Simvastatin reduces secondary brain injury caused by cortical contusion in rats: Possible involvement of TLR4/NF-κB pathway

Chen, Gang; Zhang, Shiming; Shi, Jinjie; Ai, Jinglu; Qi, Meng; Hang, Chun-Hua

doi:10.1016/j.expneurol.2008.12.019

Cited by 122 publications

(80 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…16,18,19 In cultures of human BBB endothelia, lovastatin and simvastatin were shown to decrease the translocation of both albumin and sucrose, but not normal leukocytes. 20 Microglia (i.e., the resident immune cells of the brain) are implicated in the secretion of glutamate, reactive oxygen species, and other inflammatory mediators, which may exacerbate cerebral edema and secondary neuronal injury.…”

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 97%

“…Recently, the toll-like receptor (TLR) 4 pathway has been proposed as the mechanism by which these mediators cause inflammation after TBI. 16 TLR4 is activated by molecular products of injury, including heat-shock proteins, 17 intracellular molecules from ruptured cells, and products of cell degradation or proteolysis. TLR agonism is associated with nuclear translocation of nuclear factor-B, a transcription factor that is associated with the upregulation of inflammatory mediators, including IL-1␤, TNF-␣, IL-6, and intracellular adhesion molecule-1 (ICAM-1).…”

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 99%

“…TLR agonism is associated with nuclear translocation of nuclear factor-B, a transcription factor that is associated with the upregulation of inflammatory mediators, including IL-1␤, TNF-␣, IL-6, and intracellular adhesion molecule-1 (ICAM-1). 16 In a rat TBI model, simvastatin, given after cortical contusion, decreased both the mRNA and protein expressions of TLR4 and nuclear factor-B. 16 In both pre-injury and post-injury treatment models, animal studies have demonstrated that statin treatment decreases IL-1␤, 9,16 TNF-␣, 9,10,16 IL-6, 10,16 and ICAM-1 16 levels in the acute or subacute period after traumatic injury.…”

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 99%

“…16 In a rat TBI model, simvastatin, given after cortical contusion, decreased both the mRNA and protein expressions of TLR4 and nuclear factor-B. 16 In both pre-injury and post-injury treatment models, animal studies have demonstrated that statin treatment decreases IL-1␤, 9,16 TNF-␣, 9,10,16 IL-6, 10,16 and ICAM-1 16 levels in the acute or subacute period after traumatic injury.…”

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 99%

“…The palliative effect of statins most likely represents a class effect. Preclinical studies of TBI have used mostly atorvastatin 10 -12,41,43,44,61 and simvastatin, 10,16,19,45,46,59,64,86 which are relatively lipophilic, and therefore have better BBB penetration. 87 Hydrophilic statins have minimal penetration across the BBB.…”

Section: Clinical Trial Designs For Statins In Tbimentioning

confidence: 99%

See 4 more Smart Citations

Statins in Traumatic Brain Injury

Wible

Laskowitz

2010

Neurotherapeutics

View full text Add to dashboard Cite

Summary: Traumatic brain injury (TBI) is a common cause of long-term neurological morbidity, with devastating personal and societal consequences. At present, no pharmacological intervention clearly improves outcomes, and therefore a compelling unmet clinical need remains. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or "statins," offer a potential novel therapeutic strategy for TBI. Statins are well tolerated, easy to administer, and have a long clinical track record in critically ill patients. Their side effects are well defined and easily monitored. Preclinical studies have shown significant benefit of statins in models of TBI and related disease processes, including cerebral ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage. In fact, multiple mechanisms have been defined by which statins may exert benefit after acute brain injury. Statins are currently positioned to be translated into clinical trials in acute brain injury and have the potential to improve outcomes after TBI.

show abstract

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 97%

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 99%

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 99%

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 99%

Section: Clinical Trial Designs For Statins In Tbimentioning

confidence: 99%

See 3 more Smart Citations

Statins in Traumatic Brain Injury

Wible

Laskowitz

2010

Neurotherapeutics

View full text Add to dashboard Cite

show abstract

Role of the Nrf2‐ARE pathway in early brain injury after experimental subarachnoid hemorrhage

