human tumor necrosis factor (rHuTNF) was manifested by a marked increase in the rate of mortality. The rats that died exhibited severe hypoglycemia and hypothermia. Administration of 2.5 or 10 micrograms/100 g body weight (3% or 12%) of the lethal dose in sham-operated rats (90 micrograms/100 g body weight) rHuTNF caused a mortality rate of 50% or 100%, respectively, within 4 hours of its injection. Pre-administration of dexamethasone or intermittent glucose infusion protected the animals from the lethal effect of rHuTNF. Indomethacin did not change the mortality rate in rHuTNF-treated Adex rats, but prevented it in sham-operated rats. The rats that died exhibited a marked decrease in body temperature, but only Adex rats developed hypoglycemia after low doses of TNF. Pretreatment with dexamethasone prevented the hypothermia in both Adex and sham-operated rats, while indomethacin was effective only in sham-operated rats and did not prevent the hypothermia or the hypoglycemia in Adex rats. In the surviving rHuTNF-treated Adex rats, a rapid increase in body temperature occurred, blood glucose decreased to 30 mg/dL, serum insulin concentration decreased to 6 microU/mL, liver glycogen content was reduced by 98%, and a significant reduction in liver phosphoeonolpyruvate carboxykinase (PEPCK) and liver microsomal glucose-6-phosphatase activities was observed. Repeated administration of glucose IV to rHuTNF-treated Adex rats caused an increase in blood glucose and insulin concentrations, and some repletion in liver glycogen content. Injection of rHuTNF, 2.5 to 10 micrograms/100 g body weight, to sham-operated rats caused a significant but slower increase in body temperature.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1990

Protective effect of MK801 in experimental brain injury.

The effect of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK801, was studied in a model of closed head injury in rats. Head trauma (HT) was induced over the left cerebral hemisphere by a calibrated weight-drop device. One or 3 h later, MK801 in saline was given i.p. in a single bolus of either 1, 3, or 10 mg/kg. The rats were killed at 4, 24, or 48 h after HT. Cortical tissue samples were taken from the injured zone and from the corresponding region of the contralateral hemisphere and analyzed for specific gravity (SG) by linear gradient columns. The neurological status of the traumatized rats was evaluated by a neurological severity score (NSS) 1 h after trauma and just before death. Pathological evaluation, based on size and severity of the lesion, was performed 24 and 48 h after HT on control and MK801-treated rats. A dose of 3 mg/kg MK801 given 1 h after trauma effectively prevented the reduction in tissue SG only at 24 h. The NSS could not be evaluated at 24 h after trauma because of the sedating effect of the drug. At 48 h posttrauma, however, the drug significantly improved the neurological state of the rats. No significant difference was found in the pathological score between treated and untreated rats. The results demonstrate neuroprotective properties of MK801, as expressed in two different variables--reduced edema formation and improved neurological recovery after HT. These findings support existing evidence that pharmacological intervention with NMDA receptor antagonist after head injury may be of clinical value in the management of head-injured patients.

Animals↗
PubMed1990

Experimental neoplastic spinal cord compression: effect of ketamine and MK-801 on edema and prostaglandins.

Excitotoxin-induced neural tissue damage is mediated through specific receptors. We studied the in vivo effect of two selective N-methyl-D-aspartate receptor antagonists on the compressed spinal cord segments of rats harboring a thoracolumbar epidural tumor. The effect of a single intramuscular treatment with either MK-801 (3 mg/kg) or ketamine (110 mg/kg) given at the onset of paraplegia was evaluated 30 hours later. In saline-treated control animals, significant increases in water content, prostaglandin E2, and 6-keto-prostaglandin F1 alpha were evident. Treatment with either agent resulted in a normal water content in the compressed segments but had no effect on prostaglandin synthesis. Evaluation of the effect of treatment on the course of the disease required dose reduction by 45% for ketamine and by 30% for MK-801, to avoid the excessive sedative effect. Treatment was started at the first appearance of neurological dysfunction (Grade 1) and continued to paraplegia (Grade 5). The mean time interval between Grades 1 and 5 was 2.1 +/- 0.3 days in saline-treated control animals, and it was not significantly altered by either ketamine or MK-801. Our study indicates that in the end stage of epidural compression, when ischemia is present, excitotoxins probably participate in the evolution of a cytotoxic edema. It is suggested that treatment initiated at the onset of paraplegia may still reduce the cytotoxic edema, but its potential clinical value requires further investigations.

