E. Shohami | The Hebrew University of Jerusalem (original) (raw)

Papers by E. Shohami

Proceedings of the National Academy of Sciences, 1987

In the adrenal medulla, chromaffin cells secrete high concentrations of catecholamines, ATP, pept... more In the adrenal medulla, chromaffin cells secrete high concentrations of catecholamines, ATP, peptides and other factors that must pass through an endothelial cell barrier to enter the bloodstream. We have measured the effect of several of these chromaffin cell secretory products on cultured bovine adrenal medullary endothelial cells and have found that only ATP stimulates prostacyclin formation. The stimulation of prostacyclin formation by ATP coincides with the metabolism of inositol phospholipids and the accumulation of the putative second messenger inositol trisphosphate. The time course, concentration dependence, and P2-purinergic receptor specificity were similar for ATP-stimulated prostacyclin formation and ATP-stimulated inositol phospholipid metabolism. Thus, the increase in prostacyclin formation may be secondary to mobilization of intracellular Ca2+ by inositol trisphosphate, leading to activation of phospholipase A2, liberation of arachidonic acid, and the conversion of a...

Stroke, 1987

Secondary motor dysfunction is often observed following ischemic episodes in the central nervous ... more Secondary motor dysfunction is often observed following ischemic episodes in the central nervous system. To study potential mechanisms of postischemic motor deterioration, we developed a rabbit spinal cord ischemia model that has characteristics similar to the clinical condition termed deteriorating stroke. In this model, 70% of the rabbits regained substantial motor function by 4 hours after complete hindlimb paralysis during lumbar spinal cord ischemia; however, over the next 20 hours motor function steadily declined to the point where only 30% of the rabbits had minimal hopping function. The role of eicosanoids in spinal cord ischemia was studied by radioimmunoassay of several prostaglandins (6-keto-PGF1 alpha, PGE2, and TxB2) in the spinal cord. After 5 minutes of reperfusion, TxB2 levels were markedly elevated (p less than 0.05) while 6-keto-PGF1 alpha levels did not change. The TxB2:6-keto-PGF1 alpha ratio was also significantly increased. After 30 minutes of reperfusion, PGE2...

Neuroscience, 1997

Previous studies suggest that traumatic brain injury is associated with increased risk factor for... more Previous studies suggest that traumatic brain injury is associated with increased risk factor for developing Alzheimer's disease. Furthermore, the extent of the risk seems to be most pronounced in Alzheimer's disease patients who carry the epsilon4 allele of apolipoprotein E, suggesting a connection between susceptibility to head trauma and the apolipoprotein E genotype. Apolipoprotein E-deficient mice provide a useful model for investigating the role of this lipoprotein in neuronal maintenance and repair. In the present study apolipoprotein E-deficient mice and a closed head injury experimental paradigm were used to examine the role of apolipoprotein E in brain susceptibility to head trauma and in neuronal repair. Apolipoprotein E-deficient mice were assessed up to 40 days after closed head injury for neurological and cognitive functions, as well as for histopathological changes in the hippocampus. A neurological severity score used for clinical assessment revealed more severe motor and behavioural deficits in the apolipoprotein E-deficient mice than in the controls, the impairment persisting for at least 40 days after injury. Performance in the Morris water maze, which tests spatial memory, showed a marked learning deficit of the apolipoprotein E-deficient mice when compared with injured controls, which was apparent for at least 40 days. At this time, histopathological examination revealed overt neuronal cell death bilaterally in the hippocampus of the injured apolipoprotein E-deficient mice. The finding that apolipoprotein E-deficient mice exhibit an impaired ability to recover from closed head injury suggests that apolipoprotein E plays an important role in neuronal repair following injury and highlights the applicability of this mouse model to the study of the cellular and molecular mechanisms involved.

Pharmaceutical Research - PHARMACEUT RES, 1987

T-2 Toxin is a mycotoxin that induces toxemia characterized by numerous hematological and biochem... more T-2 Toxin is a mycotoxin that induces toxemia characterized by numerous hematological and biochemical changes. We have previously shown that prostaglandin (PG) production in brain tissue is increased following T-2 toxin. The present study was designed in order to test the effect of dexamethasone on brain prostaglandins and survival of rats subjected to T-2 toxin. Furthermore, the effect of BW 755c, a dual inhibitor of the cyclooxygenase and lipoxygenase pathways of arachidonate metabolism, on the survival of rats exposed to T-2 toxin was also examined. The present study demonstrated that dexamethasone increases the survival of rats exposed to a highly lethal T-2 toxicosis. This effect was demonstrated at low as well as high doses and at different times after T-2 administration. Dexamethasone depressed PGE2 levels in the brain cortex 6 hr after T-2 toxin but abolished the reduction of PGE2 in brain cortex seen 24 hr after T-2. BW 755c had no consistent effect on the survival of rats ...

