A nomogram for predicting the risk of poor prognosis in patients with poor-grade aneurysmal subarachnoid hemorrhage following microsurgical clipping.

Objective: Aneurysmal subarachnoid hemorrhage (aSAH) is a common and potentially fatal cerebrovascular disease. Poor-grade aSAH (Hunt-Hess grades IV and V) accounts for 20-30% of patients with aSAH, with most patients having a poor prognosis. This study aimed to develop a stable nomogram model for predicting adverse outcomes at 6 months in patients with aSAH, and thus, aid in improving the prognosis. Method: The clinical data and imaging findings of 150 patients with poor-grade aSAH treated with microsurgical clipping of intracranial aneurysms on admission from December 2015 to October 2021 were retrospectively analyzed. Least absolute shrinkage and selection operator (LASSO), logistic regression analyses, and a nomogram were used to develop the prognostic models. Receiver operating characteristic (ROC) curves and Hosmer-Lemeshow tests were used to assess discrimination and calibration. The bootstrap method (1,000 repetitions) was used for internal validation. Decision curve analysis (DCA) was performed to evaluate the clinical validity of the nomogram model. Result: LASSO regression analysis showed that age, Hunt-Hess grade, Glasgow Coma Scale (GCS), aneurysm size, and refractory hyperpyrexia were potential predictors for poor-grade aSAH. Logistic regression analyses revealed that age (OR: 1.107, 95% CI: 1.056-1.116, P < 0.001), Hunt-Hess grade (OR: 8.832, 95% CI: 2.312-33.736, P = 0.001), aneurysm size (OR: 6.871, 95% CI: 1.907-24.754, P = 0.003) and refractory fever (OR: 3.610, 95% CI: 1.301-10.018, P < 0.001) were independent predictors of poor outcome. The area under the ROC curve (AUC) was 0.909. The calibration curve and Hosmer-Lemeshow tests showed that the nomogram had good calibration ability. Furthermore, the DCA curve showed better clinical utilization of the nomogram. Conclusion: This study provides a reliable and valuable nomogram that can accurately predict the risk of poor prognosis in patients with poor-grade aSAH after microsurgical clipping. This tool is easy to use and can help physicians make appropriate clinical decisions to significantly improve patient prognosis.

Sirtuin-3: A potential target for treating several types of brain injury.

Sirtuin-3 (SIRT3) is responsible for maintaining mitochondrial homeostasis by deacetylating substrates in an NAD+-dependent manner. SIRT3, the primary deacetylase located in the mitochondria, controls cellular energy metabolism and the synthesis of essential biomolecules for cell survival. In recent years, increasing evidence has shown that SIRT3 is involved in several types of acute brain injury. In ischaemic stroke, subarachnoid haemorrhage, traumatic brain injury, and intracerebral haemorrhage, SIRT3 is closely related to mitochondrial homeostasis and with the mechanisms of pathophysiological processes such as neuroinflammation, oxidative stress, autophagy, and programmed cell death. As SIRT3 is the driver and regulator of a variety of pathophysiological processes, its molecular regulation is significant. In this paper, we review the role of SIRT3 in various types of brain injury and summarise SIRT3 molecular regulation. Numerous studies have demonstrated that SIRT3 plays a protective role in various types of brain injury. Here, we present the current research available on SIRT3 as a target for treating ischaemic stroke, subarachnoid haemorrhage, traumatic brain injury, thus highlighting the therapeutic potential of SIRT3 as a potent mediator of catastrophic brain injury. In addition, we have summarised the therapeutic drugs, compounds, natural extracts, peptides, physical stimuli, and other small molecules that may regulate SIRT3 to uncover additional brain-protective mechanisms of SIRT3, conduct further research, and provide more evidence for clinical transformation and drug development.

Mild hypothermia alleviates early brain injury after subarachnoid hemorrhage via suppressing pyroptosis through AMPK/NLRP3 inflammasome pathway in rats.

