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

Tehranian, Roya; Andell-Jonsson, Siv; Beni, Sara M.; Yatsiv, Ido; Shohami, Esther; Bartfai, Tamás; Lundkvist, Johan; Iverfeldt, Kerstin

doi:10.1089/089771502320317096

Cited by 145 publications

(111 citation statements)

References 60 publications

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“…Administration of an inhibitor of IL-1β receptors, IL-1 receptor antagonist (IL-1ra), reduces contusion volume and transgenic mice overexpressing IL-1ra have improved behavioral recovery after TBI (Sanderson et al, 1999, Tehranian et al, 2002. Similarly, knockout mice of tnfα have improved behavior recovery one week after TBI, but worsened histopathology and behavioral outcome 2-4 weeks after injury (Scherbel et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

137

151

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Traumatic brain injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated by the inflammatory response and progress from hours to days after the initial injury. Using a clinically relevant model of TBI, the parasagittal fluid-percussion brain injury (FPI) model, we found injury-induced impairments in the cyclic AMP (cAMP) signaling pathway. Levels of cAMP were depressed in the ipsilateral parietal cortex and hippocampus, as well as activation of its downstream target, protein kinase A, from 15 min to 48 hr after moderate FPI. To determine if preventing hydrolysis of cAMP by administration of a phosphodiesterase (PDE) IV inhibitor would improve outcome after TBI, we treated animals intraperitoneally with rolipram (0.3 or 3.0 mg/kg) 30 min prior to TBI, and then once per day for three days. Rolipram treatment restored cAMP to sham levels and significantly reduced cortical contusion volume and improved neuronal cell survival in the parietal cortex and CA3 region of the hippocampus. Traumatic axonal injury, characterized by β-amyloid precursor protein deposits in the external capsule, was also significantly reduced in rolipramtreated animals. Furthermore, levels of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased with rolipram treatment. These results demonstrate that the cAMP-PKA signaling cascade is downregulated after TBI, and that treatment with a PDE IV inhibitor improves histopathological outcome and decreases inflammation after TBI. Keywordscamp; Fluid-percussion; Inflammation; Interleukin-1β; PKA; Phosphodiesterase; Rolipram; TNF-α; Traumatic brain injury; TBI Traumatic brain injury (TBI) is a prevalent, debilitating health problem, occurring in 1.4 million people each year and disabling 5 million people in the United States (Langlois et al., 2004). The subsequent progressive injury after brain trauma develops from hours to days after the initiating insult, providing an accessible time window for pharmacological therapies. Despite Address correspondence to: W. Dalton Dietrich, Scientific Director, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, P.O. Box 016960, (R-48), Miami, FL 33101, E-mail: ddietrich@miami.edu, Phone: 305-243-2297, Fax: 305-243-3207. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Brain trauma results in contusion formation, neuronal apoptosis, and axonal tract damage. These pathologies are worsened by the inflammatory cascade set into motion by the initial injury (Morganti-Kossmann et al., 2002. Two pro-i...

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Section: Discussionmentioning

confidence: 99%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

137

151

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“…Although, IL-1 receptor protein levels were not measured in the present study, IL-1r1 mRNA levels were still elevated at day 3 post-TBI indicating the potential for continuous upregulation of IL-1 receptor for activation. As previously discussed, therapies including the administration of the endogenous IL-1r1 antagonist have been reported to protect against neuronal injury after FP brain injury (Sanderson et al, 1999, Toulmond andRothwell, 1995), controlled cortical impact injury (Tehranian et al, 2002), and cerebral ischemia (McColl et al, 2007, Relton andRothwell, 1992). These treatment strategies have primarily targeted endogenous sources of IL-1β that have been proposed to increase neuronal vulnerability and worsen behavioral outcome.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the proinflammatory cytokine interleukin-1β (IL-1β) is induced rapidly after TBI (Fassbender et al, 2000, Kinoshita et al, 2002, Taupin et al, 1993, and released by both activated astrocytes and microglia. Previously, strategies that target IL-1β, including the administration of anti-cytokine agents including the naturally-occurring interleukin-1 receptor antagonist (IL-1RA) have been reported to reduce damage caused by TBI (Sanderson et al, 1999, Taupin et al, 1993, Tehranian et al, 2002, Toulmond and Rothwell, 1995.…”

Section: Introductionmentioning

confidence: 99%

Systemic inflammation exacerbates behavioral and histopathological consequences of isolated traumatic brain injury in rats

