Cerebral Ischemia-Reperfusion Injury Treatment [Neurosurgery Wiki]

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====== Cerebral Ischemia-Reperfusion Injury Treatment ======

{{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/1BgfKQ37f-6cWcd2KHOO6Q3-PWAUUg2pb-GbxwkfX1tahgm55D/?limit=15&utm_campaign=pubmed-2&fc=20231129025453}}

Ischemia [[reperfusion]] injury has been treated using several therapeutic gases, including hydrogen (H2), hydrogen sulfide (H2S), NO, and carbon monoxide (CO)
((Nakao A, Kaczorowski DJ, Sugimoto R, Billiar TR, McCurry KR. Application of heme oxygenase‐1, carbon monoxide and biliverdin for the prevention of intestinal ischemia/reperfusion injury. J. Clin. Biochem. Nutr. 2008; 42: 78–8.))
((Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J. Cell Mol. Med. 2006; 10: 650–71.))
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[[Calcium]] influx into [[neuron]]s triggers [[neuronal death]] during [[cerebral ischemia-reperfusion injury]]. Various [[calcium channel]]s are involved in cerebral ischemia/reperfusion injury. [[Cav3.2 channel]] is a main subtype of T-type calcium channels. T-type calcium channel blockers, such as [[pimozide]] and [[mibefradil]], have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury. However, the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear. In vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons. The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons. We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury. Cav3.2 knockout markedly reduced infarct volume and brain water content, and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury. Additionally, Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress, inflammatory response, and neuronal apoptosis. In the hippocampus of Cav3.2-knockout mice, calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury. These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling. Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury
((Dai F, Hu C, Li X, Zhang Z, Wang H, Zhou W, Wang J, Geng Q, Dong Y, Tang C. [[Cav3.2 channel]] regulates cerebral ischemia/reperfusion injury: a promising target for intervention. Neural Regen Res. 2024 Nov 1;19(11):2480-2487. doi: 10.4103/1673-5374.390966. Epub 2023 Dec 15. PMID: 38526284.))

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A previous study showed that [[D-allose]] exerted neuroprotective effects against acute [[cerebral ischemia-reperfusion injury]] by reducing neuroinflammation. 
Luo et al. aimed to clarify the beneficial effects D-allose in suppressing IS-induced neuroinflammation damage, [[cytotoxicity]], neuronal apoptosis and neurological deficits and the underlying mechanism in vitro and in vivo.

In vivo, an I/R model was induced by middle cerebral artery occlusion and [[reperfusion]] (MCAO/R) in C57BL/6 N mice, and D-allose was given by intraperitoneal injection within 5 min after reperfusion. In vitro, mouse hippocampal neuronal cells (HT-22) with oxygen-glucose deprivation and reperfusion (OGD/R) were established as a cell model of IS. Neurological scores, some cytokines, cytotoxicity and apoptosis in the brain and cell lines were measured. Moreover, Gal-3 short hairpin RNAs, lentiviruses and adeno-associated viruses were used to modulate Gal-3 expression in neurons in vitro and in vivo to reveal the molecular mechanism.

D-allose alleviated cytotoxicity, including cell viability, LDH release and apoptosis, in HT-22 cells after OGD/R, which also alleviated brain injury, as indicated by lesion volume, brain edema, neuronal apoptosis, and neurological functional deficits, in a mouse model of I/R. Moreover, D-allose decreased the release of inflammatory factors, such as IL-1β, IL-6 and TNF-α. Furthermore, the expression of Gal-3 was increased by I/R in wild-type mice and HT-22 cells, and this factor further bound to TLR4, as confirmed by three-dimensional structure prediction and Co-IP. Silencing the Gal-3 gene with shRNAs decreased the activation of TLR4 signaling and alleviated IS-induced neuroinflammation, apoptosis and brain injury. Importantly, the loss of Gal-3 enhanced the D-allose-mediated protection against I/R-induced HT-22 cell injury, inflammatory insults and apoptosis, whereas activation of TLR4 by the selective agonist LPS increased the degree of neuronal injury and abolished the protective effects of D-allose.

