Galectin-3 modulates microglial activation and neuroinflammation in early brain injury after subarachnoid hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is a devastating acute cerebrovascular event with high mortality and permanent disability rates. Higher galectin-3 levels on days 1-3 have been shown to predict the development of delayed cerebral infarction or adverse outcomes after SAH. Recent single-cell analysis of microglial transcriptomic diversity in SAH revealed that galectin could influence the development and course of neuroinflammation after SAH. METHODS: This study aimed to investigate the role and mechanism of galectin-3 in SAH and to determine whether galectin-3 inhibition prevents early brain injury by reducing microglia polarization using a mouse model of SAH and oxyhemoglobin-treated activation of mouse BV2 cells in vitro. RESULTS: We found that the expression of galectin-3 began to increase 12 h after SAH and continued to increase up to 72 h. Importantly, TD139-inhibited galectin-3 expression reduced the release of inflammatory factors in microglial cells. In the experimental SAH model, TD139 treatment alleviated neuroinflammatory damage after SAH and improved defects in neurological functions. Furthermore, we demonstrated that galectin-3 inhibition affected the activation and M1 polarization of microglial cells after SAH. TD139 treatment inhibited the expression of TLR4, p-NF-κB p65, and NF-κB p65 in microglia activated by oxyhemoglobin as well as eliminated the increased expression and phosphorylation of JAK2 and STAT3. CONCLUSION: These findings suggest that regulating microglia polarization by galectin-3 after SAH to improve neuroinflammation may be a potential therapeutic target.

Transfer of cGAMP from neuron to microglia activates microglial type I interferon responses after subarachnoid hemorrhage.

Primary subarachnoid hemorrhage (SAH) is a type of acute stroke, accounting for approximately 10% of cases, with high disability and mortality rate. Early brain injury (EBI) is a critical factor in determining SAH mortality; however, there are no effective treatment interventions for EBI. Based on our results, the transmission of cyclic GMP-AMP (cGAMP) from neurons to microglia is a key molecular event that triggers type I interferon response, amplifies neuroinflammation, and leads to neuronal apoptosis. Abnormal intracytoplasmic mitochondrial DNA (mtDNA) is the initiating factor of the cGAS-cGAMP-STING signaling axis. Overall, the cGAS-cGAMP-STING signaling axis is closely associated with neuroinflammation after subarachnoid hemorrhage. Targeting cGAS triggered by cytoplasmic mtDNA may be useful for comprehensive clinical treatment of patients after SAH. Further studies targeting cGAS-specific antagonists for treating SAH are warranted. Video Abstract.

Endovascular treatment of multiple intracranial aneurysms in patients with subarachnoid hemorrhage: one or multiple sessions?

Objective: This study aimed to compare the safety and efficacy of single- and multiple-stage endovascular treatment in aneurysmal subarachnoid hemorrhage (SAH) patients with multiple intracranial aneurysms. Methods: We retrospectively analyzed the clinical and imaging data of 61 patients who harbored multiple aneurysms and presented to our institution with aneurysmal subarachnoid hemorrhage. Patients were grouped according to endovascular treatment strategy: one-stage or multiple-stage. Result: The 61 study patients harbored 136 aneurysms. One aneurysm in each patient had ruptured. In the one-stage treatment group, all 66 aneurysms in 31 patients were treated in one session. The mean follow-up was 25.8 months (range, 12-47). At the last follow-up, the modified Rankin scale was ≤2 in 27 patients. In total, 10 complications occurred (cerebral vasospasm, six patients; cerebral hemorrhage, two patients; and thromboembolism, two patients). In the multiple-stage treatment group, only the ruptured aneurysm (30 in total) was treated at the time of presentation, and the remaining aneurysms (40 in total) were treated later. The mean follow-up was 26.3 months (range, 7-49). At the last follow-up, the modified Rankin scale score was ≤2 in 28 patients. In total, five complications occurred (cerebral vasospasm, four patients; and subarachnoid hemorrhage, one patient). During the follow-up period, there was one recurrence of aneurysm with subarachnoid hemorrhage in the single-stage treatment group and four recurrences in the multiple-stage treatment group. Conclusion: Both single- and multiple-stage endovascular treatment is safe and effective in aneurysmal subarachnoid hemorrhage patients who harbor multiple aneurysms. However, multiple-stage treatment is associated with a lower rate of hemorrhagic and ischemic complications.

