Biomedical subjects

Esther Shohami

Publications and source records attributed to Esther Shohami.

34 records · Page 2Linked to original sources

PubMed2004

Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits.

Traumatic brain injury is a leading cause of mortality and morbidity among young people. For the last couple of decades, it was believed that excess stimulation of brain receptors for the excitatory neurotransmitter glutamate was a major cause of delayed neuronal death after head injury, and several major clinical trials in severely head injured patients used blockers of the glutamate N-methyl-D-aspartate (NMDA) receptor. All of these trials failed to show efficacy. Using a mouse model of traumatic brain injury and quantitative autoradiography of the activity-dependent NMDA receptor antagonist MK801, we show that hyperactivation of glutamate NMDA receptors after injury is short-lived (<1 h) and is followed by a profound and long-lasting (> or =7 days) loss of function. Furthermore, stimulation of NMDA receptors by NMDA 24 and 48 h postinjury produced a significant attenuation of neurological deficits (blocked by coadministration of MK801) and restored cognitive performance 14 days postinjury. These results provide the underlying mechanism for the well known but heretofore unexplained short therapeutic window of glutamate antagonists after brain injury and support a pharmacological intervention with a relatively long (> or =24 h) time window easily attainable for treatment of human accidental head injury.

Animals↗

PubMed2004

Brain trauma induces X-box protein 1 processing indicative of activation of the endoplasmic reticulum unfolded protein response.

Brain trauma was induced in mice using a closed head injury (CHI) model. At 1, 6 or 24 h after trauma, brains were dissected into the cortex, striatum and hippocampus. Changes in levels of processed X-box protein 1 (xbp1), glucose-regulated protein 78 (grp78), growth arrest and DNA damage-inducible gene 153 (gadd153) and heat-shock protein 70 (hsp70) mRNA, indicating impaired endoplasmic reticulum (ER) and cytoplasmic functioning, were evaluated by quantitative PCR. In the cortex, processed xbp1 mRNA levels rose to 2000% of control 1 h after CHI, and stayed high throughout the experiments. In the hippocampus and striatum, processed xbp1 mRNA levels rose in a delayed fashion, peaking at 6 h (1000% of control) and 24 h after CHI (1500% of control) respectively. Levels of grp78 mRNA were only slightly increased in the cortex 24 h after CHI (150% of control), and were unchanged or transiently decreased in the hippocampus and striatum. Levels of gadd153 mRNA did not change significantly after trauma. A transient rise in hsp70 mRNA levels was observed only in the cortex, peaking at 1 h after CHI (600% of control). Processing of xbp1 mRNA is a sign of activation of the unfolded protein response indicative of ER dysfunction. The results suggest that brain trauma induces ER dysfunction, which spreads from the ipsilateral cortex to the hippocampus and striatum. These observations may have clinical implications and should therefore be considered for future investigations on therapeutic intervention of brain injury caused by contusion-induced neurotrauma.

Animals↗

PubMed2004

Brain injury-dependent expression of activity-dependent neuroprotective protein.

Activity-dependent neuroprotective protein (ADNP), a crucial brain development factor, contains a unique sequence, termed NAPVSIPQ, which protects mice against closed head injury (CHI). The aim of this study was to determine whether CHI affects ADNP mRNA expression in the injured brain hemisphere. Male C57JBL/6J mice were subjected to CHI. Brains were removed 5 h, 24 h, 7 d, and 29 d post-CHI. A comparison was made between ADNP mRNA in the injured versus the noninjured hemisphere using real-time polymerase chain reaction. A nonsignificant change (p >0.05) was found 5 h, 24 h, and 7 d post-CHI. However, a significant increase (p <0.05) in ADNP mRNA expression was detected in the injured cerebral hemisphere 29 d post-CHI. The data presented may be associated with ADNP's crucial involvement in brain development and response to injury.

Amino Acid Sequence↗

PubMed2003

Synergism between tumor necrosis factor-alpha and H2O2 enhances cell damage in rat PC12 cells.

Tumor necrosis factor-alpha (TNFalpha) is harmful in the early phase and beneficial in the long-term phase after brain injury. Reactive oxygen species (ROS) are among the most toxic mediators activated by injury. We speculate that part of the TNFalpha toxicity is mediated by its synergism with ROS. Thus, toxicity of TNFalpha and ROS, alone or together, were studied in PC12 cells. PC12 cells were exposed for 18 h to TNFalpha (0-100 ng/ml), to H2O2 (1-300 microM) or to both, each at sub-toxic concentrations. Lactic dehydrogenase release, prostaglandin E2 accumulation and morphology indicated cell death and stress response. TNFalpha toxicity was seen at >50 ng/ml, and that of H2O2 at >150 microM, however, when together, sub-lethal levels (25 ng/ml TNFalpha and 30 microM H2O2) induced toxicity. Dexanabinol, an N-methyl-D-aspartate antagonist with antioxidant and anti-TNFalpha properties, completely rescued the cells. These findings corroborate our hypothesis on the cooperative toxicity exerted by TNFalpha and ROS after brain injury.