Analysis of Variance↗
PubMed1989

Treatment of articular effusions with local deep microwave hyperthermia.

Local deep microwave hyperthermia (LDMWH) may be considered as a therapeutic tool for joint diseases because it has the advantage of heating the target organ e.g. synovium, while sparing the adjacent tissues, as demonstrated in animals. The effect of this new microwave device has been evaluated on seven rheumatoid arthritis patients with knee effusion. The hyperthermia apparatus consists of a 915 MHz power source with a cooling system to the skin. LDMWH was operated for one hour, twice a week for two weeks. Intra-articular knee temperature reached the level of 40.6 +/- 1.1 degrees C within 15 minutes, raised to 41.2 +/- 0.7 degrees C after 30 minutes and to 41.3 +/- 0.9 degrees C at one hour. The skin temperature over the heated knee joints remained at 24.3 +/- 1.1 degrees C during treatment. All patients noted a sensation of warmth in the treated knee. Aspiration of synovial fluid was performed before and immediately after each treatment. Walking time was improved (p = 0.04) and significant decrease in pain (p = 0.01) was noted following treatment. Synovial fluid leukocyte count and prostaglandin E2 level, knee circumference and range of motion did not change. Severity of pain, walking time, knee circumference and range of motion remained stable in the six weeks following the last hyperthermia application. No adverse reaction could be observed. These results suggest LDMWH to be safe and successful as an adjuvant treatment of chronic inflammatory joint effusions.

Adult↗
PubMed1989

Opposite effect of adrenalectomy on rat brain prostaglandin synthesis in basal conditions and in response to insulin or 2-deoxy-glucose.

In the present study we evaluated the role of endogenous glucocorticoids in the biosynthesis of prostaglandins (PG) in cortical brain tissue of the rat. Experiments were carried out under basal conditions and in response to insulin-induced hypoglycemia and 2-deoxyglucose (2-DG) induced-cytoglucopenia. In intact rats, following hypoglycemia and cytoglucopenia, the production of brain PG was decreased. These two stress stimuli also activated adrenocortical secretory responses, as manifested by an increase in circulating ACTH and corticosterone. Bilateral adrenalectomy did not modify the brain production of PG under basal conditions. In contrast, in adrenal-ectomized rats, the biosynthesis of brain cortical PG was markedly increased in response to insulin and 2-DG. These results suggest that adrenal hormones may be involved in the modulation of cortical PG production under stressful conditions.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

OKY-046 inhibits thromboxane synthesis with no effect on brain edema and neurological status in head traumatized rats.

Head trauma (HT) was induced in the left hemisphere of rats by a weight drop device. Edema was maximal 24 h after HT in the injured zone, and PGE2, TXB2 and 6-keto-PGF1 alpha were elevated in both the injured and remote areas. The effect of a specific thromboxane synthetase inhibitor, OKY-046, on the outcome of HT was studied. OKY-046, 100 mg/kg, was given to rats immediately and 8 h after HT. The neurological severity score (NSS) was evaluated at 1 h after HT, and at 24 h, just prior to sacrifice. Specific gravity (SG) of both hemispheres was measured after decapitation. Prostaglandins (PGs) were extracted from the site of injury and from the frontal lobes, remote from the injury, and assayed by RIA. Basal levels of PGE2 and 6-keto-PGF1 alpha were not reduced by the drug while basal TXB2 levels were lowered. However, the increased production due to HT of all PGs, was inhibited by OKY-046, especially that of TXB2. The ratio of TXB2/6-keto-PGF1 alpha, known to affect vascular tone, was reduced by OKY-046 treatment as a result of TXA2 synthesis inhibition. Still, no effect was found on the neurological outcome (as evaluated by the NSS), or on edema formation (expressed by reduced SG). Thus, based on the present findings increased TXA2 synthesis cannot be implicated in the pathophysiology of cerebral edema or dysfunction following HT.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Accumulation of calcium in the brain following head trauma.