Association of gut microbiome with risk of intracranial aneurysm: a mendelian randomization study.

OBJECTIVE: To investigate the potential causal link between genetic variants associated with gut microbiome and risk of intracranial aneurysm (IA) using two-sample mendelian randomization (MR). METHODS: We performed two sets of MR analyses. At first, we selected the genome-wide statistical significant(P < 5 × 10-8) single nucleotide polymorphisms (SNPs) as instrumental variables (IVs). Then, we selected the locus-wide significant (P < 1 × 10-5) SNPs as IVs for the other set of analyses to obtain more comprehensive conclusions. Gut microbiome genetic association estimates were derived from a genome-wide association study (GWAS) of 18,473 individuals. Summary-level statistics for IA were obtained from 79,429 individuals, which included 7,495 cases and 71,934 controls. RESULTS: On the basis of locus-wide significance level, inverse variance weighted(IVW) showed that Clostridia [(odds ratio (OR): 2.60; 95% confidence interval (CI): 1.00-6.72, P = 0.049)], Adlercreutzia (OR: 1.81; 95% CI: 1.10-2.99, P = 0.021) and Victivallis (OR: 1.38; 95% CI: 1.01-1.88, P = 0.044) were positively related with the risk of unruptured intracranial aneurysm(UIA); Weighted median results of MR showed Oscillospira (OR: 0.37; 95% CI: 0.17-0.84, P = 0.018) was negatively with the risk of UIA and Sutterella (OR: 1.84; 95% CI: 1.04-3.23, P = 0.035) was positively related with the risk of UIA; MR-Egger method analysis indicated that Paraprevotella (OR: 0.32; 95% CI: 0.13-0.80, P = 0.035) was negatively with the risk of UIA and Rhodospirillaceae (OR: 13.39; 95% CI: 1.44-124.47, P = 0.048) was positively related with the risk of UIA. The results suggest that Streptococcus (OR: 5.19; 95% CI: 1.25-21.56; P = 0.024) and Peptostreptococcaceae (OR: 4.92; 95% CI: 1.32-18.32; P = 0.018) may increase the risk of UIA according to genome-wide statistical significance thresholds. CONCLUSION: This MR analysis indicates that there exists a beneficial or detrimental causal effect of gut microbiota composition on IAs.

Endovascular treatment strategy and clinical outcome of tentorial dural arteriovenous fistula.

Introduction: To evaluate treatment strategies and clinical outcomes following endovascular embolization of tentorial dural arteriovenous fistulas. Methods: We retrospectively analyzed 19 patients with tentorial dural arteriovenous fistulas admitted to the Department of Neurosurgery at Jiangsu Provincial People's Hospital between October 2015 and May 2022, all treated with endovascular therapy. To collect and analyze patients' clinical presentation, imaging data, postoperative complications, and prognosis and to analyze the safety and clinical outcomes of endovascular treatment of tentorial dural arteriovenous fistulas. Results: Imaging cure was achieved in 18 patients, with the arterial route chosen for embolization in 17 patients and the venous route in one patient; one patient received partial embolization. Staged embolization was performed in four patients. At postoperative follow-up of 9-83 months (37.8 ± 21.2), all 19 patients had recovered well (mRS score ≤ 2). Three patients experienced perioperative complications: intraoperative Onyx reflux into the middle cerebral artery in one patient; postoperative permanent limited left visual field loss and deafness in the left ear in one patient; and transient diplopia, vertigo, and decreased pain and temperature sensation of the left limb in one patient, with no abnormalities on post-procedure magnetic resonance examinations. A total of 17 patients completed a postoperative digital subtraction angiography review during follow-up, and one patient had a recurrence of an arteriovenous fistula. Conclusion: Endovascular treatment of tentorial dural arteriovenous fistulas is safe and effective. Reduction of the Borden or Cognard classification via eliminating cortical venous reflux through multi-staged embolization or combined open surgery is a reasonable goal of treatment where complete obliteration of the fistula is not achievable.