Animals↗

PubMed2003

Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-kappaB and AP-1.

Traumatic brain injury (TBI) is followed by massive production of reactive oxygen species (ROS), which mediate secondary cellular damage. Low molecular weight antioxidants (LMWA) constitute one of the defense mechanisms of the brain, and their levels correlate with post-TBI outcome. Melatonin, the main pineal hormone, possesses antioxidant properties. We investigated the effects of melatonin on neurobehavioral recovery, brain LMWA, and activation of the redox-sensitive transcription factors nuclear factor-kappaB (NF-kappaB) and AP-1 in mice subjected to closed head injury (CHI). Given 1 h after CHI, melatonin facilitated recovery during at least 1 wk (P<0.05) and decreased lesion size by approximately twofold (P<0.01). The dose response displayed a bell-shape, i.e., neuroprotection was achieved with 5 but not 1 or 10 mg/kg. At the neuroprotective dose, melatonin treatment was associated with sustained (4 days) elevation of brain LMWA, including ascorbic acid (P<0.05). In contrast, LMWA were unaffected by the administration of the neuroprotective endocannabinoid 2-arachidonoyl glycerol. Furthermore, melatonin did not alter early phase (24 h) CHI-induced activation of NF-kappaB and AP-1; however, it blocked the robust late-phase (8 days) activation of NF-kappaB and decreased that of AP-1 to below basal levels. Our results demonstrate that melatonin induces neuroprotection, presumably via potentiation of brain antioxidants and attenuation of NF-kappaB and AP-1 activation.

Animals↗

PubMed2003

Injections of the neuroprotective peptide NAP to newborn mice attenuate head-injury-related dysfunction in adults.

The prophylactic neuroprotective effects of NAP, a femtomolar-acting neuroprotective peptide were tested in a mouse model of head trauma. NAP was injected for the first 3 weeks of life and head injury was initiated at 4 months. After trauma, mice were tested for their performance by evaluating damaged motor ability, balance and alertness. Comparison of the performance 1 h and 1 week after injury indicated that NAP treatment resulted in faster and enhanced recovery. In a 5-day Morris water maze test with mice suffering moderate to severe injuries, only the NAP-treated group learned to find the hidden platform in the maze. Furthermore, NAP treatment resulted in decreased mRNA expression of the inflammation marker, Mac-1. Thus, a potentially new prophylactic treatment against neurodegeneration is suggested.

Aging↗

PubMed2003

Therapeutic vaccination for closed head injury.

Closed head injury often has a devastating outcome, partly because the insult, like other injuries to the central nervous system (CNS), triggers self-destructive processes. During studies of the response to other CNS insults, it was unexpectedly discovered that the immune system, if well controlled, provides protection against self-destructive activities. Here we show that in mice with closed head injury, the immune system plays a key role in the spontaneous recovery. Strain-related differences were observed in the ability to harness a T cell-dependent protective mechanism against the effects of the injury. We further show that the trauma-induced deficit could be reduced, both functionally and anatomically, by post-traumatic vaccination with Cop-1, a synthetic copolymer used to treat patients with multiple sclerosis and found (using a different treatment protocol) to effectively counteract the loss of neurons caused by axonal injury or glutamate-induced toxicity. We suggest that a compound such as Cop-1 can be safely developed as a therapeutic vaccine to boost the body's immune repair mechanisms, thereby providing multifactorial protection against the consequences of brain trauma.

Animals↗

PubMed2003

The Ras inhibitor S-trans, trans-farnesylthiosalicylic acid exerts long-lasting neuroprotection in a mouse closed head injury model.

Traumatic brain injury activates N-methyl-d-aspartate receptors (NMDAR) inducing activation of the Ras protein (a key regulator of cell growth, survival, and death) and its effectors. Thus, trauma-induced increase in active Ras-GTP might contribute to traumatic brain injury pathology. Based on this hypothesis, a new concept of neuroprotection is proposed, examined here by investigating the effect of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) in a mouse model of closed head injury (CHI). Mice subjected to CHI were treated systemically 1 h later with FTS (5 mg/kg) or vehicle. After 1 h, Ras-GTP in the contused hemisphere showed a significant (3.8-fold) increase, which was strongly inhibited by FTS (82% inhibition) or by the NMDA-receptor antagonist MK-801 (53%). Both drugs also decreased active (phosphorylated) extracellular signal-regulated kinase. FTS prevented the CHI-induced reduction in NMDAR binding in cortical, striatal, and hippocampal regions, measured by [3H]-MK-801 autoradiography, and decreased lesion size by 50%. It also reduced CHI-induced neurologic deficits, indicated by the highly significant (P < 0.0001) 60% increase in extent of recovery. Thus, FTS provided long-term neuroprotection after CHI, rescuing NMDAR binding in the contused hemisphere and profoundly reducing neurologic deficits. These findings suggest that nontoxic Ras inhibitors such as FTS may qualify as neuroprotective drugs.