Brain Research, 2014

Despite years of research, no effective therapy is yet available for the treatment of traumatic b... more Despite years of research, no effective therapy is yet available for the treatment of traumatic brain injury (TBI). The most prevalent and debilitating features in survivors of TBI are cognitive deficits and motor dysfunction. A potential therapeutic method for improving the function of patients following TBI would be to restore, at least in part, plasticity to the CNS in a controlled way that would allow for the formation of compensatory circuits. Inosine, a naturally occurring purine nucleoside, has been shown to promote axon collateral growth in the corticospinal tract (CST) following stroke and focal TBI. In the present study, we investigated the effects of inosine on motor and cognitive deficits, CST sprouting, and expression of synaptic proteins in an experimental model of closed head injury (CHI). Treatment with inosine (100 mg/kg i.p. at 1, 24 and 48 h following CHI) improved outcome after TBI, significantly decreasing the neurological severity score (NSS, po0.04 vs. saline), an aggregate measure of performance on several tasks. It improved non-spatial cognitive performance (object recognition, po0.016 vs. saline) but had little effect on sensorimotor coordination (rotarod) and spatial cognitive functions (Y-maze). Inosine did not affect CST sprouting in the lumbar spinal cord but did restore levels of the growth-associated protein GAP-43 in the hippocampus, though not in the cerebral cortex. Our results suggest that inosine may improve functional outcome after TBI.

Prostaglandins, Leukotrienes and Essential Fatty Acids, 1997

Incubation of L6 myotubes for 24 h under hypoxic conditions leads to a 5.8 _+ 1.2 fold increase i... more Incubation of L6 myotubes for 24 h under hypoxic conditions leads to a 5.8 _+ 1.2 fold increase in 2-deoxyglucose uptake. In those conditions phospholipase A2 is activated, leading to a 2.4 + 0.8 fold increased release of arachidonic acid (AA) to the medium, and to 95% increased synthesis of PGF2~, but not of PGE2 as compared to cells incubated in normoxic conditions. Under hypoxia, the PLA2 inhibitor bromophenacyl bromide (BPB) inhibited AA release and PGF2~ synthesis, yet it did not affect the increase in glucose uptake into L6 myotubes. The amount of GLUT1 immunoreactive proteins in total membranes of hypoxia treated cells was elevated 5.1 _+ 1.2 fold compared to control cells. Neither 10 #M BPB nor 100 mM aspirin (ASA) prevented this increase in GLUT1 expression. Preincubation of myotubes for either 1 or 23 h with 50 pM exogenous AA, prevented insulin induced 2deoxyglucose uptake stimulation, suggesting that although AA or one of its metabolites did not regulate the synthesis or stability of GLUT1, it may interfere with the signal transduction of insulin in muscle cells.

Biophysical Journal, 1973

Two models of hydrophobic ion exchange membranes were examined theoretically with regard to the c... more Two models of hydrophobic ion exchange membranes were examined theoretically with regard to the characteristics of cellulose acetate-nitrate membranes saturated with hydrophobic solvents. The first model, consisting of fixed negative sites dispersed in a homogeneous medium of low dielectric constant, was shown to be invalid for the experimental membranes. The second model, consisting of fixed negative sites in an aqueous channel surrounded by a medium of low dielectric constant, explains many properties of the cellulose acetate-nitrate hydrophobic membranes and was analyzed in some detail. Organic cations can enter the membranes through the hydrophobic phase as well as through the aqueous channels. The mechanism of counterion movement in such a model is assumed to consist of exchange of vacancies and or double-occupied sites positions. The presence of the medium of low dielectric constant around the aqueous channel increases the "self"-energy of the ions in the channel and the electrostatic interaction between a fixed site and a counterion in the membrane. Both these factors can account for the marked dependence of ion mobility in the aqueous channels on the dielectric constant of the surrounding medium. The model predicts membrane preference for monovalent counterions over divalent ones.