Previous studies have reported accumulation of calcium (Ca) in brain tissue of injured or ischaemic experimental animals. In the present study, head trauma (HT) was induced in the left hemisphere of rats which were subsequently sacrificed 15 min, 1, 2, 4, 24 or 48 h later. Their brains were analysed for oedema formation by the determination of specific gravity (SG), using linear gradient columns, and water content, by dry to wet weight ratio. Total tissue Ca content was measured by atomic absorption spectroscopy. These values, in both the injured and contralateral hemispheres were compared with values obtained from sham-operated rats. Specific gravity of the contused hemisphere was lower than that of the contralateral hemisphere or sham and its water content was higher, at all time points studied. Calcium content was significantly higher in the contused grey matter at 1 h, and in the grey and white matter of both hemispheres at 24 and 48 h after HT. Statistical analysis revealed excellent correlation (cc = 0.65, p less than 0.001) between Ca levels and water content in the grey matter, whenever Ca concentrations were elevated (1, 24 and 48 h). These findings suggest that in the late phase of the post-HT period, Ca accumulation might play a role, along with other mediators, in the development of brain oedema after HT.

Animals↗
PubMed1989

Brain phospholipase A2 is activated after experimental closed head injury in the rat.

Head injury was induced in rats by a weight drop device, falling over the left hemisphere. The rats were killed at 15 min, 4 h, and 24 h after injury. Cortical slices were taken from the injured zone, from the corresponding region of the contralateral hemisphere, and from the frontal lobe of both hemispheres. These cortical slices were incubated in the presence of a fluorescent phospholipid analogue, 1-acyl-2-(N-4-nitrobenzo-2-oxa-1,3-diazole)aminocaproylphosphatidylch oli ne (C6-NBD-PC) which is a substrate for phospholipase A2 (PLA2) in intact cells. The interaction of this substrate with cells produces only one fluorescent product, the fatty acid C6-NBD-FA, released from the 2-position of C6-NBD-PC. Thus, the level of C6-NBD-FA produced is a direct measure of PLA2 activity. Fifteen minutes after trauma, a 75% increase of PLA2 activity was found in the injured zone. At 4 h, the frontal lobe of the contused, left hemisphere had elevated PLA2 activity, as well as the injured zone (92 and 81%, respectively). At 24 h, PLA2 activity at the site of injury was 245% of sham. In the right, noninjured zone, no significant changes in PLA2 activity were noticed during the entire time course of the experiment. Prostaglandin E2 (PGE2) was extracted from the same cortical slices as those used for PLA2 activity measurement.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Inhibition of prostaglandin synthesis in brain of rat by dexamethasone: lack of effect of dexamethasone phosphate ester and various hormonal steroids.

The present study was designed in order to characterize the inhibitory effect of dexamethasone upon the synthesis of prostaglandins (PG) in the brain of the rat. Rats were treated with dexamethasone (20 mg/kg b.w.) and sacrificed 0-76 hr after administration of the drug. The rate of synthesis and release of PGE2 was followed by 1 hr of incubation of slices of cortex taken from these rats, in Krebs-Ringer solution. A significant inhibition occurred at 8 hr and maximal inhibition (45%) was attained at 16 hr after injection. A gradual increase in the rate of synthesis up to control values occurred between 24 and 76 hr. A dose-response study, at the range of 2-40 mg/kg, showed that a significant decrease was noted at 6 mg/kg and it was maximal (45% inhibition) at 20 and 40 mg/kg. Administration of dexamethasone-sodium-phosphate, as well as other synthetic glucocorticoids and various steroidal hormones (20 microM), failed to inhibit the biosynthesis of prostaglandins under the same experimental conditions. The effect of dexamethasone and dexamethasone phosphate on synthesis of PGE2 was also studied under in vitro conditions at 5 and 20 microM. When slices of cortex from intact rats were incubated for 1 or 2 hr in the presence of either dexamethasone or dexamethasone phosphate only dexamethasone was effective in inhibiting the synthesis of PGE2. The present results demonstrate that the inhibition of the synthesis of prostaglandins in brain by dexamethasone is both time- and dose-dependent. The lack of effect of closely related glucocorticoids demonstrate that the effect is highly specific to dexamethasone.

Animals↗
PubMed1988

Experimental closed head injury in rats: mechanical, pathophysiologic, and neurologic properties.