In summary, D-allose plays a crucial role in inhibiting inflammation after IS by suppressing Gal-3/TLR4/PI3K/AKT signaling pathway in vitro and in vivo
((Luo Y, Cheng J, Fu Y, Zhang M, Gou M, Li J, Li X, Bai J, Zhou Y, Zhang L, Gao D. D-allose Inhibits TLR4/PI3K/AKT Signaling to Attenuate Neuroinflammation and Neuronal Apoptosis by Inhibiting Gal-3 Following Ischemic Stroke. Biol Proced Online. 2023 Nov 28;25(1):30. doi: 10.1186/s12575-023-00224-z. PMID: 38017376.)).
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[[Caspase-1]] was found to play a vital role in regulating inflammation pathways and pyroptosis in many inflammation-associated diseases, especially in cerebral ischemia-reperfusion injury. Not only that, Caspase-1 inhibitors have been shown to reduce the damage of cerebral ischemia-reperfusion injury by inhibiting inflammation and pyroptosis. And the Caspase-1 inhibitor, Belnacasan, has been proved to modify the active site of Caspase-1 and lead to the blocking of Caspase-1, thus correlating with tissue protection of inflammatory diseases in animal models. Therefore, it's essential to screen and design potential [[Caspase-1 inhibitor]]s to reduce cerebral ischemia-reperfusion injury and protect brain function by reducing inflammation and pyroptosis, which provides a new idea for clinical treatment of the cerebral ischemia-reperfusion injury. This study applied a group of computer-aided technology, such as Discovery Studio 4.5, Schrodinger, and PyMol, to screen and assess potential Caspase-1 inhibitors. Moreover, the ADME (absorption, distribution, metabolism, excretion) and TOPKAT (Toxicity Prediction by Computer Assisted Technology) molecules of Discovery Studio 4.5 were conducted to evaluate molecules' pharmacological and toxicological features. Then, precise molecular docking was applied to assess the binding mechanism and affinity between Caspase-1 and selected compounds. Besides, molecular dynamics simulations were performed to determine the stability of ligand-receptor complexes in the natural environment. In summary, this study lists promising drug candidates and their pharmacological properties, promoting the development of Caspase-1 inhibitors and deepening the understanding of the interaction between inhibitors and Caspase-1
((Li H, Guo Z, Chen J, Du Z, Lu H, Wang Z, Xi J, Bai Y. Computational research of Belnacasan and new Caspase-1 inhibitor on cerebral ischemia reperfusion injury. Aging (Albany NY). 2022 Feb 22;14(undefined). doi: 10.18632/aging.203907. Epub ahead of print. PMID: 35193116.)).
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The purpose of a study was to further explore the specific [[cerebral ischemia pathogenesis]] by studying the role of [[p53]] in cerebral ischemia-reperfusion injury and its mechanism to provide a new target for the [[cerebral ischemia treatment]].

[[Middle cerebral artery occlusion]] (MCAo) was established in [[rat]]s. The changes in [[p53]] and apoptotic proteins in the [[rat model]] were detected by quantitative [[real-time polymerase chain reaction]] (qRT-PCR) and [[Western blot]]. The effects of [[p53 inhibition]] on cerebral ischemia-reperfusion injury in rats were evaluated by modified neurological severity score (mNSS) and [[infarct]] area. Subsequently, [[neural stem cell]]s (NSCs) were isolated and cultured in vitro, and oxygen and glucose deprivation (OGD) was induced to establish an in vitro ischemia-reperfusion injury model. Cell viability and migration were detected by CCK-8 and transwell assays. Apoptosis of NSCs was detected by flow cytometry. Finally, protein expression in the Wnt pathway activated by p53 was detected by Western blotting.

Compared with the sham group, p53 levels, mNSS, cerebral infarction area, and apoptosis were significantly increased in the MCAo group (p < 0.05). When the p53 inhibitor PFT-α was injected, the increase in these levels was reversed. Also, the viability and migration of cells decreased and apo-ptosis increased in the in vitro OGD model, whereas the viability, migration, and apoptosis were significantly reversed after the addition of p53 inhibitors (p < 0.05). Finally, p53 induced Wnt signaling pathway proteins β-catenin and cyclin D1 decrease in the MCAo group, while p53 inhibitors reversed their inhibitory effect on the Wnt signaling pathway.