As a subtype of stroke, subarachnoid hemorrhage (SAH) has a notoriously high rate of disability and mortality owing to the lack of effective intervention. Early brain injury (EBI) is the main factor responsible for the dismal prognosis of SAH patients. The current study intends to explore the molecular mechanism underlying the effect of MH on EBI after SAH from a novel perspective of pyroptosis, a highly specific inflammatory programmed cell death, in the SAH rat model. Sprague-Dawley (SD) rats were divided into different groups in accordance with various treatments. In the treatment group, the rats underwent mild hypothermia for 4 h after modeling; in the inhibitor group, Compound C (an inhibitor of AMPK) was administered intravenous injections (i.v.) 30 min before modeling. Neurological score, neuronal death, brain water content, inflammatory reaction, and expression levels of pyroptosis-related proteins were evaluated in the rats. Our results indicate that the MH therapy significantly increased the neurological score and assuaged brain edema, neuronal injury, and inflammatory reaction induced by SAH. Meanwhile, MH therapy upregulated the level of AMPK phosphorylation whereas downregulated the protein expressions of NLRP3, ASC, cleaved caspase-1, GSDMD, IL-1ß, and IL-18. The reversed effect of MH therapy by Compound C concretely indicated that MH therapy inhibited pyroptosis through an AMPK-dependent pathway. Our study also found that MH therapy potently curbed the increasing trend of brain temperature (BT), rectal temperature (RT), and ICP after SAH. Taken together, our data indicate that the neuroprotective effects of MH therapy were manifested by inhibiting pyroptosis via the AMPK/NLRP3 inflammasome pathway, which may serve as a promising therapy for the intervention of SAH.

Astragaloside IV attenuates ferroptosis after subarachnoid hemorrhage via Nrf2/HO-1 signaling pathway.

Subarachnoid hemorrhage (SAH) is a severe type of stroke featuring exceptionally high rate of morbidity and mortality due to the lack of effective management. Ferroptosis can be defined as a novel iron-dependent programmed cell death in contrast to classical apoptosis and necrosis. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with established therapeutic effect on CNS diseases. However, the exact role of ferroptosis in Astragaloside IV-mediated neuroprotection after SAH is yet to be demonstrated. In the present study, the SAH model of SD male rats with endovascular perforation was used to gauge the neuroprotective effect of AS-IV on SAH-induced early brain injury (EBI) and to clarify the potential molecular mechanism. We found that the induction of SAH reduced the levels of SLC7A11 and glutathione peroxidase 4 (GPX4) in the brain, exacerbated iron accumulation, enhanced lipid reactive oxygen species (ROS) level, and stimulated neuronal ferroptosis. However, the administration of AS-IV and the ferroptosis inhibitor Ferrostatin-1 (Fer-1) enhanced the antioxidant capacity after SAH and suppressed the accumulation of lipid peroxides. Meanwhile, AS-IV triggered Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of SAH. The Nrf2 inhibitor ML385 blocked the beneficial effects of neuroprotection. These results consistently suggest that ferroptosis is profoundly implicated in facilitating EBI in SAH, and that AS-IV thwarts the process of ferroptosis in SAH by activating Nrf2/HO-1 pathway.

Controlled decompression attenuates brain damage in a rat model of epidural extreme intracranial hypertension: Partially via inhibiting necroptosis and inflammatory response.

Intracranial hypertension (IH) remains a common symptom of neurological diseases, and requires stepwise treatments to release intracranial pressure (ICP). In the present study, we built a rat model of epidural extreme intracranial hypertension (EEIH) and verified the effectiveness of a surgery method called controlled decompression on attenuating brain injury induced by EEIH. For the model part, we determined the level of EEIH of rats via recording ICP and cerebral perfusion pressure (CPP) and the variation tendency of survival rates, mean blood artery pressure and mean velocity (Vm) of left middle cerebral artery (LMCA) as ICP ascending. SD rats were assigned into 4 groups: Sham group, Controlled decompression group (Con group), Rapid decompression group (Rap group) and Rapid decompression + Necrostatin-1 (Nec-1) group (Rap+Nec-1 group). The results suggested that controlled decompression lowered cerebral water content, improved neurological function, and attenuated EEIH-induced inflammation response and ROS generation to a greater extent than rapid decompression. Meanwhile, controlled decompression functioned to preserve more Nissl bodies, indicating alleviated neuron injury after EEIH. Additionally, the permeability of blood brain barrier (BBB) was also safeguarded in the Con group. Western blotting (WB) and Real-time Polymerase Chain Reaction (rt-PCR) assays consistently determined lower protein and mRNA levels of necroptosis-related molecules receptor interacting protein kinase 1 (RIPK1), interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) (WB only) in the Con and Rap+Nec-1 group. Double immunofluorescent staining found weaker fluorescence intensity of RIPK3 in the compressed cortex of the Con and Rap+Nec-1 group.