Ac-YVAD-CMK Decreases Blood–Brain Barrier Degradation by Inhibiting Caspase-1 Activation of Interleukin-1β in Intracerebral Hemorrhage Mouse Model

Bi-hua, WU; Ma, Qingyi; Khatibi, Nikan H.; Chen, Wanqiu; Sozen, Takumi; Cheng, Oumei; Tang, Jiping

doi:10.1007/s12975-009-0002-z

Cited by 78 publications

(71 citation statements)

References 15 publications

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“…For example, ischaemic brain injury is markedly reduced in IL-1α/β-deficient (–/–) mice [11,12], a selective IL-1β antibody reduces ischaemic damage after transient middle cerebral artery occlusion (MCAo) in rat [13], and caspase-1 inhibitors (which prevent IL-1 processing and release) reduce brain damage in focal cerebral ischaemia [14,15,16]. Similarly, caspase-1 inhibitors are protective in experimental models of subarachnoid haemorrhage (SAH), and prevent neurogenic pulmonary oedema after SAH [17,18]. Inhibition of the neuronal NLRP1 inflammasome (which is involved in the processing and release of IL-1 through the activation of caspase-1) improves outcome after stroke, traumatic or spinal cord injury [19,20,21].…”

Section: Il-1 and Acute Brain Injurymentioning

confidence: 99%

Interleukin-1 and Stroke: Biomarker, Harbinger of Damage, and Therapeutic Target

Pinteaux¹,

Rothwell²,

Allan³

2011

Cerebrovasc Dis

102

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Inflammation is established as a contributor to cerebrovascular disease. Risk factors for stroke include many conditions associated with chronic or acute inflammation, and inflammatory changes in the brain after cerebrovascular events contribute to outcome in experimental studies, with growing evidence from clinical research. The brain is extremely susceptible to inflammatory challenge, but resident glia, endothelial cells and neurones can all mount a pronounced inflammatory response to infection or injury. Recent discoveries highlight the importance of peripherally-derived immune cells and inflammatory molecules in various central nervous system disorders, including stroke. The inflammatory cytokine, interleukin-1 (IL-1), plays a pivotal role in both local and systemic inflammation, and is a key driver of peripheral and central immune responses to infection or injury. Inhibition of IL-1 has beneficial effects in a variety of experimental paradigms of acute brain injury and is a promising clinical target in stroke. We propose that blockade of IL-1 could be therapeutically useful in several diseases which are risk factors for stroke, and there is already considerable pre-clinical and clinical evidence that inhibition of IL-1 by IL-1 receptor antagonist may be valuable in the management of acute stroke.

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Section: Il-1 and Acute Brain Injurymentioning

confidence: 99%

Interleukin-1 and Stroke: Biomarker, Harbinger of Damage, and Therapeutic Target

Pinteaux¹,

Rothwell²,

Allan³

2011

Cerebrovasc Dis

102

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“…6 Our previous work has shown that the inhibition of caspase-1, the converting enzyme of active IL-1 β , reduced ICH induced brain injury. 7 However, how IL-1 β is processed following ICH remains unclear.…”

