Immunoproteasome modulates NLRP3 inflammasome‐mediated neuroinflammation under cerebral ischaemia and reperfusion conditions

Background and Objective: Hydroxysafflor yellow A (HSYA) was reported to suppress inflammation in ischaemic microglia. However, the mechanism through which HSYA inhibits inflammation caused by cerebral ischaemia and reperfusion injury remains unknown. Here, we have mimicked acute cerebral ischaemia and reperfusion injury by subjecting male Sprague-Dawley rats to transient middle cerebral artery occlusion for 90 minutes and have demonstrated that toll-like receptor 9 (TLR9) was upregulated from day 3 after reperfusion, accompanied by the persistent activation of the pro-inflammatory nuclear factor-κB (NF-κB) pathway from 6 hours to day 7. HSYA was injected intraperitoneally at a dose of 6 mg/kg per day, which activated TLR9 in microglia of ischaemic cortex at 6 hours after reperfusion and then obviously suppressed the NF-κB pathway from day 1 to day 7. Meanwhile, HSYA also activated the anti-inflammatory pathway through interferon regulatory factor 3 from day 1 to day 3. The anti-inflammatory effect of HSYA was partially reversed by TLR9-siRNA interference in primary microglia, which was stimulated by oxygen-glucose deprivation and reoxygenation treatment. The regulation of TLR9-mediated inflammation by HSYA was consistent with the recovery of neurological deficits in rats. Conclusion: Therefore, our findings support that HSYA exerts anti-inflammatory effects by reprogramming the TLR9 signalling pathway during treatment of acute cerebral ischaemia and reperfusion injury.

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Electroacupuncture Pre-treatment Exerts an Anti-apoptotic Effect in Cerebral Ischaemia and Reperfusion Injury in Rats

Acupuncture & Electro-Therapeutics Research ◽

10.3727/036012921x16237619666067 ◽

2021 ◽

Author(s):

Zhu Luwen ◽

Ye Tao ◽

Tang Qiang, ◽

Yan Wang ◽

Li Hongyu ◽

...

Keyword(s):

Cerebral Ischaemia ◽

Neurological Deficits ◽

Tunel Staining ◽

Caspase 9 ◽

Brain Infarct ◽

Severity Scores ◽

Ischaemia And Reperfusion ◽

Apoptotic Effect ◽

Cyt C ◽

Pre Treatment

Background: Electroacupuncture (EA) pre-treatment can play a significant neuroprotective role in rats with cerebral ischaemia and reperfusion (CIR) injury, but the specific mechanism needs to be further elucidated. Objective: To investigate the effects of EA pre-treatment on apoptosis-related proteins Bax, Bcl-2, Cytochrome c (cyt c), cleaved caspase-9 and -3 in rats with CIR injury. Methods: CIR injury was induced using middle cerebral artery occlusion (MCAO) ischaemia-reperfusion. Thirty-six male Specific Pathogen Free (SPF) Sprague-Dawley rats were randomly divided into three groups: Sham (n=12), MCAO (n=12), and the EA+MCAO group (n=12). EA+MCAO group rats received electroacupuncture at DU20 for 2 consecutive weeks before MCAO model preparation. After 24 h of reperfusion, neurological deficits were evaluated by modified neurological severity scores. Brain infarct volumes were examined by 2,3,5-triphenyltetrazolium chloride staining. Expression of Bax, Bcl-2, cyt c, cleaved caspase-9 and -3 in the ischaemic penumbra were detected by Western blotting, and apoptosis evaluated by TUNEL staining. Results: After perfusion for 24 h, compared with the MCAO group, the neurological deficit scores and brain infarct volumes in the EA+MCAO group were significantly decreased (P<0.05), as was the level of Bax (P<0.05) or the Bax/Bcl-2 ratio (P<0.05), levels of cyt c, cleaved caspase-9 and -3 also decreased (P<0.05), like the number of TUNEL-positive cells (P<0.05), in contrast, the level of Bcl-2 increased (P<0.05). Conclusion: EA pre-treatment exerts an anti-apoptotic effect through Bax-to-Bcl-2 ratio downregulation, blockage of mitochondrial cyt c release to the cytosol, and reduction of caspase-9 and -3 expression in rats with CIR injury.

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Exogenous nitric oxide negatively regulates the S-nitrosylation p38 mitogen-activated protein kinase activation during cerebral ischaemia and reperfusion

Neuropathology and Applied Neurobiology ◽

10.1111/j.1365-2990.2012.01284.x ◽

2013 ◽

Vol 39 (3) ◽

pp. 284-297 ◽

Cited By ~ 14

Author(s):

S. H. Qi ◽

L. Y. Hao ◽

J. Yue ◽

Y. Y. Zong ◽

G. Y. Zhang

Keyword(s):

Nitric Oxide ◽

Protein Kinase ◽

Cerebral Ischaemia ◽

Mitogen Activated Protein Kinase ◽

Kinase Activation ◽

Protein Kinase Activation ◽

Ischaemia And Reperfusion ◽

Mitogen Activated Protein ◽

Exogenous Nitric Oxide

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GlyT1 Inhibitor NFPS Exerts Neuroprotection via GlyR Alpha1 Subunit in the Rat Model of Transient Focal Cerebral Ischaemia and Reperfusion

Cellular Physiology and Biochemistry ◽

10.1159/000445556 ◽

2016 ◽

Vol 38 (5) ◽

pp. 1952-1962 ◽

Cited By ~ 1

Author(s):

Baosheng Huang ◽

Qingsong Xie ◽

Xiaocheng Lu ◽

Tengda Qian ◽

Shuai Li ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Rat Model ◽

Cerebral Ischaemia ◽

Artery Occlusion ◽

High Dose ◽

Focal Cerebral Ischaemia ◽

Ischaemia And Reperfusion ◽

Cerebral Artery Occlusion

Background/Aims: Glycine is a strychnine-sensitive inhibitory neurotransmitter in the central nervous system (CNS), especially in the spinal cord, brainstem, and retina. The objective of the present study was to investigate the potential neuroprotective effects of GlyT1 inhibitor N [3-(4'-fluorophenyl)-3-(4'-phenylphenoxy) propyl] sarcosine (NFPS) in the rat model of experimental stroke. Methods: In vivo ischaemia was induced by transient middle cerebral artery occlusion (tMCAO). The methods of Western Blotting, Nissl Staining and Morris water maze methods were applied to analyze the anti-ischaemia mechanism. Results: The results showed that high dose of NFPS (H-NFPS) significantly reduced infarct volume, neuronal injury and the expression of cleaved caspase-3, enhanced Bcl-2/Bax, and improved spatial learning deficits which were administered three hours after transient middle cerebral artery occlusion (tMCAO) induction in rats, while, low dose of NFPS (L-NFPS) exacerbated the injury of ischaemia. These findings suggested that low and high dose of NFPS produced opposite effects. Importantly, it was demonstrated that H-NFPS-dependent neuronal protection was inverted by salicylate (Sal), a specific GlyR ɑ1 antagonist. Such effects could probably be attributed to the enhanced glycine level in both synaptic and extrasynaptic clefts and the subsequently altered extrasynaptic GlyRs and their subtypes. Conclusions: These data imply that GlyT1 inhibitor NFPS may be a novel target for clinical treatment of transient focal cerebral ischaemia and reperfusion which are associated with altered GlyR alpha 1 subunits.

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