Chen

Fang

Zhang

et al. 2011

J of Neuroscience Research

Self Cite

121

100

View full text Add to dashboard Cite

The nuclear factor erythroid 2-related factor 2 and antioxidant-response element (Nrf2-ARE) pathway is a key regulator for modulating inflammation and oxidative damage, which are involved in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have demonstrated that Nrf2-ARE pathway play neural protective roles in traumatic brain injury, cerebral ischemia, and intracerebral hemorrhage models; however, it has not been investigated whether, and to what degree, the Nrf2-ARE pathway is induced by SAH, and the role of the Nrf2-ARE pathway in development of EBI following SAH remains unknown. Experiment 1 sought to investigate the time course of Nrf2-ARE activation in the cortex in the early stage of SAH. In experiment 2, we assessed the effect of sulforaphane (SUL; a specific Nrf2 activator) on regulation of the Nrf2-ARE pathway in the SAH model and evaluated the impact of SUL on EBI after SAH. The rat SAH model was used injection of 0.3 ml fresh arterial, nonheparinized blood into the prechiasmatic cistern over 20 sec. As a result, Nrf2 and its target gene product, heme oxygenase-1 (HO-1), were up-regulated in the cortex after SAH and peaked at 24 hr post-SAH. After intraperitoneal SUL administration, the elevated expression of Nrf2-ARE-related factors such as Nrf2, HO-1, NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutathione S-transferase-α1 (GST-α1) was detected in the cortex at 48 hr following blood injection. In the SUL-treated group, early brain damage such as brain edema, blood-brain barrier (BBB) impairment, cortical apoptosis, and motor deficits was significantly ameliorated compared with vehicle-treated SAH rats. Our results suggest that the Nrf2-ARE pathway is activated in the brain after SAH, playing a beneficial role in EBI development, possibly through inhibiting cerebral oxidative stress by inducing antioxidant and detoxifying enzymes.

show abstract

A cannabinoid type 2 receptor agonist attenuates blood–brain barrier damage and neurodegeneration in a murine model of traumatic brain injury

Amenta

Jallo

Tuma

et al. 2012

J of Neuroscience Research

View full text Add to dashboard Cite

After traumatic brain injury (TBI), inflammation participates in both the secondary injury cascades and the repair of the CNS, both of which are influenced by the endocannabinoid system. This study determined the effects of repeated treatment with a cannabinoid type 2 receptor (CB(2) R) agonist on blood-brain barrier integrity, neuronal degeneration, and behavioral outcome in mice with TBI. We also looked for the presence of a prolonged treatment effect on the macrophage/microglial response to injury. C57BL/6 mice underwent controlled cortical impact (CCI) and received repeated treatments with a CB(2) R agonist, 0-1966, or vehicle. After euthanasia at 6 hr or 1, 2, 3, or 7 days postinjury, brains were removed for histochemical analysis. Blood-brain barrier permeability changes were evaluated by using sodium fluorescein (NaF). Perilesional degenerating neurons, injury volumes, and macrophage/microglia cells were quantified by stereological methods. Rota-rod and open-field testing were performed to evaluate motor function and natural exploratory behavior in mice. 0-1966 Treatment resulted in a significant reduction in NaF uptake and number of degenerating neurons compared with the vehicle-treated group. 0-1966-Treated mice demonstrated improvement on rota-rod and open-field testing compared with vehicle-treated mice. These changes in CCI mice treated with 0-1966 were associated with a prolonged reduction in macrophage/microglia cell counts. In conclusion, repeated treatments with a CB(2) R agonist, 0-1966, result in attenuated blood-brain barrier disruption and neuronal degeneration. In addition, repeated treatment with 0-1966 shows prolonged treatment effects on behavior and the macrophage/microglia cell response over several days.

show abstract

Simvastatin reduces secondary brain injury caused by cortical contusion in rats: Possible involvement of TLR4/NF-κB pathway

Cited by 122 publications

References 44 publications

Statins in Traumatic Brain Injury

Statins in Traumatic Brain Injury

Role of the Nrf2‐ARE pathway in early brain injury after experimental subarachnoid hemorrhage

A cannabinoid type 2 receptor agonist attenuates blood–brain barrier damage and neurodegeneration in a murine model of traumatic brain injury

Contact Info

Product

Resources

About