Pharmacological therapy of acute ischaemic stroke: Achievements and problems

Moretti, Antonio; Ferrari, Francesca; Villa, R. F.

doi:10.1016/j.pharmthera.2015.06.004

Cited by 45 publications

(29 citation statements)

References 168 publications

(121 reference statements)

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“…The use of a selective ROCK-2 inhibitor such as KD025 together with rt-PA strengthens all cellular layers of the BBB (unlike nonselective ROCK inhibitors which are less efficient in BECs) and may therefore effectively reduce sICH with minimal hypotensive side effects. Since intravenous thrombolysis with rt-PA is likely to remain a mainstay in AIS owing to its relative simplicity and proven cost versus benefit profile [1], such an outcome may greatly impact the limited number of treated stroke patients.…”

Section: Discussionmentioning

confidence: 99%

“…Thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) continues to serve as the primary treatment option for acute ischaemic stroke (AIS) within a confining therapeutic window of 3–4.5 h from stroke onset [1, 2]. Other major limitations, such as poor efficacy for large clots and large vessel occlusions as well as increased risk for development of lethal symptomatic intracerebral haemorrhage (sICH) [2, 3] translate into a low percentage (≤10%) of eligible patients and fuel ongoing search for therapeutic improvement [1, 2].…”

Section: Introductionmentioning

confidence: 99%

“…Other major limitations, such as poor efficacy for large clots and large vessel occlusions as well as increased risk for development of lethal symptomatic intracerebral haemorrhage (sICH) [2, 3] translate into a low percentage (≤10%) of eligible patients and fuel ongoing search for therapeutic improvement [1, 2]. More than a decade of research has indicated that rt-PA also has off-target effects in neurons, glia [4, 5], but especially at the blood-brain barrier (BBB) [6], where it compromises BBB integrity in a variety of plasmin-dependent and independent mechanisms [7, 8].…”

Section: Introductionmentioning

confidence: 99%

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Selective inhibition of brain endothelial Rho-kinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin

et al. 2017

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Rho-kinase (ROCK) inhibition, broadly utilised in cardiovascular disease, may protect the blood-brain barrier (BBB) during thrombolysis from rt-PA-induced damage. While the use of nonselective ROCK inhibitors like fasudil together with rt-PA may be hindered by possible hypotensive side-effects and inadequate capacity to block detrimental rt-PA activity in brain endothelial cells (BECs), selective ROCK-2 inhibition may overcome these limitations. Here, we examined ROCK-2 expression in major brain cells and compared the ability of fasudil and KD025, a selective ROCK-2 inhibitor, to attenuate rt-PA-induced BBB impairment in an in vitro human model. ROCK-2 was highly expressed relative to ROCK-1 in all human and mouse brain cell types and particularly enriched in rodent brain endothelial cells and astrocytes compared to neurons. KD025 was more potent than fasudil in attenuation of rt-PA- and plasminogen-induced BBB permeation under normoxia, but especially under stroke-like conditions. Importantly, only KD025, but not fasudil, was able to block rt-PA-dependent permeability increases, morphology changes and tight junction degradation in isolated BECs. Selective ROCK-2 inhibition further diminished rt-PA-triggered myosin phosphorylation, shape alterations and matrix metalloprotease activation in astrocytes. These findings highlight ROCK-2 as the key isoform driving BBB impairment and brain endothelial damage by rt-PA and the potential of KD025 to optimally protect the BBB during thrombolysis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective inhibition of brain endothelial Rho-kinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin

et al. 2017

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“…It is estimated that 15 million people worldwide have a stroke each year and nearly six million die and another five million are left permanently disabled 1. Intravenous tissue plasminogen activator (IV-rtPA) has been proven to be effective but the narrow therapeutic time window restricts its clinical application to no more than 10% of AIS patients 2. Meanwhile, IV-rtPA has a low recanalization rate (13% to 50%) for large brain vessel occlusion 3…”

Section: Introductionmentioning

confidence: 99%

No inferiority of Tonbridge thrombectomy device for acute thrombus retrial compared with Solitaire device: an experimental evaluation with a canine distal external carotid-maxillary artery occlusion model

Zhou

Lü

et al. 2018

J NeuroIntervent Surg

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“…The mechanisms of neuronal death in stroke are complex; involving cell membrane depolarization, free radical generation, excitotoxicity, and neuroinflammation (Dirnagl et al, 1999; Moskowitz et al, 2010). Despite extensive efforts, therapeutic strategies focusing on the pathological signaling cascades have not been successful (Moretti et al, 2015). Effective treatments for ischemic brain damage remain one of the major unfulfilled medical needs of clinical care (Fisher and Saver, 2015).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Histone Deacetylase 3 (HDAC3) Mediates Ischemic Preconditioning and Protects Cortical Neurons against Ischemia in Rats

Yang

Zhang

et al. 2016

Front. Mol. Neurosci.

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Brain ischemic preconditioning (PC) provides vital insights into the endogenous protection against stroke. Genomic and epigenetic responses to PC condition the brain into a state of ischemic tolerance. Notably, PC induces the elevation of histone acetylation, consistent with evidence that histone deacetylase (HDAC) inhibitors protect the brain from ischemic injury. However, less is known about the specific roles of HDACs in this process. HDAC3 has been implicated in several neurodegenerative conditions. Deletion of HDAC3 confers protection against neurotoxicity and neuronal injury. Here, we hypothesized that inhibition of HDAC3 may contribute to the neuronal survival elicited by PC. To address this notion, PC and transient middle cerebral artery occlusion (MCAO) were conducted in Sprague-Dawley rats. Additionally, primary cultured cortical neurons were used to identify the modulators and effectors of HDAC3 involved in PC. We found that nuclear localization of HDAC3 was significantly reduced following PC in vivo and in vitro. Treatment with the HDAC3-specific inhibitor, RGFP966, mimicked the neuroprotective effects of PC 24 h and 7 days after MCAO, causing a reduced infarct volume and less Fluoro-Jade C staining. Improved functional outcomes were observed in the neurological score and rotarod test. We further showed that attenuated recruitment of HDAC3 to promoter regions following PC potentiates transcriptional initiation of genes including Hspa1a, Bcl2l1, and Prdx2, which may underlie the mechanism of protection. In addition, PC-activated calpains were implicated in the cleavage of HDAC3. Pretreatment with calpeptin blockaded the attenuated nuclear distribution of HDAC3 and the protective effect of PC in vivo. Collectively, these results demonstrate that the inhibition of HDAC3 preconditions the brain against ischemic insults, indicating a new approach to evoke endogenous protection against stroke.

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Pharmacological therapy of acute ischaemic stroke: Achievements and problems

Cited by 45 publications

References 168 publications

Selective inhibition of brain endothelial Rho-kinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin

Selective inhibition of brain endothelial Rho-kinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin

No inferiority of Tonbridge thrombectomy device for acute thrombus retrial compared with Solitaire device: an experimental evaluation with a canine distal external carotid-maxillary artery occlusion model

Inhibition of Histone Deacetylase 3 (HDAC3) Mediates Ischemic Preconditioning and Protects Cortical Neurons against Ischemia in Rats

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