Hyperhomocysteinemia and intracranial aneurysm: A mendelian randomization study.

Objective: To investigate the link between genetic variants associated with plasma homocysteine levels and risk of intracranial aneurysm (IA) using two-sample Mendelian randomization. Methods: We used single-nucleotide polymorphisms associated with human plasma homocysteine levels as instrumental variables for the primary analysis in a genome-wide association study of 44,147 subjects of European ancestry. Summary-level statistics were obtained for 79,429 individuals, including 7,495 IA cases and 71,934 controls. To enhance validity, five different Mendelian randomization methods (MR-Egger, weighted median, inverse variance weighted, simple mode, and weighted mode) were used for the analyses. Results: The inverse variance weighted analysis method produced P-values of 0.398 for aneurysmal subarachnoid hemorrhage [odds ratio (OR): 1.104; 95% confidence interval (CI): 0.878-1.387], 0.246 for IA (OR: 1.124; 95% CI: 0.923-1.368), and 0.644 for unruptured IA (OR: 1.126; 95% CI: 0.682-1.858). The MR-Egger analysis showed no association between IAs and homocysteine, with all P > 0.05. Conclusion: Using gene-related instrumental variables, the Mendelian randomization analyses demonstrated a lack of an association between plasma homocysteine levels and IAs or aneurysmal subarachnoid hemorrhage.

T3 alleviates neuroinflammation and reduces early brain injury after subarachnoid haemorrhage by promoting mitophagy via PINK 1-parkin pathway.

Subarachnoid haemorrhage (SAH) is a common and devastating complication of haemorrhagic stroke. SAH is characterised by high mortality rates, permanent disabilities, and is often caused by the rupture of intracranial aneurysms. Low serum triiodothyronine (T3) concentrations have been associated with severe SAH and poor prognosis. T3 has been previously described as an inhibitor of lung fibrosis, and it acts by stimulating autophagy and mitophagy. Here, we indicated in vitro that T3 treatment suppressed neuronal apoptosis by reducing the release of mitochondrial reactive oxygen species (ROS), leading to mitochondrial membrane potential (MMP) decrease. Moreover, this preventative effect was reversed by PINK 1-siRNA treatment. We showed that in vivo T3 treatment promoted mitophagy, decreased microglial activation, alleviated neuroinflammation, and reduced neuronal apoptosis following SAH. Overall, this thyroid hormone (TH) exerts a protective effect on neurones after SAH via the PINK 1/PARKIN pathway. Considering the protective function of TH against neuronal damage, further research can establish TH treatment as a promising and effective therapeutic option for early brain injury (EBI) after SAH.

Associations between morphological parameters and ruptured anterior communicating artery aneurysm: A propensity score-matched, single center, case-control study.

