Development and external validation of a dynamic nomogram for delayed cerebral ischaemia after aneurysmal subarachnoid hemorrhage: a study protocol for a multicentre retrospective cohort study

IntroductionDelayed cerebral ischaemia (DCI) caused by aneurysmal subarachnoid haemorrhage (aSAH) is the most frequent complication and typically contributes to poor neurological outcome or deterioration of patients’ condition. Therefore, early accurate and effective prediction of DCI is urgently needed. This study aims to construct a dynamic nomogram for precisely calculating the risk of DCI in patients with aSAH. Internal validation of this tool is conducted using the training cohort, and independent external validation is completed by using other medical centre datasets.Methods and analysisThis study is a multicentre, retrospective, observational cohort study using data from patients with aSAH. The participants include all adult patients who received surgical treatment in neurosurgery of multiple medical centres from 1 September 2019 to 1 April 2021, including Renmin Hospital of Wuhan University, Huzhou Central Hospital, First Affiliated Hospital of Harbin Medical University, General Hospital of Northern Theatre Command and Affiliated Hospital of Panzhihua University. Clinical information is collected via the electronic medical record system, including demographic data, clinical state on admission and serum laboratory tests. Modified Fisher grade at admission, admission subarachnoid clot and cerebral oedema density, and residual postoperative subarachnoid clot density are determined using the electronic imagine record software. The primary outcome is DCI.Ethics and disseminationThis study protocol was reviewed and approved by the Medical Ethics Committee of Renmin Hospital of Wuhan University, which is the principal affiliation of this study (approval number: WDRM2021-K022). The other Ethics Committees, including Huzhou Central Hospital (approval number: 202108005–01), First Affiliated Hospital of Harbin Medical University (approval number: H202156), General Hospital of Northern Theater Command (approval number: Y2021060) and Affiliated Hospital of Panzhihua University (approval number: 202105002), also approved the protocol. The results of this research will be published in a peer-reviewed medical journal.Trial registration numberChiCTR2100044448.

Yiqi Dingxuan Yin improves cerebral ischaemic injury in rats by inhibiting apoptosis and promoting angiogenesis

Background Clinically, Yiqi Dingxuan Yin promotes nerve function recovery and improves nerve function defect symptoms; however, the underlying molecular pathways remain unknown. In this study, we established a rat model of cerebral ischaemia induced by middle cerebral artery occlusion (MCAO). The effects of Yiqi Dingxuan Yin on the neurological function and local neuron morphology were compared with those of butylphthalide, which is used to treat ischemic stroke, and the possible mechanisms of action were explored. Methods Of 97 healthy adult male Sprague‒Dawley rats, 20 were randomly assigned to the sham operation group. The remaining rats underwent MCAO. Model generation was successful in 60 rats, which were randomly divided into a model group, butylphthalide group, and Yiqi Dingxuan Yin group (n = 20/group) administered distilled water, butylphthalide capsule, and Yiqi Dingxuan Yin, respectively. Zea-Longa scores were used to assess the neurological function of the rats at 1, 3, 7, and 14 days. Haematoxylin and eosin staining of brain sections was used to observe morphological changes in the rat hippocampus. Apoptosis of nerve cells was detected using TUNEL staining. The expression levels of erythropoietin/erythropoietin receptor (EPO/EPOR), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor/tyrosine receptor kinase B (BDNF/TrkB) protein in the ischaemic brain tissue were detected using immunohistochemistry. Results The apoptosis rate, and EPO/EPOR, VEGF, and BDNF/TrkB expression levels were higher in the model group than in the sham operation group (P < 0.05). Among MCAO groups, the nerve function deficit score and cell apoptosis rate were lower (P < 0.05), whereas the EPO/EPOR, VEGF, and BDNF/TrkB protein expression levels were higher (P < 0.05) in both the butylphthalide and Yiqi Dingxuan Yin groups than in the model group. Conclusions Yiqi Dingxuan Yin can improve the neural function and morphology of neurons after cerebral ischaemia injury in rats, with a more significant effect at 14 days. This may be related to the upregulation of EPO/EPOR, VEGF, and BDNF/TrkB protein expression, which may promote angiogenesis to improve cerebral blood flow and oxygen supply, thereby protecting the form and function of neurons and promoting the restoration of impaired neural function.

Beneficial Effect of Sodium Nitrite on EEG Ischaemic Markers in Patients with Subarachnoid Haemorrhage

Subarachnoid haemorrhage (SAH) is associated with long-term disability, serious reduction in quality of life and significant mortality. Early brain injury (EBI) refers to the pathological changes in cerebral metabolism and blood flow that happen in the first few days after ictus and may lead on to delayed cerebral ischaemia (DCI). A disruption of the nitric oxide (NO) pathway is hypothesised as a key mechanism underlying EBI. A decrease in the alpha-delta power ratio (ADR) of the electroencephalogram has been related to cerebral ischaemia. In an experimental medicine study, we tested the hypothesis that intravenous sodium nitrite, an NO donor, would lead to increases in ADR. We studied 33 patients with acute aneurysmal SAH in the EBI phase. Participants were randomised to either sodium nitrite or saline infusion for 1 h. EEG measurements were taken before the start of and during the infusion. Twenty-eight patients did not develop DCI and five patients developed DCI. In the patients who did not develop DCI, we found an increase in ADR during sodium nitrite versus saline infusion. In the five patients who developed DCI, we did not observe a consistent pattern of ADR changes. We suggest that ADR power changes in response to nitrite infusion reflect a NO-mediated reduction in cerebral ischaemia and increase in perfusion, adding further evidence to the role of the NO pathway in EBI after SAH. Our findings provide the basis for future clinical trials employing NO donors after SAH.

The emerging possibility of the use of geniposide in the treatment of cerebral diseases: a review

With the advanced discoveries in the field of pathogenesis, a series of cerebral diseases, such as cerebral ischaemia, Alzheimer's disease, and depression, have been found to have multiple signalling targets in the microenvironment. Only a few existing agents have been shown to have curative effects due to this specific circumstance. In recent decades, active ingredients isolated from natural plants have been shown to be crucial for original drug development. Geniposide, mainly extracted from Gardenia jasminoides Ellis, is representative of these natural products. Geniposide demonstrates various biological activities in the treatment of cerebral, cardiovascular, hepatic, tumorous, and other diseases. The multiple protective effects of geniposide on the brain have especially drawn increasing attention. Thus, this article specifically reviews the characteristics of current models of cerebral ischaemia and illustrates the possible effects of geniposide and its pathogenetic mechanisms on these models. Geniposide has been shown to significantly reduce the area of cerebral infarction and alleviate neuronal damage and necrosis mainly by inhibiting inflammatory signals, including NLRP3, TNF-α, IL-6, and IL-1β. Neuronal protection was also involved in activating the PI3K/Akt and Wnt/catenin pathways. Geniposide was able to increase autophagy and inhibit apoptosis by regulating the function of mTOR in treating Alzheimer's disease. Geniposide has also been shown to act as a glucagon-like peptide-1 receptor (GLP-1R) agonist to reduce amyloid plaques and inhibit oxidative stress to alleviate memory impairment as well as synaptic loss. Moreover, geniposide has been shown to exert antidepressant effects primarily by regulating the hypothalamic–pituitary–adrenal (HPA) axis. Detailed explorations have shown that the biological activities of inhibiting inflammatory cytokine secretion, alleviating oxidative stress, and suppressing mitochondrial damage are also involved in the mechanism of action of geniposide. Therefore, geniposide is a promising agent awaiting further exploration for the treatment of cerebral diseases via various phenotypes or signalling pathways.