Pyruvate and cilostazol protect cultured rat cortical pericytes against tissue plasminogen activator (tPA)-induced cell death

Kim, Hana; TaeYoun, Kim; Yoon, Young Hee; Koh, Jae‐Young

doi:10.1016/j.brainres.2015.06.022

Cited by 7 publications

(5 citation statements)

References 49 publications

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“…The results suggested that rt-PA significantly decreases pericyte survival and proliferation. A previous study also demonstrated that rt-PA is toxic to pericytes [12]. In addition, our results showed that rt-PA disrupted the integrity of an in vitro coculture model.…”

Section: Discussionsupporting

confidence: 79%

“…TGF-β (3 ng/ml), TPO427736HCL (200 nM), etanercept (40 μg/ml) or rt-PA (50 μg/ml) was administered at the moment of reoxygenation. We used the dosage of rt-PA according to as previously described [12].…”

Section: Methodsmentioning

confidence: 99%

“…Studies have shown that pericytes contribute to the brain inflammatory response by generating cytokines, chemokines and adhesion molecules [9–11]. rt-PA was shown to be toxic to pericytes [12] and can affect the function of pericytes through several mechanisms, such as the detachment of pericytes from astrocytes, a reduction in pericyte coverage of endothelial cells and a reduction in neurotrophic factor secretion [13]. However, few studies have examined the effects of the rt-PA-induced inflammatory response on pericytes.…”

Section: Introductionmentioning

confidence: 99%

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Tissue plasminogen activator disrupts the blood-brain barrier through increasing the inflammatory response mediated by pericytes after cerebral ischemia

Yang

Cai

Yao

et al. 2019

Aging

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Pericytes, important elements of the blood-brain barrier (BBB), play critical roles in maintaining BBB integrity and modulating hemostasis, angiogenesis, inflammation and phagocytic function. We investigated whether pericytes are involved in the recombinant tissue plasminogen activator (rt-PA)-induced inflammatory response, which disrupts the BBB, and investigated the potential mechanisms. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) were employed to mimic hypoxic-ischemic conditions. Rt-PA was intravenously injected into mice 1 h after 1 h MCAO, and Rt-PA was added to the culture medium after 4 h OGD. Rt-PA treatment aggravated the disruption of the BBB compared with hypoxia treatment, and etanercept (TNF-α inhibitor) combined with rt-PA alleviated the rt-PA-induced BBB disruption in vivo and in vitro. Rt-PA treatment increased the TNF-α and MCP-1 levels and decreased the TGF-β, p-Smad2/3 and PDGFR-β levels compared with hypoxia treatment in vivo and vitro. TGF-β combined with rt-PA decreased TNF-α and MCP-1 secretion and alleviated BBB disruption compared with rt-PA; these changes were abrogated by TPO427736 HCL (a TGF-β/p-Smad2/3 pathway inhibitor) cotreatment in vitro. Rt-PA did not decrease TGF-β and p-Smad2/3 expression in PDGFR-β-overexpressing pericytes after OGD. These findings identify PDGFR-β/TGF-β/p-Smad2/3 signaling in pericytes as a new therapeutic target for the treatment of rt-PA-induced BBB damage.

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Section: Discussionsupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tissue plasminogen activator disrupts the blood-brain barrier through increasing the inflammatory response mediated by pericytes after cerebral ischemia

Yang

Cai

Yao

et al. 2019

Aging

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“…Cho et al reported that 40 microM ZnCl 2 incubation for 4 h significantly increased mRNA and protein levels of tPA in brain endothelial cells (Cho et al 2013). Another study showed that free zinc enhanced tPAinduced cell death, which was substantially attenuated by zinc chelator TPEN, suggesting that zinc dyshomeostasis deteriorated tPA toxicity (Kim et al 2015). These studies indicated that zinc might serve as a novel target to regulate tPA level, providing potential treatment for stroke, trauma, and cancer.…”

Section: Increasing Tpa Toxicitymentioning

confidence: 96%

The interaction of zinc and the blood-brain barrier under physiological and ischemic conditions

Liu

2019

Toxicology and Applied Pharmacology

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Zinc is the second most abundant metal in human and serves as an essential trace element in the body. During the past decades, zinc has been found to play important roles in central nervous system, such as the development of neurons and synaptic activities. An imbalance of zinc is associated with brain diseases. The blood-brain barrier (BBB) maintains the homeostasis of the microenvironment, regulating the balance of zinc in the brain. A compromised BBB is the main cause of severe complications in cerebral ischemic patients, such as hemorrhage transformation, inflammation and edema. Recent studies reported that zinc in the brain may be a potential target for integrative protection against ischemic brain injury. Although zinc has long been regarded as important transmitters in central nervous system, the critical role of zinc dyshomeostasis in damage to the BBB has not been fully recognized. In this review, we summarize the role of the BBB in regulating homeostasis of zinc in physiological conditions and the effects of changes in zinc levels on the permeability of the BBB in cerebral ischemia. The integrity of BBB maintains the homeostasis of zinc in pathological conditions, while the balance of zinc in the brain and the circulation maintains the normal function of the BBB. Interrupting the zinc/BBB system will disturb the microenvironment in the brain, leading to pathological diseases. In stroke patients, zinc may serve as a potential target for protecting the BBB and reducing hemorrhage transformation, inflammation and edema.

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“…It may reduce small vessel wall constriction, thereby increasing perfusion and preventing pericyte degeneration and BBB leakage, a mechanism that also has been shown in experimental stroke models [ 69 ]. Cilostazol, a phosphodiesterase type 3 inhibitor (antiplatelet) already in clinical use for obstructive large artery disease, has experimentally shown to reduce pericyte detachment from endothelial cells, promote pericyte proliferation and protect pericytes against apoptosis, thereby maintaining BBB integrity [ 152 , 153 ]. Intracerebroventricular application of recombinant human platelet-derived growth factor β (PDGF-β) has further entered one clinical trial in PD [ 154 ].…”

Section: Targeting Brain Vascular Health To Preserve Microvascular In...mentioning

confidence: 99%

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

Schreiber

Bernal

Ulbrich

et al. 2023

Cells

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Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood–brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology.

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Pyruvate and cilostazol protect cultured rat cortical pericytes against tissue plasminogen activator (tPA)-induced cell death

Cited by 7 publications

References 49 publications

Tissue plasminogen activator disrupts the blood-brain barrier through increasing the inflammatory response mediated by pericytes after cerebral ischemia

Tissue plasminogen activator disrupts the blood-brain barrier through increasing the inflammatory response mediated by pericytes after cerebral ischemia

The interaction of zinc and the blood-brain barrier under physiological and ischemic conditions

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

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