Animals↗

PubMed2002

The endocannabinoid system: function in survival of the embryo, the newborn and the neuron.

Since the identification and cloning of the first cannabinoid (CB1) receptor and the subsequent discovery of the endogenous cannabinoid ligands (endocannabinoids), anandamide, 2-arachidonoyl glycerol (2-AG) and noladin ether, a intensive search for their function in health and disease has been launched. The endocannabinoids in the central nervous system bind Gi/o coupled CB1 receptors that modulate adenylyl cyclase, ion channels and extracellular signal-regulated kinases. The present review discusses the nature of endocannabinoid (anandamide and 2-AG) neurotransmission, the activity of cannabinoids and the possibility that some of these activities are mediated via a receptor, yet to be discovered, which is distinct from the brain specific CB1 receptor. Three physiological functions in which the endocannabinoids play a critical role are also discussed: embryonal implantation, feeding and appetite, and neuroprotection.

Animals↗

PubMed2002

Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal.

Cerebral ischemia stimulates increased activity of polyamine oxidase, a ubiquitous enzyme that catabolizes polyamines to produce 3-aminopropanal. 3-Aminopropanal is a reactive aldehyde that mediates progressive neuronal necrosis and glial apoptosis. Here we report that increased levels of 3-aminopropanal-modified protein levels in humans after aneurysmal subarachnoid hemorrhage correlate with the degree of cerebral injury as measured by admission Hunt/Hess grade. In vitro screening of clinically approved drugs reveals that N-2-mercaptopropionyl glycine (N-2-MPG), an agent clinically approved for prevention of renal stones in patients with cysteinuria, significantly inhibits the cytotoxicity of 3-aminopropanal. N-2-MPG reacts with 3-aminopropanal to yield a nontoxic thioacetal adduct, as confirmed by electrospray ionization mass spectroscopy. Administration of N-2-MPG in clinically relevant doses to rats significantly reduces cerebral 3-aminopropanal-modified protein immunoreactivity and infarct volume in a standardized model of middle cerebral artery occlusion, even when the agent is administered after the onset of ischemia. These results implicate 3-aminopropanal as a therapeutic target for cerebral ischemia.

Aldehydes↗

PubMed2002

Cerebral ischemia and trauma-different etiologies yet similar mechanisms: neuroprotective opportunities.

Cerebral ischemia leads to brain damage caused by pathogenetic mechanisms that are also activated by neurotrauma. These mechanisms include among others excitotoxicity, over production of free radicals, inflammation and apoptosis. Furthermore, cerebral ischemia and trauma both trigger similar auto-protective mechanisms including the production of heat shock proteins, anti-inflammatory cytokines and endogenous antioxidants. Neuroprotective therapy aims at minimizing the activation of toxic pathways and at enhancing the activity of endogenous neuroprotective mechanisms. The similarities in the damage-producing and endogenous auto-protective mechanisms may imply that neuroprotective compounds found to be active against one of these conditions may indeed be also protective in the other. This review summarizes the pathogenetic events of ischemic and traumatic brain injury and reviews the neuroprotective strategies employed thus far in each of these conditions with a special emphasize on their clinical relevance and on future directions in the field of neuronal protection.

Animals↗

PubMed2002

Cannabinoids and brain injury: therapeutic implications.

Mounting in vitro and in vivo data suggest that the endocannabinoids anandamide and 2-arachidonoyl glycerol, as well as some plant and synthetic cannabinoids, have neuroprotective effects following brain injury. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission and reduce the production of tumour necrosis factor-alpha and reactive oxygen intermediates, which are factors in causing neuronal damage. The formation of the endocannabinoids anandamide and 2-arachidonoyl glycerol is strongly enhanced after brain injury, and there is evidence that these compounds reduce the secondary damage incurred. Some plant and synthetic cannabinoids, which do not bind to the cannabinoid receptors, have also been shown to be neuroprotective, possibly through their direct effect on the excitatory glutamate system and/or as antioxidants.

Animals↗

PubMed2002

Improved recovery and delayed cytokine induction after closed head injury in mice with central overexpression of the secreted isoform of the interleukin-1 receptor antagonist.