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confidence: 99%

NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage

Chen

et al. 2014

Annals of Neurology

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235

222

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Objective The NLRP3 (NALP3, cryopyrin) inflammasome, a key component of the innate immune system, facilitates caspase-1 and interleukin (IL)–1β processing, which amplifies the inflammatory response. Here, we investigated whether NLRP3 knockdown decreases neutrophil infiltration, reduces brain edema, and improves neurological function in an intracerebral hemorrhage (ICH) mouse model. We also determined whether mitochondrial reactive oxygen species (ROS) governed by mitochondrial permeability transition pores (mPTPs) would trigger NLRP3 inflammasome activation following ICH. Methods ICH was induced by injecting autologous arterial blood (30μl) into a mouse brain. NLRP3 small interfering RNAs were administered 24 hours before ICH. A mPTP inhibitor (TRO-19622) or a specific mitochondria ROS scavenger (Mito-TEMPO) was coinjected with the blood. In naive animals, rotenone, which is a respiration chain complex I inhibitor, was applied to induce mitochondrial ROS production, and followed by TRO-19622 or Mito-TEMPO treatment. Neurological deficits, brain edema, enzyme-linked immunosorbent assay, Western blot, in vivo chemical cross-linking, ROS assay, and immunofluorescence were evaluated. Results ICH activated the NLRP3 inflammasome. NLRP3 knockdown reduced brain edema and decreased myeloper-oxidase (MPO) levels at 24 hours, and improved neurological functions from 24 to 72 hours following ICH. TRO-19622 or Mito-TEMPO reduced ROS, NLRP3 inflammasome components, and MPO levels following ICH. In naive animals, rotenone administration induced mPTP formation, ROS generation, and NLRP3 inflammasome activation, which were then reduced by TRO-19622 or Mito-TEMPO. Interpretation The NLRP3 inflammasome amplified the inflammatory response by releasing IL-1β and promoting neutrophil infiltration following ICH. Mitochondria ROS may be a major trigger of NLRP3 inflammasome activation. The results of our study suggest that the inhibition of the NLRP3 inflammasome may effectively reduce the inflammatory response following ICH.

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“…Zymography MMP-9 activity was measured by gelatin zymography as previously described (Chen et al, 2009;Tsubokawa et al, 2006;Wu et al, 2010). The rats were euthanized at 24 h post-SAH (n = 5, respectively), and transcardially perfused with chilled (4°C) PBS, pH 7.4.…”

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confidence: 99%

Minocycline Improves Functional Outcomes, Memory Deficits, and Histopathology after Endovascular Perforation-Induced Subarachnoid Hemorrhage in Rats

Sherchan

Lekic

Suzuki

et al. 2011

Journal of Neurotrauma

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Subarachnoid hemorrhage (SAH) results in significant long-lasting cognitive dysfunction. Therefore, evaluating acute and long-term outcomes after therapeutic intervention is important for clinical translation. The aim of this study was to use minocycline, a known neuroprotectant agent, to evaluate the long-term benefits in terms of neurobehavior and neuropathology after experimental SAH in rats, and to determine which neurobehavioral test would be effective for long-term evaluation. SAH was induced by endovascular perforation in adult male Sprague-Dawley rats (n=118). The animals were treated with intraperitoneal injection of minocycline (45 mg/kg or 135 mg/kg) or vehicle 1 h after SAH induction. In the short-term, animals were euthanized at 24 and 72 h for evaluation of neurobehavior, brain water content, and matrix metalloproteinase (MMP) activity. In the long-term, neurobehavior was evaluated at days 21-28 post-SAH, and histopathological analysis was done at day 28. High-dose but not low-dose minocycline reduced brain water content at 24 h, and therefore only the high-dose regimen was used for further evaluation, which reduced MMP-9 activity at 24 h. Further, high-dose minocycline improved spatial memory and attenuated neuronal loss in the hippocampus and cortex. The rotarod, T-maze, and water maze tests, but not the inclined plane test, detected neurobehavioral deficits in SAH rats at days 21-28. This study demonstrates that minocycline attenuates long-term functional and morphological outcomes after endovascular perforation-induced SAH. Long-term neurobehavioral assessments using the rotarod, T-maze, and water maze tests could be useful to evaluate the efficacy of therapeutic intervention after experimental SAH.

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Ac-YVAD-CMK Decreases Blood–Brain Barrier Degradation by Inhibiting Caspase-1 Activation of Interleukin-1β in Intracerebral Hemorrhage Mouse Model

Cited by 78 publications

References 15 publications

Interleukin-1 and Stroke: Biomarker, Harbinger of Damage, and Therapeutic Target

Interleukin-1 and Stroke: Biomarker, Harbinger of Damage, and Therapeutic Target

NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage

Minocycline Improves Functional Outcomes, Memory Deficits, and Histopathology after Endovascular Perforation-Induced Subarachnoid Hemorrhage in Rats

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