A model of closed head injury in rats was developed using a calibrated weight-drop device. The development of edema was studied in various brain regions (cerebral hemispheres, brain stem, cerebellum) using a linear specific gravity gradient column. Regional brain tissue density was measured within 1 min, at 15 and 60 min, 18 h, 4 and 10 days after injury to the left cerebral hemisphere, and was compared with values in sham-operated and control rats. Significant edema (i.e., reduced specific gravity) occurred only in the traumatized hemisphere and was maximal at 18 h. A neurologic severity score (NSS) was developed to evaluate the status of the rat after injury. Specific gravity was significantly correlated with NSS at 18 h after injury. The affected hemisphere displayed hemorrhagic lesions as early as one hour post head trauma (HT), which evolved into hemorrhagic necrosis at 18 h. A pathologic score, evaluated 18 h post HT based on size and severity of the lesion, was correlated with the NSS and evaluated for each rat at one hour and 18 h postimpact. This correlation was found to be highly significant. This model of brain injury may be useful in future studies on the effects of therapeutic agents.

Animals↗
PubMed1988

Comparison of soluble dexamethasone sodium phosphate with free dexamethasone and indomethacin in treatment of experimental neoplastic spinal cord compression.

In an experimental rat model of neoplastic spinal cord compression, the in vivo effect of steroidal and nonsteroidal anti-inflammatory agents on the water content, prostaglandin E2 (PGE2) production, and specific gravity of the compressed cord segments were assessed, as well as the effect on the course of the disease. Paraplegic animals presented a consistent increase in the water content, PGE2 synthesis, and specific gravity in the compressed cord segments. The effect of treatment given on onset of paraplegia with either dexamethasone sodium phosphate (Dex-p; 10 mg/kg twice daily), or free dexamethasone (F-dex; 8.25 mg/kg twice daily) or indomethacin (10 mg/kg twice daily), was evaluated after 30 hours of therapy. Both F-dex and indomethacin eliminated spinal cord edema but varied in the rate of inhibitory effect on PGE2 production (dexamethasone less than indomethacin). Dexamethasone sodium phosphate failed to reduce spinal cord edema and PGE2 synthesis, but specific gravity changes were corrected by each of the administered agents. Evaluation of the effect of treatment on the course of the disease required dose reduction by 50% for Dex-p and F-dex, and to 25% for indomethacin, to avoid lethal toxicity. Treatment was started on appearance of the first sign of neurologic dysfunction (Grade 1) and continued to paraplegia (Grade 5). In the saline-treated rats, the mean time interval between Grades 1 and 5 was 2.7 +/- 0.3 days. Free dexamethasone, Dex-p, and indomethacin significantly prolonged this interval by 57%, 54%, and 48% respectively (P less than 0.005). The three agents differed in their ability to control the increases in water content and in PGE2 production, but proved almost equally effective in the prompt control of the specific gravity changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Indomethacin and dexamethasone treatment in experimental neoplastic spinal cord compression: Part 2. Effect on edema and prostaglandin synthesis.

Edema formation and prostanoid production (prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were studied in a model of neoplastic epidural cord compression (NSCC) in rats harboring a thoracolumbar tumor. Tumor-free and tumor-bearing animals were randomized for three treatments at 12-hour intervals with saline, dexamethasone (10 mg/kg i.p.), or indomethacin (10 mg/kg i.p.). Increase in water content was observed only in the compressed lumbar cord segments of paralyzed rats; the cervical and thoracic segments did not differ from controls. The rate of release of prostaglandins was evenly distributed along the spinal segments in tumor-free rats. In tumor-bearing rats, a consistent significant increase in PGE2 production was found in the compressed lumbar segment in the presence of neurological dysfunction: early (limp tail), P less than 0.05; paraplegia, P less than 0.001. A significantly elevated PGE2 synthesis preceded the increase in water content by 2 to 3 days. A 2-fold increase in TXB2 was detected in only one of three experiments, and synthesis of 6-keto-PGF1 alpha was elevated to 4 times the normal value (P less than 0.005) in two of three experiments. Dexamethasone failed to inhibit prostaglandin synthesis in the spinal cord of normal controls or paralyzed rats, whereas in nonneural tissues (liver, uterus) it reduced synthesis of the three metabolites by at least 50%, thus demonstrating a differential effect on central nervous system (CNS) vs. non-CNS tissues. Dexamethasone also failed to reduce the increased water content of the compressed segments.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