The acute inflammatory response following traumatic brain injury (TBI) has been shown to play an important role in the development of secondary tissue damage. The proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNFalpha), are induced early after brain injury and have been implicated in the delayed damage. The IL-1 receptor antagonist (IL-1ra) has been shown to modulate the proinflammatory cytokine cascade by blocking the binding of IL-1 to its signaling receptor. In this study, we investigated the effect of transgenic overexpression of IL-1ra on the cytokine expression and neurological damage in a closed head injury (CHI) model of TBI. The neurological recovery, as analyzed by neurological severity score (NSS), was significantly higher in transgenic mice overexpressing the human secreted form of IL-1ra in astrocytes, directed by the murine glial fibrillary acidic protein promoter, as compared to wild-type mice. Analysis of tissue levels of cytokines by ELISA showed increased levels of TNFalpha in the cerebral cortex from the wild type mice 1 h after injury. After 4 h significant increases in the levels of IL-1beta and IL-6 were observed in the wild type mice. In the transgenic mice, on the other hand, no effect on TNFalpha levels was observed and no significant increases in IL-1beta and IL-6 levels could be detected until 6 h after injury. Thus, it can be concluded that blockage of IL-1 signaling by elevated levels of IL-1ra has a neuroprotective effect, in agreement with previous reports, and that central overexpression of IL-1ra results in delayed proinflammatory cytokine induction and improved neurological recovery after traumatic brain injury.

Animals↗

PubMed2002

Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury.

Proinflammatory cytokines are important mediators of neuroinflammation after traumatic brain injury. The role of interleukin (IL)-18, a new member of the IL-1 family, in brain trauma has not been reported to date. The authors investigated the posttraumatic release of IL-18 in murine brains following experimental closed head injury (CHI) and in CSF of CHI patients. In the mouse model, intracerebral IL-18 was induced within 24 hours by ether anesthesia and sham operation. Significantly elevated levels of IL-18 were detected at 7 days after CHI and in human CSF up to 10 days after trauma. Published data imply that IL-18 may play a pathophysiological role in inflammatory CNS diseases; therefore its inhibition may ameliorate outcome after CHI. To evaluate the functional aspects of IL-18 in the injured brain, mice were injected systemically with IL-18-binding protein (IL-18BP), a specific inhibitor of IL-18, 1 hour after trauma. IL-18BP-treated mice showed a significantly improved neurological recovery by 7 days, accompanied by attenuated intracerebral IL-18 levels. This demonstrates that inhibition of IL-18 is associated with improved recovery. However, brain edema at 24 hours was not influenced by IL-18BP, suggesting that inflammatory mediators other than IL-18 induce the early detrimental effects of intracerebral inflammation.

Adult↗

PubMed2001

Induction of the complement component C1qB in brain of transgenic mice with neuronal overexpression of human cyclooxygenase-2.

We report that overexpression of human (h) cyclooxygenase-2 h(COX-2) in the brain of a transgenic mouse line leads to selective induction of endogenous complement component C1qB expression in neurons. No detectable induction of the C3 and C4 complement components in the brain was found. Chronic treatment of mice with the selective COX-2 inhibitor nimesulide reduced the hCOX-2-mediated induction of hippocampal C1qB mRNA expression. The data suggest that neuronal COX-2 expression may influence inflammatory responses in the brain, in part through modulation of complement gene expression. Because there is extensive evidence that C1q and other complement components are involved in Alzheimer's disease (AD) neurodegeneration, this study advances our understanding of the apparent benefits of COX-2 inhibition in AD.

Alzheimer Disease↗

PubMedDate not supplied

A single administration of the peptide NAP induces long-term protective changes against the consequences of head injury: gene Atlas array analysis.

The femtomolar-acting eight-amino-acid peptide (NAP), derived from activity-dependent neuroprotective protein (ADNP), provides long-term protection against the deleterious effects of closed head injury (CHI) in mice. Fifteen minutes after injury, mice were divided into two groups, control and NAP-treated and a single subcutaneous injection of NAP or vehicle was administered. A third group served as sham-treated (not subjected to head trauma). Each mouse was assessed for its clinical function, using neurological severity score, at various time intervals following CHI, up to 30-45 d. Total cerebral cortex RNA was prepared from the site of injury of CHI mice, and from parallel regions in peptide-treated and sham brains. RNA was then reversed transcribed to yield radioactive cDNA preparations that were hybridized to Atlas array membranes containing 1200 cDNAs spots. Comparison of sham-treated individual mice showed differential expression levels of at least 15 mRNA species. Furthermore, results indicated that one of the genes that did not change among individuals but specifically increased after CHI and decreased after NAP treatment was the cell surface glycoprotein Mac-1 (CD11B antigen). Thus, Mac-1 is suggested as a marker for the long-term outcome of head injury and as a potential target for NAP protective actions.

Animals↗