Role of Elevated Thrombospondin-1 in Kainic Acid-Induced Status Epilepticus

Zhang, Yurong; Zhang, Mengdi; Zhu, Wei; Pan, Xiaohong; Wang, Qiaoyun; Xue, Guanhua; Wang, Chaoyun; Zhang, Xiuli; Liu, Yuxia; Li, Shucui; Sun, Hongliu

doi:10.1007/s12264-019-00437-x

Cited by 13 publications

(9 citation statements)

References 51 publications

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“…On the one hand, microglial activation could lead to Müller gliosis due to microglia‐Müller cell crosstalk, and theoretically, the inhibition of microglia activation could down‐regulated GFAP expression after treatment with THBS‐1 in the blue light‐exposed retina. However, on the other hand, the latest study has reported that THBS‐1 could up‐regulate the GFAP expression (Y. Zhang, Zhang, et al, 2020). In our study, GFAP expression was not significantly affected in blue light‐exposed retina with THBS‐1 treatment, but the underlying mechanism needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Protection against light‐induced retinal degeneration via dual anti‐inflammatory and anti‐angiogenic functions of thrombospondin‐1

Tang

Dai

et al. 2020

British J Pharmacology

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Background and Purpose Retinal photodamage is a high‐risk factor for age‐related macular degeneration (AMD), the leading cause of irreversible blindness worldwide. However, both the pathogenesis and effective therapies for retinal photodamage are still unclear and debated. Experimental Approach The anti‐inflammatory effects of thrombospondin‐1 on blue light‐induced inflammation in ARPE‐19 cells and in retinal inflammation were evaluated. Furthermore, the anti‐angiogenic effects of thrombospondin‐1 on human microvascular endothelial cells (hMEC‐1 cells) and a laser‐induced choroidal neovascularisation (CNV) mouse model were evaluated. in vitro experiments, including western blotting, immunocytochemistry, migration assays and tube formation assays, as well as in vivo experiments, including immunofluorescence, visual electrophysiology, spectral‐domain optical coherence tomography, and fluorescein angiography, were employed to evaluate the anti‐inflammatory and anti‐angiogenic effects of thrombospondin‐1. Key Results Specific effects of blue light‐induced retinal inflammation and pathological angiogenesis were reflected by up‐regulation of pro‐inflammatory factors and activation of angiogenic responses, predominantly regulated by the NF‐κB and VEGFR2 pathways respectively. During the blue light‐induced pathological progress, THBS‐1 derived from retinal pigment epithelium down‐regulated proteomics and biological assays. Thrombospondin‐1 treatment also suppressed inflammatory infiltration and neovascular leakage. The protective effect of Thrombospondin‐1 was additionally demonstrated by a substantial rescue of visual function. Mechanistically, thrombospondin‐1 reversed blue light‐induced retinal inflammation and angiogenesis by blocking the activated NF‐κB and VEGFR2 pathways, respectively. Conclusion and Implications Thrombospondin‐1, with dual anti‐inflammatory and anti‐neovascularisation properties, is a promising agent for protection against blue light‐induced retinal damage and retinal degenerative disorders which are pathologically associated with inflammatory and angiogenic progress. LINKED ARTICLES This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc

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Section: Discussionmentioning

confidence: 99%

Protection against light‐induced retinal degeneration via dual anti‐inflammatory and anti‐angiogenic functions of thrombospondin‐1

Tang

Dai

et al. 2020

British J Pharmacology

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“…To evaluate the effects of TSP-1, siRNA targeting TSP-1 [ 78 ] was synthesized by Tuoran Biological Technology (Shanghai, China) with the sequences: 5’-GCCAGUAUGUUUACAACGUdTdT-3’ and 5’-ACGUUGUAAACAUACUGGCdTdT-3’; negative control (siRNA-NC), 5’-UUCUCCGAACGUGUCACGUTT-3’, and 5’-ACGUGACACGUUCGGAGAATT-3’.…”

Section: Methodsmentioning

confidence: 99%

Increased thrombospondin-1 levels contribute to epileptic susceptibility in neonatal hyperthermia without seizures via altered synaptogenesis

Zhai,

Cheng,

Yuan

et al. 2024

Cell Death Discov.

