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

Yatsiv, Ido; Morganti-Kossmann, Maria Cristina; Perez, Daniel; Dinarello, Charles A.; Novick, Daniela; Rubinstein, Menachem; Otto, Viviane I.; Rancan, Mario; Kossmann, Thomas; Redaelli, C.; Trentz, O.; Shohami, Esther; Stahel, Philip F.

doi:10.1097/00004647-200208000-00008

Cited by 165 publications

(109 citation statements)

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“…The injury resulted in timedependent pathological changes in brain morphology, including intraparenchymal bleeding and edema, as described (27,28,39,(41)(42)(43). Animals killed 15 min to 24 h after CHI had some intracranial bleeding at the site of impact but no lesions.…”

Section: Resultsmentioning

confidence: 84%

“…The study was approved by the Institutional Animal Care Committee of the Hebrew University. Experimental CHI was induced by using a modified weight-drop device developed in our laboratory (27,28). Briefly, after induction of ether anesthesia, a midline longitudinal incision was performed, the skin was retracted and the skull was exposed.…”

Section: Methodsmentioning

confidence: 99%

“…Excessive activation followed within a relatively short time by desensitization and loss of functional NMDAR could explain the preclinical and clinical experience with NMDAR antagonists and suggest alternative modes of treatment. This hypothesis was tested in a mouse model of closed head injury (CHI) (27,28) produced by a free-falling weight impacting the intact skull, in combination with quantitative autoradiography of the radiolabeled NMDAR noncompetitive antagonist MK801 (29,30). Because noncompetitive NMDAR antagonists (e.g., TCP and MK801) are thought to be ''usedependent'' ligands, i.e., they bind to a site inside the channel made accessible when the receptor is activated by glutamate (31), an increase in binding of agents of this class can be used as a functional marker of excessive NMDAR activation in the brain (32,33).…”

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confidence: 99%

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

Biegon

Fry

Paden

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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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 (>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 (>24 h) time window easily attainable for treatment of human accidental head injury.H ead trauma is a leading cause of mortality and morbidity among young people in the western world (1). Traumatic and ischemic brain injury triggers a large, transient increase in excitatory amino acid transmitter efflux in the brain of experimental animals and human subjects (2-6). Glutamate activation of the N-methyl-D-aspartate (NMDA) receptor (NMDAR), which is a ligand-gated ion (calcium and sodium) channel, results in channel opening and ion influx into the cell. It has been suggested that this process mediates delayed excitotoxic neuronal death after brain ischemia and trauma (7,8), although the concept is not universally accepted (9, 10). Support for the involvement of NMDAR activation in neuronal death after brain injury has come from numerous studies showing that NMDAR antagonists reduce cell death and improve outcome in animal models of traumatic brain injury (TBI) and stroke. NMDAR antagonists appear to be most efficacious when given before or immediately after the insult and lose efficacy if administered Ͼ30-60 min postinjury (11)(12)(13)(14)(15).Microdialysis studies of extracellular glutamate in human TBI and stroke patients suggested that the increase in glutamate in humans is more sustained [6 h to several days (7, 8)] than in rodents, where it only lasts minutes (2-6). This result may have contributed to a decision to administer NMDAR antagonists in clinical trials of head injury for several days rather than once after severe nonpenetrating injury. All clinical trials of NMDAR antagonists to date failed to show efficacy. Furthermore, some of these trials had to be stopped prematurely because of increases in mortality and morbidity in the drug arm of the stroke trials (16-18), suggesting that prolonged bloc...

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Section: Resultsmentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Biegon

Fry

Paden

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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220

164

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“…Although one could argue that the lack of IL-18 receptors on the specialized endothelial cells of the hypothalamic thermoregulatory center explains the lack of fever, direct injection of IL-18 into the brain also does not evoke a febrile response (5). Moreover, there is not a dearth of evidence that the brain is highly responsive to endogenous as well as exogenous IL-18 (18,27), and that the brain expresses IL-18 receptors (28)(29)(30).…”

Section: Cox-2 Protein and Pge2 Levels After Il-18mentioning

confidence: 99%

Differences in signaling pathways by IL-1β and IL-18

Lee

Kim

Lewis

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…IL-18 levels were found to be elevated for up to 10 days post-TBI in the CSF of patients who had experienced a severe head injury [133] and have been associated with more severe disability [134]. In a study examining serum levels of IL-18 in TBI patients, plasma IL-18 levels were elevated at 7 days, 3 months, and 6 months post-injury and were noted to decrease over time in parallel to cognitive improvement as measured by the mini mental state examination (MMSE).…”

Section: Inlammatory Il-18 In Tbimentioning

confidence: 99%

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Dugue¹,

Nath²,

Dugue³

et al. 2017

Mechanisms of Neuroinflammation

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This chapter will introduce the reader to the pathophysiology of two devastating neurologic events, traumatic brain injury (TBI) and acute ischemic stroke (AIS). Here we focus on the role of key pro-inlammatory and anti-inlammatory cytokines. Several experimental interventions have been found to modulate cytokine production and brain injury after AIS or TBI. Here minocycline, biological response modiiers, hormonal therapies, omega-3 faty acids, N-acetylcysteine, and cannabinoids will be discussed. In addition, the role of cytokine-induced inlammasomes in both TBI and AIS will be addressed and followed by discussion of pro-inlammatory cytokines (e.g., TNF-α, IL-1β, IL-18, and IFN-γ). Finally, the main anti-inlammatory cytokines, IL-33, IL-10, IL-6, and IL-4, will be discussed in the context of both TBI and AIS. It should be noted that the role of these cytokines is diverse and the dichotomization of classically pro-versus anti-inlammatory cytokines is being re-examined, as many of these cytokines have been found to play dual roles in TBI and AIS brain injury.Keywords: traumatic brain injury, ischemic stroke, cytokines, interleukins, inlammasome Pathophysiology of traumatic brain injuryTraumatic brain injury (TBI) is a major cause of death and disability worldwide [1,2]. It is one of the most commonly diagnosed neurological disorders in the United States, impacting people of a variety of ages and segments of society [3]. In Europe, the economic cost of © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.TBI is over 33 billion euros per year [4]. Continued surveillance and research is being done to reduce primary and secondary TBI [as well as acute ischemic stroke(AIS)]-induced brain injury [1].The pathophysiology of TBI begins with the initial brain trauma (i.e., the primary injury). This primary injury results from mechanical damage that disrupts the blood-brain barrier (BBB), alters the vasculature and damages brain tissue. The resulting injured glia and neurons release their intracellular contents (i.e., damage-associated molecular paterns; (DAMPs)) into the extracellular space and activate neighboring glia and neurons. Activated glia and neurons then produce molecular signals that can both exacerbate and mend the acute injury and contribute to long-term recovery [5][6][7][8][9]. These downstream molecular and cellular processes (i.e., the secondary injury in TBI) are the focus of many pre-clinical and clinical therapeutic studies. Secondary injury in TBI involves a host of molecular and cellular responses to the The pathophysiology of AIS and TBI share common mechanisms. The initial insult in AIS, an occlusion of blood low resulting in a core infarct zone surrounded by a poorly perfused penumbra, versus the initial primary physical impact in TBI both result in pe...

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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

Cited by 165 publications

References 38 publications

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

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

Differences in signaling pathways by IL-1β and IL-18

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

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