Effects of MAPK inhibitors on cerebral vasospasm in a dog double hemorrhage model

Tibbs, Robert E.; Zubkov, Alexander Y.; Meguro, Toshinari; Badr, Ahmed; Parent, Andrew D.; Zhang, Junyi

doi:10.3171/jns.2000.93.6.1041

Cited by 42 publications

(29 citation statements)

References 18 publications

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“…Many studies have shown involvement of the MAPK signaling pathway in cerebral ischemia (Beg et al, 2006;Henriksson et al, 2007;Tibbs et al, 2000). Interestingly, it is only ERK1/2 and not p38 or JNK that is active during the first 24 hours after experimental SAH, as shown with quantitative Western blot of the proteins in large cerebral arteries and microvessels within the brain tissue proper (Ansar and Edvinsson, 2008).…”

Section: Discussionmentioning

confidence: 99%

Blockade of the MEK/ERK Pathway with a Raf Inhibitor Prevents Activation of Pro-Inflammatory Mediators in Cerebral Arteries and Reduction in Cerebral Blood Flow after Subarachnoid Hemorrhage in a Rat Model

Maddahi

Ansar

Chen

et al. 2010

J Cereb Blood Flow Metab

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Cerebral ischemia that develops after subarachnoid hemorrhage (SAH) carries high morbidity and mortality. Inflammatory mediators are involved in the development of cerebral ischemia through activation of the mitogen-activated protein kinase pathway. We hypothesized that blockade of the MAPkinase/ERK (MEK)/extracellular signal-regulated kinase (ERK) pathway upstream with a specific raf inhibitor would prevent SAH-induced activation of the cerebrovascular inflammatory response. The raf inhibitor SB-386023-b was injected intracisternally in our rat model at 0, 6, or 12 hours after the SAH. After 48 hours, cerebral arteries were harvested, and iNOS, interleukin (IL)-6, IL-1b, matrix metalloproteinase (MMP)-9, tissue inhibitors of metalloproteinase (TIMP)-1, and phosphorylated ERK1/2 were investigated by immunofluorescence, real-time polymerase chain reaction (PCR), and Western blot analysis. Cerebral blood flow (CBF) was measured using autoradiography. Protein levels of MMP-9, TIMP-1, iNOS, IL-6, and IL-1b were increased after SAH, as were mRNA levels of IL-6, MMP-9, and TIMP-1. After SAH, pERK1/2 was increased, but CBF was reduced. Treatment with SB-386023-b at 0 or 6 hours after SAH normalized CBF and prevented SAH-induced upregulation of MMPs, pro-inflammatory cytokines, and pERK1/2 proteins. These results suggested that inhibition of MEK/ERK signal transduction by a specific raf inhibitor administered up to 6 hours after SAH normalized the expression of pro-inflammatory mediators and extracellular matrix-related genes.

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Section: Discussionmentioning

confidence: 99%

Blockade of the MEK/ERK Pathway with a Raf Inhibitor Prevents Activation of Pro-Inflammatory Mediators in Cerebral Arteries and Reduction in Cerebral Blood Flow after Subarachnoid Hemorrhage in a Rat Model

Maddahi

Ansar

Chen

et al. 2010

J Cereb Blood Flow Metab

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“…15 Another study demonstrated that the mitogen-activated protein kinase inhibitor, U0126, improved behavior in dogs, despite the presence of severe aVSP, although the spasm was only moderate (≈50%). 16 This is the reverse of the question at hand. It shows outcome can improve without affecting aVSP.…”

Section: S32 Strokementioning

confidence: 96%

Does Prevention of Vasospasm in Subarachnoid Hemorrhage Improve Clinical Outcome? Yes

Macdonald

2013

Stroke

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“…7,8 We previously examined the effects of MAPK inhibitors such as PD-98059 and U-0126 on cerebral vasospasm in an animal experiment. 9 Although the MAPK inhibitors demonstrated inhibitory effects on cerebral vasospasm after SAH, the inhibitory effects were inadequate. Recently, several authors reported that directly injecting endothelin or heme oxygenase-1 antisense ODN into the subarachnoid space prevented cerebral vasospasm.…”

mentioning

confidence: 99%

Inhibitory Effect With Antisense Mitogen-Activated Protein Kinase Oligodeoxynucleotide Against Cerebral Vasospasm in Rats

Satoh

Parent

Zhang

2002

Stroke

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Background and Purpose-Mitogen-activated protein kinase (MAPK) may be associated with the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). This study aimed to clarify the role of MAPK expression and activation during cerebral vasospasm and to evaluate the therapeutic effect on cerebral vasospasm using an antisense MAPK oligodeoxynucleotide (ODN). Methods-Antisense MAPK, sense MAPK, or scrambled ODN was injected into the rats intracisternally. We used a single-hemorrhage experimental SAH model to assess vasospasm in the basilar arteries at 30 minutes, 1 day, and 2 days after SAH by cross-sectional area measurement and other histological parameters.

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Effects of MAPK inhibitors on cerebral vasospasm in a dog double hemorrhage model

Abstract: The present study is the first in which the effects of MAPK inhibitors on vasospasm have been investigated in vivo. The authors demonstrate that MAPK may play a role in vasospasm and that PD-98059 is a potential candidate for the treatment of cerebral vasospasm.

Cited by 42 publications

References 18 publications

Blockade of the MEK/ERK Pathway with a Raf Inhibitor Prevents Activation of Pro-Inflammatory Mediators in Cerebral Arteries and Reduction in Cerebral Blood Flow after Subarachnoid Hemorrhage in a Rat Model

Blockade of the MEK/ERK Pathway with a Raf Inhibitor Prevents Activation of Pro-Inflammatory Mediators in Cerebral Arteries and Reduction in Cerebral Blood Flow after Subarachnoid Hemorrhage in a Rat Model

Does Prevention of Vasospasm in Subarachnoid Hemorrhage Improve Clinical Outcome? Yes

Inhibitory Effect With Antisense Mitogen-Activated Protein Kinase Oligodeoxynucleotide Against Cerebral Vasospasm in Rats

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