Protective Effect of Ultra Low Molecular Weight Heparin on Glutamate-Induced Apoptosis in Cortical Cells

Yu, Tian; Zhang, Qing Zhu; Zhang, Zhi Guo; Wang, Wei Wei; Ji, Sheng Li; Du, Guan Hua

doi:10.3349/ymj.2008.49.3.486

Cited by 6 publications

(3 citation statements)

References 46 publications

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“…Explant-induced apoptosis of glomerular cells was similarly protected by acute treatment with heparin in vitro (42), and we speculate that this early damage may also be attributable to matrix detachment. Furthermore, ultra-low-molecular weight heparin has been reported to prevent glutamate-induced apoptosis in brain cortical cells in vitro and to prevent free radical-induced damage after ischemia/reperfusion injury in rat brain in vivo (43,44). Our demonstration that HS replacement by heparin rescued β cells from free radical damage and apoptosis in vitro is consistent with these prior reports and with the notion that islets/β cells in situ express exceptionally high levels of endogenous HS in order to execute similar prosurvival functions in vivo.…”

Section: Figurementioning

confidence: 99%

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

Ziolkowski

Popp²,

Freeman³

et al. 2012

J. Clin. Invest.

145

200

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The autoimmune type 1 diabetes (T1D) that arises spontaneously in NOD mice is considered to be a model of T1D in humans. It is characterized by the invasion of pancreatic islets by mononuclear cells (MNCs), which ultimately leads to destruction of insulin-producing β cells. Although T cell dependent, the molecular mechanisms triggering β cell death have not been fully elucidated. Here, we report that a glycosaminoglycan, heparan sulfate (HS), is expressed at extraordinarily high levels within mouse islets and is essential for β cell survival. In vitro, β cells rapidly lost their HS and died. β Cell death was prevented by HS replacement, a treatment that also rendered the β cells resistant to damage from ROS. In vivo, autoimmune destruction of islets in NOD mice was associated with production of catalytically active heparanase, an HS-degrading enzyme, by islet-infiltrating MNCs and loss of islet HS. Furthermore, in vivo treatment with the heparanase inhibitor PI-88 preserved intraislet HS and protected NOD mice from T1D. Our results identified HS as a critical molecular requirement for islet β cell survival and HS degradation as a mechanism for β cell destruction. Our findings suggest that preservation of islet HS could be a therapeutic strategy for preventing T1D.

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Section: Figurementioning

confidence: 99%

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

Ziolkowski

Popp²,

Freeman³

et al. 2012

J. Clin. Invest.

145

200

View full text Add to dashboard Cite

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“…Furthermore, LMWH has the ability to regulate cellular apoptosis (Yu et al. 2008). LMWH reduces leucocyte recruitment at the site of injury or inflammatory stimuli through the downregulation of the expression of cytokines, tumour necrosis factor (TNF)-α, endotoxins, human leukocyte elastase (HLE), and heparinase (Lever and Page 2012).…”

Section: Introductionmentioning

confidence: 99%

Investigation of the protective effect of heparin pre-treatment on cerebral ischaemia in gerbils

Ye¹,

Hai²,

Liu³

et al. 2019

Pharmaceutical Biology

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Context: The interruption of cerebral blood circulation may cause stroke characterized by high neurological deficits (NDs) as a result of neuronal dysfunction or destruction. Heparin may exert a neuroprotective effect against cerebral ischaemia/reperfusion injury. Objective: The objective of this study was to investigate the mechanism underlying the effects of heparin pre-treatment on cerebral injury in the gerbil. Materials and methods: A total of 80 healthy Mongolian gerbils were randomly divided into four groups to establish cerebral ischaemia model by bilateral carotid artery occlusion: control (no anaesthesia and surgery), sham (no occlusion), non-anticoagulation (occlusion), and anti-coagulation treatment groups (50 IU/100 g heparin pre-treated, occlusion). Gerbils were anesthetized with 40 mg/kg pentobarbital sodium through intraperitoneal injection before operation except for the control group. Then, the ND and histopathological damage (HD) scores were determined. The percentage of tumour necrosis factor (TNF)-α- and interleukin (IL)-1β-positive cells were calculated based on immunohistochemical results. The mRNA and protein levels of caspase-9, caspase-8, FasL, and calpain were evaluated with real-time polymerase chain reaction (RT-PCR) and western blotting, respectively. Results: Compared with non-anticoagulation group, heparin pre-treatment (50 IU/100 g) delayed the onset of dyspnoea ( p < 0.05), and showed a significant decrease in ND ( p < 0.01), mortality rate ( p < 0.05), HD ( p < 0.01) and percentage of positive cells for TNF-α, IL-1β ( p < 0.01) in cerebral ischaemia gerbils. Besides, the expression levels of caspase-9, caspase-8, FasL, and calpain were reduced after pre-treatment with 50 IU/100 g heparin. Discussion and conclusions: The damage caused to gerbil brain was reduced upon pre-treatment with heparin, possibly through the amelioration of neuronal cell apoptosis and expression of TNF-α and IL-1β. These findings are expected to provide a new breakthrough in the study and treatment of cerebral ischaemia.

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“…ULMWH can obviously reduce Aβ25-35-induced neurotoxic effects and might act as a potential agent for Alzheimer’s disease [2]. ULMWH can also antagonize glutamate-induced apoptosis in cortical cells through a decrease of Ca 2+ release and modulation of apoptotic processes [3]. Our previous study [4] showed the beneficial effects of ULMWH on ischemia-reperfusion injury in rats by decreasing infarct, reducing the neurologic deficit, inhibiting Ca 2+ accumulation, decreasing MDA content and increasing SOD activity in ischemic brain.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effects of Ultra-Low-Molecular-Weight Heparin on Cerebral Ischemia/Reperfusion Injury in Rats: Involvement of Apoptosis, Inflammatory Reaction and Energy Metabolism

Zhang

Sun

Zhang

et al. 2013

IJMS

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Previous experiments showed that ultra-low-molecular-weight heparin (ULMWH) reduced the infarct and neurologic deficit in rats followed by transient cerebral ischemia, but the mechanisms of its neuroprotective effect are unclear. This study reported the effect of ULMWH on energy metabolism, inflammatory reaction and neuronal apoptosis. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. ULMWH (0.5, 1 mg/kg, i.v.) was administered after the MCAO and reperfusion. 24 h after the reperfusion, Spectrophotometric assay was used to determine the activity of ATPase and the content of lactic acid in the brain. The ICAM-1 and Caspase-3 genes were investigated by RT-PCR. Furthermore, the apoptotic percentage of cells in hippocampus was quantified by flow cytometry. Compared with the model group, ULMWH significantly decreased lactic acid content and increased ATPase activity in ischemic brain. At the same time, ULMWH inhibited the neural apoptosis and decreased the expressions of ICAM-1 and Caspase-3 mRNA in hippocampus. These findings suggest that ULMWH exhibits a neuroprotective effect against cerebral ischemia/reperfusion injury, partly through improving energy metabolism, inhibiting apoptosis and attenuating inflammatory reaction.

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Protective Effect of Ultra Low Molecular Weight Heparin on Glutamate-Induced Apoptosis in Cortical Cells

Cited by 6 publications

References 46 publications

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

Investigation of the protective effect of heparin pre-treatment on cerebral ischaemia in gerbils

Neuroprotective Effects of Ultra-Low-Molecular-Weight Heparin on Cerebral Ischemia/Reperfusion Injury in Rats: Involvement of Apoptosis, Inflammatory Reaction and Energy Metabolism

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