Utagawa

Truettner

Dietrich

et al. 2008

Experimental Neurology

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The proinflammatory cytokine interleukin-1β (IL-1β) is induced rapidly after traumatic brain injury (TBI) and contributes to the inflammatory events that lead to neuronal loss. Although an important source of IL-1β is from the injured brain itself, in patients with multiple organ trauma (polytrauma) IL-1β is also released into the bloodstream which may potentially influence brain vulnerability. The purpose of this study was to determine the effects of systemic inflammation induced by peripheral administration of IL-1β on histopathological and behavioral outcome after moderate fluid percussion (FP) brain injury in rats. At 30 min or 24 hr after TBI, saline, 20μg/kg or 40μg/kg of IL-1β was injected (n=4-9/group) intraperitoneally (IP). Sham operated animals (n=9) received either saline or IL-1β (20 or 40 μg/kg) injections. The somatosensory tactile placing test was administered at 1, 2 and 3 days posttrauma. IL-1β treated animals showed significant placing deficits compared to vehicle-treated TBI animals. Three days after injection, contusion areas and volumes were significantly increased (p<0.05) with both IL-1β doses and at both treatment times compared to vehicle treated animals. IL-1β treated rats showed more contusion injury and hippocampal neuronal damage as well as enhanced perivascular neutrophil accumulation. Cortical IL-1r1 mRNA increased as early as 1 hr following TBI, peaking at 24 hr and remained elevated 3 days posttrauma. These data show that the posttraumatic administration of IL-1β significantly aggravates behavioral outcome and increases overall contusion volume after TBI. Increased systemic inflammatory processes, including extravasation of activated leukocytes and proinflammatory cytokines could participate in this detrimental outcome. Because peripherally circulating cytokines and other neurotoxic factors may be increased following multi-organ trauma, these findings may be important in targeting therapeutic interventions in this patient population.

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“…Inhibition of IL-1b signaling by central overexpression of an IL-1b-receptor antagonist has a neuroprotective effect, and results in delayed proinflammatory cytokine induction and improved neurological recovery after TBI (Tehranian et al, 2002). After experimental brain trauma, IL-1b is upregulated within hours (Fassbender et al, 2000), and may act synergistically with TNF-a to increase injury (Chao et al, 1995).…”

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confidence: 99%

Minozac Treatment Prevents Increased Seizure Susceptibility in a Mouse “Two-Hit” Model of Closed Skull Traumatic Brain Injury and Electroconvulsive Shock-Induced Seizures

Chrzaszcz

Venkatesan

Dragisic

et al. 2010

Journal of Neurotrauma

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The mechanisms linking traumatic brain injury (TBI) to post-traumatic epilepsy (PTE) are not known and no therapy for prevention of PTE is available. We used a mouse closed-skull midline impact model to test the hypotheses that TBI increases susceptibility to seizures in a ''two-hit'' injury model, and that suppression of cytokine upregulation after the first hit will attenuate the increased susceptibility to the second neurological insult. Adult male CD-1 mice underwent midline closed skull pneumatic impact. At 3 and 6 h after impact or sham procedure, the mice were injected IP with either Minozac (Mzc), a suppressor of proinflammatory cytokine upregulation, or vehicle (saline). On day 7 after sham operation or TBI, seizures were induced using electroconvulsive shock (ECS), and susceptibility to seizures was measured by the current required for seizure induction. Activation of glia, neuronal injury, and metallothionein-immunoreactive cells were quantified in the hippocampus by immunohistochemical methods. Neurobehavioral function over 14-day recovery was quantified using the Barnes maze. Following TBI there was a significant increase in susceptibility to seizures induced by ECS, and this susceptibility was prevented by suppression of cytokine upregulation with Mzc. Astrocyte activation, metallothionein expression, and neurobehavioral impairment were also increased in the two-hit group subjected to combined TBI and ECS. These enhanced responses in the two-hit group were also prevented by suppression of proinflammatory cytokine upregulation with Mzc. These data implicate glial activation in the mechanisms of epileptogenesis after TBI, and identify a potential therapeutic approach to attenuate the delayed neurological sequelae of TBI.

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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

Cited by 145 publications

References 60 publications

Modulation of the cAMP signaling pathway after traumatic brain injury

Modulation of the cAMP signaling pathway after traumatic brain injury

Systemic inflammation exacerbates behavioral and histopathological consequences of isolated traumatic brain injury in rats

Minozac Treatment Prevents Increased Seizure Susceptibility in a Mouse “Two-Hit” Model of Closed Skull Traumatic Brain Injury and Electroconvulsive Shock-Induced Seizures

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