They confirmed in vivo and in vitro that inhibition of p53 has a protective effect on the cerebral ischemia-reperfusion injury, which may be related to the activation of the [[Wnt signaling pathway]]
((Liu Y, Wu X, Du D, Liu J, Zhang W, Gao Y, Zhang H. p53 Inhibition Provides a Pivotal Protective Effect against Cerebral Ischemia-Reperfusion Injury via the Wnt Signaling Pathway. Cerebrovasc Dis. 2021 Aug 2:1-9. doi: 10.1159/000516889. Epub ahead of print. PMID: 34340236.)).
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The aim of a study of Zhao et al. from the Department of Neurosurgery, [[People's Liberation Army General Hospital]], No. 5 Nanmencang Hutong, Dongcheng District, [[Beijing]], was to explore whether cerebral IR injury is modulated by Nur77 via modification of mitochondrial homeostasis. Our results indicated that Nur77 was upregulated in reperfused brain tissues. Genetic ablation of Nur77 reduced infarction area and promoted neuron survival under IR burden. Biochemical analysis demonstrated that Nur77 deletion protected mitochondrial function, attenuated mitochondrial oxidative stress, preserved mitochondrial potential, and blocked mitochondria-related cell apoptosis. In addition, we illustrated that Nur77 mediated mitochondrial damage via evoking mitochondrial fragmentation that occurred through increased mitochondrial fission and decreased fusion. Besides, this results also demonstrated that Nur77 controlled mitochondrial fragmentation via upregulating [[INF2]] in a manner dependent on the Wnt/β-catenin pathway; inhibition of the Wnt pathway abrogated the protective effect of Nur77 deletion on reperfused-mediated neurons. Altogether, this study highlights that the pathogenesis of cerebral IR injury is associated with Nur77 activation followed by augmented mitochondrial fragmentation via an abnormal Wnt/β-catenin/INF2 pathway. Accordingly, Nur77-dependent mitochondrial fragmentation and the Wnt/β-catenin/INF2 axis may represent novel therapeutic targets to reduce cerebral IR injury
((Zhao H, Pan W, Chen L, Luo Y, Xu R. Nur77 promotes cerebral
ischemia-reperfusion injury via activating INF2-mediated mitochondrial
fragmentation. J Mol Histol. 2018 Oct 8. doi: 10.1007/s10735-018-9798-8. [Epub
ahead of print] PubMed PMID: 30298449.
)).
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Xu et al. provided data indicating that gradual flow restoration (GFR) would be superior to rapid flow restoration (RFR) in alleviating cerebral IRIs in middle cerebral artery occlusion (MCAO) rats. A total of 94 MCAO rats with 15, 30 and 60-minute occlusion were randomly assigned to receive either GFR or RFR intervention. There were significant differences between GFR and RFR group in mean neurological severity score (1.02 versus 1.28; p < 0.05), median infarct ratio (0.016 versus 0.12; p < 0.001), median neuronal apoptosis ratio (1.81 versus 14.46; p < 0.001), and mean histopathological abnormality score (0.92 versus 1.66; p < 0.001). In addition, these differences were mainly distributed in 30-minute and 60-minute occlusion rats, not in 15-minute occlusion rats. These results indicated that GFR rather than RFR could effectively alleviate cerebral IRIs in MCAO rats, especially in rats with longer occlusion duration, suggesting that GFR may be particularly applicable to AOMIA patients who are presented to neurointerventionalists in the later-time of recanalization therapy window
((Xu WW, Zhang YY, Su J, Liu AF, Wang K, Li C, Liu YE, Zhang YQ, Lv J, Jiang WJ.
Ischemia Reperfusion Injury after Gradual versus Rapid Flow Restoration for
Middle Cerebral Artery Occlusion Rats. Sci Rep. 2018 Jan 26;8(1):1638. doi:
10.1038/s41598-018-20095-9. PubMed PMID: 29374244.
)).
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Post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin (LEH), can reduce I/R injury through reducing the effect of MMP-9, most likely produced by neutrophils. This therapeutic strategy may be a promising candidate to prevent I/R injury after thrombolysis and/or thromboectomy
((Shimbo D, Abumiya T, Shichinohe H, Nakayama N, Kazumata K, Houkin K.
Post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin can
reduce ischemia reperfusion injury. Brain Res. 2014 Jan 30. pii:
S0006-8993(14)00105-X. doi: 10.1016/j.brainres.2014.01.038. [Epub ahead of print]
PubMed PMID: 24486612.)).
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[[Chrysin]] prevents brain damage caused by global [[cerebral ischemia]]/[[reperfusion injury]] in a C57BL/J6 mouse model
((Durak MA, Öztanır MN, Başak Türkmen N, Çiftçi O, Taşlıdere A, Tecellioğlu M,
Önder A. Chrysin prevents brain damage caused by global
cerebralischemia/reperfusion in a C57BL/J6 mouse model. Turk J Med Sci. 2016 Dec 
20;46(6):1926-1933. doi: 10.3906/sag-1508-119. PubMed PMID: 28081349.
)).

====== Calenduloside E ======

[[Calenduloside E]]