Restorative Neurology and Neuroscience, 1994

ABSTRACT Closed head injury leads to delayed tissue-edema, necrosis and impaired neurological fun... more ABSTRACT Closed head injury leads to delayed tissue-edema, necrosis and impaired neurological function. In the present study the effect of chronic exposure to heat on the outcome of head injury in rats was investigated. Rats were held at ambient temperature of 24°C (CON) or 34°C (heat acclimated, ACC) for one month, before induction of trauma. Injury was induced by a weight drop device, falling over the left cerebral hemisphere. Twenty-four or 48 h later the rats were sacrificed and their brains removed for evaluation of edema (specific gravity or water content). Blood-brain barrier integrity (Evans blue extravasation) was evaluated 4 h after injury. One, 24 and 48 h after injury the rats were evaluated by a set of criteria which yields their clinical status (Neurological Severity Score - NSS). Forty-eight hours after trauma specific gravity of the contused hemispheres was 1.0389 ± 0.0019 and 1.0364 ± 0.0007 (P < 0.01) and water content 81.44 ± 1.28 and 84.17 ± 1.03% (P < 0.001), for ACC and CON rats, respectively. Lower degree of edema was also evident at 24 h suggesting slower rate of edema formation in ACC rats. Evans blue uptake by the contused hemisphere was 315 ± 61 and 50 ± 23 ng/g tissue in the CON and ACC rats, respectively (P < 0.001). Clinical recovery of the ACC rats was significantly better (P < 0.001) than that of the matched controls as exhibited at 48 h by median NSS values of: 10.8 (range 6-16) and 5 (range 4-6) for CON and ACC, respectively. Based on the present results we suggest that heat acclimation offers protection to rats subjected to head trauma.

Neurological Research, 1989

Previous studies have reported accumulation of calcium (Ca) in brain tissue of injured or ischaem... more 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.

Journal of Steroid Biochemistry, 1986

Brain Edema IX, 1994

Cerebral edema is one of the major consequences of head trauma (HT); its evolution may cause seco... more Cerebral edema is one of the major consequences of head trauma (HT); its evolution may cause secondary ischemia and neuronal damage. In a closed head injury model in rats, we have shown BBB disruption and edema formation during the post traumatic period. We have previously shown that chronic exposure to moderate heat improves clinical outcome of rats subjected to HT. Long term exposure to heat results in the achievement of a stable acclimated state, characterized by a lower metabolic rate and improved heat tolerance. In the present study, we investigated the effect of chronic exposure to heat on edema formation after HT. Rats were held at 24 degrees C (CON) or 34 degrees C (ACC) for one month. Injury was then induced under ether anesthesia by a weight drop device. Four or 48 hours later, they were sacrificed for evaluation of BBB integrity (Evans blue, EB, extravasation) or edema formation (specific gravity, SG, or percent water). We found that EB uptake by the contused hemisphere was 6 fold lower in the ACC rats as compared to CON (p < 0.001). Furthermore, edema measured at 48 h by both SG and percent water methods was significantly lower in the acclimated rats (p < 0.01). We suggest that heat acclimation offers protection to rats subjected to head injury, possibly by reduction of plasma proteins extravasation.

Prostaglandins, Leukotrienes and Essential Fatty Acids, 1989

Head trauma (HT) was induced in the left hemisphere of rats by a weight drop device. Edema was ma... more 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.

Prostaglandins, Leukotrienes and Essential Fatty Acids, 1996

Prostacyclin production in cultured cardiomyocytes is not induced by cellular ATP depletion per s... more Prostacyclin production in cultured cardiomyocytes is not induced by cellular ATP depletion per se, suggesting that the mechanism of ischemic injury is more complex. In the present study we subjected cultured ventricular myocytes to 'simulated ischemia' followed by reoxygenation, A slight increase in 6-keto-PGFl~ (the stable metabolite of PGI2) was found during 'ischemia', which continued to increase markedly during reoxygenation. PGE2 levels were pronouncedly enhanced during ischemia but decreased during reoxygenation, and TXB2 levels remained undetectable throughout, These findings reflect a cardiomyocyte response to anoxic injury, suggesting that they act to protect against cardiac injury by producing the potent vasodilators PGI2 and PGE2 during ischemia and reoxygenation.

The Journal of pharmacology and experimental therapeutics, 1999

Pardaxin, an excitatory neurotoxin, induced dopamine release from pheochromocytoma (PC12) cells b... more Pardaxin, an excitatory neurotoxin, induced dopamine release from pheochromocytoma (PC12) cells both in the presence and absence of extracellular calcium ([Ca]o). In the presence of extracellular calcium, nifedipine, an L-type calcium channel blocker, did not affect dopamine release, whereas 1,2-bis (2-aminophenoxy) ethane N,N, N'N'-tetra-acetic acid (BAPTA), a chelator of cytosolic calcium, and dantrolene, a blocker of calcium release from intracellular stores, inhibited only partially (30-40%) pardaxin-induced dopamine release. In the absence of [Ca]o, BAPTA and dantrolene were ineffective. Pardaxin stimulated the arachidonic acid (AA) cascade in PC12 cells independently of [Ca]o. The phospholipase inhibitors mepacrine and bromophenacyl bromide inhibited both pardaxin-induced AA release and pardaxin-induced dopamine release. Dopamine release induced by pardaxin also was blocked by the lipoxygenase inhibitors nordihydroguaiaretic acid, esculetin, and 2-(12-hydroxydodeca-5, ...

