Spatiotemporal Pattern of Neuroinflammation After Impact‐Acceleration Closed Head Injury in the Rat

Rooker, Servan; Jander, Sebastian; Reempts, Jos Van; Stoll, Guido; Jorens, Philippe G.; Borgers, M.; Verlooy, Jan

doi:10.1155/mi/2006/90123

Cited by 19 publications

(14 citation statements)

References 29 publications

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“…However, within seconds of the insult, both NO concentration and cNOS activity decrease significantly and remain suppressed for up to 7 days. At the same time iNOS expression and activity-not detectable under physiological conditions in brain tissue-markedly increase in neurons, macrophages, neutrophils, astrocytes, and oligodendrocytes, reaching a peak 4 to 48 h after trauma (Walker et al, 1997;Wada et al, 1999;Knerlich et al, 1999;Orihara et al, 2001;Cherian and Robertson, 2003;Hlatky et al, 2003;Cherian et al, 2004;Steiner et al, 2004;Rooker et al, 2006). This upregulation of FIG.…”

Section: Terpolilli Et Almentioning

confidence: 99%

The Novel Nitric Oxide Synthase Inhibitor 4-amino-tetrahydro-L-biopterine Prevents Brain Edema Formation and Intracranial Hypertension following Traumatic Brain Injury in Mice

Terpolilli¹,

Zweckberger²,

Trabold³

et al. 2009

Journal of Neurotrauma

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Brain edema formation, resulting in increased intracranial pressure (ICP), is one of the most deleterious consequences of traumatic brain injury (TBI). Nitric oxide (NO) has previously been shown to be involved in the damage of the blood-brain barrier (BBB) and, thus, in the formation of post-traumatic brain edema; however, this knowledge never resulted in a clinically relevant therapeutic option because available NO synthase inhibitors have serious side effects in man. The aim of the current study was to investigate the therapeutic efficacy of VAS203, a novel tetrahydrobiopterine (BH3)-based NOS inhibitor, in experimental TBI. When added to isolated vessels rings obtained from rat basilar and middle cerebral arteries (n = 32-35) VAS203 showed the same vasoconstrictive effect as the classical NO synthase inhibitor L-(G)-nitro-arginine-methylester (L-NAME). VAS203 passed the BBB both in healthy and traumatized mouse brain (C57/BL6, n = 5 per group) and did not show any systemic side effects at therapeutic concentrations. When administered 30 min after experimental TBI (controlled cortical impact, 2.2 mg/kg/min i.v., n = 7 per group), VAS203 prevented any further increase in ICP or deterioration of cerebral blood flow. This effect was dose-dependent and long-lasting (i.e., 24 h after trauma, brain edema formation was still significantly reduced [-40%, p < 0.008; n = 7 per group] and functional improvements were present up to 7 days after TBI [p < 0.02 on post-trauma day 6; n = 8 per group]). Therefore, VAS203 may represent a promising candidate for the treatment of acute intracranial hypertension following TBI.

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Section: Terpolilli Et Almentioning

confidence: 99%

The Novel Nitric Oxide Synthase Inhibitor 4-amino-tetrahydro-L-biopterine Prevents Brain Edema Formation and Intracranial Hypertension following Traumatic Brain Injury in Mice

Terpolilli¹,

Zweckberger²,

Trabold³

et al. 2009

Journal of Neurotrauma

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“…Further studies are needed, with two catheters per patient, in distant and perilesional sites. It has been shown in experimental rodent TBI that rapid induction of inflammatory gene expression, including mRNA for IL-1␤, far exceeded the primary impact site so might contribute to damage at distant sites (Rooker et al, 2006). Monitoring at a "distant" site can thus yield potentially useful information.…”

Section: Figmentioning

confidence: 99%

Inflammation in Human Brain Injury: Intracerebral Concentrations of IL-1α, IL-1β, and Their Endogenous Inhibitor IL-1ra