BACKGROUND: To identify an association between morphological parameters and the rupture risk of anterior communicating artery (ACoA) aneurysms using propensity score matching (PSM). METHODS: Data for 109 patients with ACoA aneurysms treated from January 2018 to October 2021 were reviewed; 94 patients were enrolled. The geometrical parameters of the ACoA aneurysms were measured and calculated using three-dimensional reconstructed digital subtraction angiography images. The aneurysms' morphological parameters were analyzed using a propensity score for six factors (age, sex, excess alcohol intake, smoking, hypertension, diabetes mellitus). Univariate logistic regression was used to analyze the relationship between the aneurysms' morphological parameters and rupture risk. RESULTS: Twenty-five patients each with or without ruptured aneurysms were selected. After matching, no statistically significant differences were seen between the groups in their baseline characteristics. Aneurysm neck size (p = 0.038) was higher in the unruptured group than that in the ruptured group, and the dome-to-neck ratio (D/N; p = 0.009) and aspect ratio (AR; p = 0.003) were higher in the ruptured group than those in the unruptured group. Univariable logistic regression analysis demonstrated that ACoA aneurysm rupture was associated with AR (odds ratio: 8.047; 95% confidence interval: 1.569-41.213; p = 0.012) and D/N (odds ratio: 4.253; 95% confidence interval: 1.228-14.731; p = 0.022). The areas under the receiver operating characteristic curves for AR and D/N were 0.746 and 0.715, respectively. CONCLUSIONS: After PSM, ACoA aneurysms with higher AR and D/N, and smaller neck size were more likely to rupture. AR may be a much more important predictor of aneurysm rupture than other predictors.

Safety and Efficacy of Endovascular Therapy for Blood Blister-Like Aneurysms: Willis Covered Stents and Double Stents Assistant Coils-A Single Center Cohort Study.

Objective: To summarize and discuss the application of Willis covered stents (WCSs) and double stent-assisted coils in the treatment of blood blister-like aneurysms (BBAs). Materials and Methods: Thirty-two patients with BBAs treated from January 2015 to October 2020 were included in the study. Among them, 18 were treated using WCSs and 14 using double stents-assisted coils. The indications for treatment, perioperative findings, and postoperative follow-up results were collected and analyzed. Results: All 32 patients had successful stent deployments. Complete aneurysm occlusion was achieved in all 18 patients treated with WCSs immediately. WCS-related adverse events included 2 cases of mild vasospasm and 4 aggressive procedure-related vasospasms during WCS deployment, a case of dissection after WCS deployment, and 1 death due to ipsilateral temporal lobe rebleeding at the sixth day after WCS deployment. In patients treated with double stent-assisted coils, there were 3 cases of neck remnants, 1 acute occlusion of the ipsilateral MCA branch, and 4 mild procedure-related intraoperative vasospasms. The mean follow-up period was 4.2±1.6 months (range 3-6 months). Follow-up imaging data were available for 25 patients (78.1%). In the first postoperative angiographic follow-up, all BBAs were completely occluded. Mild asymptomatic stent stenosis was observed in 3 patients treated with WCSs. Follow-up examination at 6 months after the employment of WCSs showed that the modified Rankin score (mRs) was 0 in 6 patients, 1 in 5 patients, 2 in 3 patients, 3 in 1 patient, 4 in 2 patients, and 6 in 1 patient. After treatment with double stents-assisted coils, the mRs was 0 in 4 patients, 1 in 5 patients, 2 in 3 patients, and 4 in 2 patients. Conclusions: WCSs and double stent-assisted coils for the treatment of BBAs are both safe and efficient. WCSs provide a higher rate of immediate occlusion; however, there was no significant difference in the long term.

Dual effects of thyroid hormone on neurons and neurogenesis in traumatic brain injury.

Thyroid hormone (TH) plays a crucial role in neurodevelopment, but its function and specific mechanisms remain unclear after traumatic brain injury (TBI). Here we found that treatment with triiodothyronine (T3) ameliorated the progression of neurological deficits in mice subjected to TBI. The data showed that T3 reduced neural death and promoted the elimination of damaged mitochondria via mitophagy. However, T3 did not prevent TBI-induced cell death in phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (Pink1) knockout mice suggesting the involvement of mitophagy. Moreover, we also found that T3 promoted neurogenesis via crosstalk between mature neurons and neural stem cells (NSCs) after TBI. In neuron cultures undergoing oxygen and glucose deprivation (OGD), conditioned neuron culture medium collected after T3 treatment enhanced the in vitro differentiation of NSCs into mature neurons, a process in which mitophagy was required. Taken together, these data suggested that T3 treatment could provide a therapeutic approach for TBI by preventing neuronal death via mitophagy and promoting neurogenesis via neuron-NSC crosstalk.