European journal of anaesthesiology, 1993

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Research and Publishing in Neurosurgery, 2002

Journal of Basic and Clinical Physiology and Pharmacology, 1992

Closed head injury in rats induces edema formation, which is indicated by a decrease in cerebral ... more Closed head injury in rats induces edema formation, which is indicated by a decrease in cerebral specific gravity and an increase in water content. We previously described the activation of the eicosanoid metabolic cascade, namely, activation of PLA2 and accumulation of products of both 5-lipoxygenase (5-LO) and cyclo-oxygenase (CO) in the same model of head injury. The present study was designed to determine the effect of a novel drug, SK&amp;amp;F 105809, a dual inhibitor of 5-LO and CO on cerebral edema formation after head injury in rats. Rats, under ether anesthesia, were subjected to sham operation or trauma induced by weight-drop device impacting over the left calvarium. One group of traumatized rats received 0.9% saline and served as control and two other groups were treated with SK&amp;amp;F 105809, 20 or 30 mg/kg, i.p. immediately after the impact. In one group treatment was repeated additionally 2.5 h post-trauma. Four hours after trauma, rats were sacrificed and brain edema was evaluated. SK&amp;amp;F 105809 treated rats which received 30 mg/kg had significantly less brain edema, as measured by both gravimetry and water content, at 4 h after trauma. The lower dose, 20 mg/kg, had no effect. Our results suggest that treatment with a mixed 5-LO/CO inhibitor shortly after head injury will result in less brain edema and ultimately improved functional outcome.

Prostaglandins, 1986

T-2 toxin is a trichothecene mycotoxin which is a member of a family of closely related sesquiter... more T-2 toxin is a trichothecene mycotoxin which is a member of a family of closely related sesquiterpenoids. It was recently shown that T-2 toxemia is associated with elevated plasma levels of eicosanoids. To study further the effect of T-2 on the cyclooxygenase pathway of arachidonate we examined the release of PGE2, TXB and 6-keto-PGF vi& from brain tissue exposed to T-2 toxin 1 n vivo or in-* Administration of T-2 toxin (0.75 or 2 mgfkg) K conscious rats caused a transient increase in the rate of the release of 6-keto-PGFIo and TXB Q from brain slices taken from the cortex (C); no effec was found in the hypothalamus (HT) or the nucleus tractus solitarius (NTS) region of the medulla oblogata. PGE2 showed time and dose related increments (over 5 folds) in both the C and HT but not in the NTS. Incubation of cortical or hypothalamic ;

Blood—Brain Barrier, 2001

The importance of endothelial involvement in vascular relaxation induced by acetylcholine drew at... more The importance of endothelial involvement in vascular relaxation induced by acetylcholine drew attention to the role of endothelial mediators in controlling vascular function (Furchgott and Zawadzki, 1980). Since this time, a great number of endothelial factors have been demonstrated to influence not only the vascular tone but also additional parameters including blood flow and blood-brain barrier (BBB) permeability (Rubanyi and Polokoff, 1994; Spatz, et al.,1995a; Gellai, et al.,1997; Thorin, et al.,1998). At the present time, there is substantial agreement that the mechanisms responsible for many of these events involve the interplay among a number of factors in either the circulation or produced locally. Studies in vivo and in vitro have shown that the most potent endothelialderived vasoactive substances, NO and ET-1, are primarily responsible for regulating the vascular reactivity (Gellai, et al.,1997; Bakker, et al.,1997). Our initial studies demonstrated that NO was involved in the postischemic hypoperfusion observed in animal models of cerebral ischemia (Spatz, et al.,1995b). This effect was related to increased levels of ET-1 in the cerebrospinal fluid (CSF). Treatment with ET-1 receptor antagonists abolished the hypoperfusion which resulted in neuronal protection from ischemic damage (Dawson, et al.,1999; Spatz, et al.,1996). These observations highlight the existence of the close relationship between these vasoactive factors and implicate their involvement in maintaining vascular tone and regulating circulation (e.g.,cerebral blood flow and blood pressure) as well as BBB function.