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Childhood febrile seizures (FS) represent one of the most common types of seizures and may lead to severe neurological damage and an increased risk of epilepsy. However, most children with fevers do not show clinical manifestations of convulsions, and the consequences of hyperthermia without seizures remain elusive. This study focused on hyperthermia not reaching the individual’s seizure threshold (sub-FS stimulus). Changes in thrombospondin-1 (TSP-1) levels, synapses, seizure susceptibility, and seizure severity in subsequent FS were investigated in rats exposed to sub-FS stimuli. Pharmacological and genetic interventions were used to explore the role of TSP-1 in sub-FS-induced effects. We found that after sub-FS stimuli, the levels of TSP-1 and synapses, especially excitatory synapses, were concomitantly increased, with increased epilepsy and FS susceptibility. Moreover, more severe neuronal damage was found in subsequent FS. These changes were temperature dependent. Reducing TSP-1 levels by genetic intervention or inhibiting the activation of transforming growth factor-β1 (TGF-β1) by Leu-Ser-Lys-Leu (LSKL) led to lower synapse/excitatory synapse levels, decreased epileptic susceptibility, and attenuated neuronal injury after FS stimuli. Our study confirmed that even without seizures, hyperthermia may promote synaptogenesis, increase epileptic and FS susceptibility, and lead to more severe neuronal damage by subsequent FS. Inhibition of the TSP-1/TGF-β1 pathway may be a new therapeutic target to prevent detrimental sub-FS sequelae.

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“…The rats were anesthetized using sodium pentobarbital (50 mg/kg, intraperitoneal injection, CAS, 57-33-0, Xiya Reagent, China) and fixed on a stereotactic apparatus (Anhui Zheng Hua Biological Instrument Equipment Company Limited, China). As previously described (Zhang et al, 2020a ), stainless steel cannulas (Reward, China) were implanted into the right lateral cerebral ventricle (AP: −1.8 mm, ML: −0.96 mm, and DV: −3.8 mm). The rats were allowed 7 days for recovery.…”

Section: Methodsmentioning

confidence: 99%

Xenon Exerts Neuroprotective Effects on Kainic Acid-Induced Acute Generalized Seizures in Rats via Increased Autophagy

Zhu

Zhao³

et al. 2020

Front. Cell. Neurosci.

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Xenon has been shown to have neuroprotective effects and is clinically used as a favorable safe inhalation anesthetic. We previously confirmed the neuroprotective effects of xenon treatment in epileptic animals. However, the mechanism underlying these protective effects remains unclear. We aimed to assess the effects of xenon inhalation on autophagy in neuronal injury induced by acute generalized seizures. Kainic acid (KA) was injected into the lateral ventricle of male Sprague–Dawley rats to induce acute generalized seizures. Next, the rats were treated via inhalation of a 70% xenon/21% oxygen/9% nitrogen mixture for 60 min immediately after KA administration. The control group was treated via inhalation of a 79% nitrogen/21% oxygen mixture. Subsequently, two inhibitors (3-methyladenine or bafilomycin A 1 ) or an autophagy inducer (rapamycin) were administered, respectively, before KA and xenon administration to determine the role of autophagy in the protective effects of xenon. The levels of apoptosis, neuronal injury, and autophagy were determined in all the rats. Xenon inhalation significantly attenuated the severity of the seizure-induced neuronal injury. Increased autophagy accompanied this inhibitive effect. Autophagy inhibition eliminated these xenon neuroprotective effects. A simulation of autophagy using rapamycin recapitulated xenon’s protective effects on KA-induced acute generalized seizures in the rats. These findings confirmed that xenon exerts strong neuroprotective effects in KA-induced acute generalized seizures. Further, they indicate that increased autophagy may underlie the protective effects of xenon. Therefore, xenon and autophagy inducers may be useful clinical options for their neuroprotective effects in epileptic seizures.

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Role of Elevated Thrombospondin-1 in Kainic Acid-Induced Status Epilepticus

Cited by 13 publications

References 51 publications

Protection against light‐induced retinal degeneration via dual anti‐inflammatory and anti‐angiogenic functions of thrombospondin‐1

Protection against light‐induced retinal degeneration via dual anti‐inflammatory and anti‐angiogenic functions of thrombospondin‐1

Increased thrombospondin-1 levels contribute to epileptic susceptibility in neonatal hyperthermia without seizures via altered synaptogenesis

Xenon Exerts Neuroprotective Effects on Kainic Acid-Induced Acute Generalized Seizures in Rats via Increased Autophagy

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