Hutchinson

O’Connell

Rothwell

et al. 2007

Journal of Neurotrauma

174

109

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Following traumatic brain injury (TBI), cascades of inflammatory processes occur. Laboratory studies implicate the cytokines interleukin-1alpha (IL-1alpha) and IL-1beta in the pathophysiology of TBI and cerebral ischemia, whilst exogenous and endogenous interleukin-1 receptor antagonist (IL-1ra) is neuroprotective. We analyzed IL-1alpha, IL-1beta, and IL-1ra in brain microdialysates (100-kDa membrane) in 15 TBI patients. We also analyzed energy-related molecules (glucose, lactate, pyruvate, glutamate, and the lactate/pyruvate ratio) in these brain microdialysates. Mean of mean (+/-SD) in vitro microdialysis percentage recoveries (extraction efficiencies) were IL-1alpha 19.7+/-7.6%, IL-1beta 23.9+/-10.5%, and IL-1ra 20.9+/-6.3%. In the patients' brain microdialysates, mean of mean cytokine concentrations (not corrected for percentage recovery) were IL-1alpha 5.6+/-14.8 pg/mL, IL-1beta 10.4+/-14.7 pg/mL, and IL-1ra 2796+/-2918 pg/mL. IL-1ra was consistently much higher than IL-1alpha and IL-1beta. There were no significant relationships between IL-1 family cytokines and energy-related molecules. There was a significant correlation between increasing IL-1beta and increasing IL-1ra (Spearman r=0.59, p=0.028). There was also a significant relationship between increasing IL-1ra and decreasing intracranial pressure (Spearman r=-0.57, p=0.041). High concentrations of IL-1ra, and also high IL-1ra/IL-1beta ratio, were associated with better outcome (Mann Whitney, p=0.018 and p=0.0201, respectively), within these 15 patients. It is unclear whether these IL-1ra concentrations are sufficient to antagonize the effects of IL-1beta in vivo. This study demonstrates feasibility of our microdialysis methodology in recovering IL-1 family cytokines for assessing their inter-relationships in the injured human brain, and suggests a neuroprotective role for IL-1ra. It remains to be seen whether exogenous IL-1ra or other agents can be used to manipulate cytokine levels in the brain, for potential therapeutic effect.

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“…Increased ROS in the brain following TBI appears to be linked to NOX up-regulation. Increased O 2 .− can intensify oxidative stress, participate in the inflammation [28], and increase further ROS/RNS production [14,26,32,33]. Elevated ROS/RNS can cause mitochondrial dysfunction and ultimately neuronal degeneration [34-36].…”

Section: Introductionmentioning

confidence: 99%

A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma

Ansari

Roberts

Scheff

2014

Free Radical Biology and Medicine

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Nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase; NOX) is a complex enzyme responsible for increased levels of reactive oxygen species (ROS), superoxide (O2.−). NOX derived O2.− is a key player in oxidative stress and inflammation mediated multiple secondary injury cascades (SIC) following traumatic brain injury (TBI). The O2.− reacts with nitric oxide (NO), produces various reactive nitrogen species (RNS), and contributes to apoptotic cell death. Following a unilateral cortical contusion, young adult rats were killed at various times post injury (1, 3, 6, 12, 24, 48, 72, and 96 h). Fresh tissue from the hippocampus was analyzed for NOX activity, and level of O2.−. In addition we evaluated the translocation of cytosolic NOX proteins (p67Phox, p47Phox and p40Phox) to the membrane, along with total NO and the activation (phosphorylation) of endothelial nitric oxide synthase (p-eNOS). Results show that both enzymes and levels of O2.− and NO have time dependent injury effects in the hippocampus. Translocation of cytosolic NOX proteins into membrane, NOX activity and O2.− were also increased in a time dependent fashion. Both, NOX activity and O2.− were increased at 6 h. Levels of p-eNOS increased within 1 h, with significant elevation of NO at 12 h post TBI. Levels of NO failed to show a significant association with p-eNOS, but did associate with O2.−. NOX up-regulation strongly associated with both the levels of O2.− and also total NO. The initial 12 hours post TBI are very important as a possible window of opportunity to interrupt SIC. It may be important to selectively target the translocation of cytosolic subunits for the modulation of NOX function.

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Spatiotemporal Pattern of Neuroinflammation After Impact‐Acceleration Closed Head Injury in the Rat

Cited by 19 publications

References 29 publications

The Novel Nitric Oxide Synthase Inhibitor 4-amino-tetrahydro-L-biopterine Prevents Brain Edema Formation and Intracranial Hypertension following Traumatic Brain Injury in Mice

The Novel Nitric Oxide Synthase Inhibitor 4-amino-tetrahydro-L-biopterine Prevents Brain Edema Formation and Intracranial Hypertension following Traumatic Brain Injury in Mice

Inflammation in Human Brain Injury: Intracerebral Concentrations of IL-1α, IL-1β, and Their Endogenous Inhibitor IL-1ra

A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma

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