Cerebral revascularization for complex vertebrobasilar artery dissecting aneurysms.

Vertebrobasilar artery dissecting aneurysms (VBDAs) are the most surgically challenging type of aneurysm. Cerebral revascularization is the ultimate treatment for complex VBDAs. We retrospectively analysed the characteristics, surgical outcomes and follow-up data of 21 patients who underwent cerebral revascularization to treat complex VBDAs from 2015 to 2022. According to the location of the aneurysm and the anatomic relationship between the VBDA and the PICA, VBDA patients were classified into four groups: aneurysms located at the VA with PICA involvement (10 patients), aneurysms located at the VA without PICA involvement (1 patient), aneurysms located at the basilar apex segment (1 patient) and aneurysms located at the basilar trunk segment (9 patients). A surgical algorithm for complex VBDAs was determined primarily by the location of the aneurysm, the status of the aneurysm and the ability of retrograde blood flow to reach the proximal vertebrobasilar artery. Surgical modalities for patients with aneurysms in the VA with PICA involvement included low-flow (OA-PICA) bypasses with aneurysm trapping, aneurysm excision or reconstructive clip in 8 patients and STA-PCA bypass combined with PICA preservation and aneurysm trapping in 2 patients. In patients with aneurysms in the VA without PICA involvement, aneurysm excision was performed without cerebral bypass. In patients with aneurysms in the basilar apex segment, high-flow bypass (ECA-RA-P2) with aneurysm trapping was performed. In patients with aneurysms in the basilar trunk segment, surgical modalities included high-flow bypasses (ECA-RA-P2 and LVA-RA-P2) with aneurysm trapping or proximal occlusion in 6 patients, ECA-RA-P2 bypass with partial proximal occlusion in 1 patient, ECA-RA-P2 bypass alone in 1 patient, and STA-PCA bypass with R-VA narrowing in 1 patient. Of the 21 patients, 20 experienced clinical improvement or no change, and 17 of 21 patients achieved favourable functional outcomes (mRS ≤ 2). However, one patient died of infarction and respiratory failure postoperatively. Aneurysms were completely obliterated in 13 patients, shrank in 5 patients and stabilized in 2 patients. The median follow-up period was 32.5 months. During the follow-up period, all bypasses were patent, and further clinical improvement was observed in 11 patients. Cerebral revascularization appears to be safe and effective for the treatment of complex VBDAs, and cerebral revascularization could act as a complementary treatment strategy.

Quantitative Analysis of Occipital Artery Bypass Donor Vessels by Ultrasonography and DSA.

BACKGROUND: Occipital artery (OA) acts as a vital donor vessel in intra-cranialand extra-cranial bypass. Ultrasonography and digital subtracted angiography (DSA) are becoming increasingly important in the assessment of vascular morphology and hemodynamically; however, quantitative analysis of occipital artery bypass donor vessels by Ultrasonography and DSA are seldom discussed. METHODS: A retrospective study involving 62 cases accepted occipital artery bypass to treat posterior circulation aneurysms or artery occlusion/stenosis. The characteristics of OA are collected and analyzed. RESULTS: Occipital artery bypasses were performed to treat posterior circulation aneurysms in 34 patients and to treat posterior circulation artery occlusion or stenosis in 28 patients. Compared with the ultrasonography group, the DSA group had a greater diameter of OA, and Bland Altman analysis indicated that the discrepancy between the 2 groups was about 0.555 mm. Ultrasonography showed the characteristics of OA: the mean Peak Systolic Velocity (PSV) was 42.98 cm/s, the mean End Diastolic Velocity (EDV) was 8.811 cm/s, and the mean Resistance Index (RI) was 1.46. There were no statistical differences in the diameter of OA, PSV, EDV, and RI between the male group and female group, the elderly group and younger adult group or the left occipital artery group and right occipital artery group. However, compared with patients with posterior circulation aneurysms, patients with artery occlusion or stenosis were older and had higher PSV, RI, and greater diameter in occipital arteries. The mean diameter of occipital arteries was increased in the first postoperative years but reduced in 3 patients during 1 year follow-up. CONCLUSIONS: Both ultrasonography and DSA were effective assessment methods of occipital artery bypasses, and the DSA group had a greater diameter of OA. Age, gender, and left or right sides had little effect on the diameter of OA, PSV, EDV, and RI. Posterior circulation occlusion or stenosis had higher PSV, RI, and greater diameter of the occipital artery when compared with posterior circulation aneurysms. Occipital artery bypasses could increase the diameter of OA in most cases.

Treatment of Pineal Region Lesions in Children.

BACKGROUND: Pineal region lesions are more common in children than adults; however, therapeutic strategies for pineal region lesions in children are controversial. METHODS: A retrospective study involving 54 pediatric with pineal region lesions was conducted. The therapeutic strategies for lesions and hydrocephalus were classified and analyzed. RESULTS: Radiotherapy of pineal region lesions was shown to result in better postoperative recovery and fewer complications in the short-term compared with lesion resection. Total resection was related to smaller lesion size, endoscopic procedures, and a better prognosis. Cerebrospinal fluid (CSF) diversion before the resection reduced hydrocephalus recurrences, whereas further lesion resection had a negative short-term influence on CSF diversion. Among the 4 therapeutic strategies to manage hydrocephalus, a third ventriculostomy (ETV) was reasonable and further resection did not have a negative impact on the ETV. The relief of hydrocephalus was also related to better postoperative recovery, a higher total resection rate, fewer complications, and a better prognosis. Logistical regression analysis indicated that lesion size and intracranial complications were predictors of outcome. CONCLUSIONS: For lesion treatment, total resection and radiotherapy are essential components in children. Total resection and CSF diversion before resection were beneficial, whereas further lesion resection had a negative impact on CSF diversion. For hydrocephalus treatment, ETV was shown to be the best therapeutic strategy for management of pediatric hydrocephalus. Total resection and better preoperative health status were associated with greater hydrocephalus relief. For the overall prognosis, a lack of hydrocephalus relief was associated with poor outcomes. Lesion size and intracranial complications may be the best predictors of outcome.

Optimal therapeutic strategies for pineal region lesions.

Background: The removal of pineal region lesions are challenging, and therapeutic strategies for their removal remain controversial. The current study was conducted to identify the characteristics and the optimal therapeutic strategies for pineal region lesions. Methods: This retrospective study reviewed the treatments of 101 patients with pineal region lesions, and different characteristics and therapeutic strategies were observed. Results: There were no statistical differences in the total resection ratio, complications, and prognosis outcomes between the hydrocephalus group and non-hydrocephalus group, except patients in the hydrocephalus group were younger and pediatric patients had an increased level of intracranial infections. Treatments of lesions and hydrocephalus secondary to pineal region lesions were two integral parts to therapeutic strategies. For the management of lesions, germinoma or non-germinoma were diagnosed preoperatively, and resection or diagnostic radiation were chosen to deal with pineal region lesions. Endoscopic-assisted surgery provided a higher total resection rate. For the management of hydrocephalus, endoscopic third ventriculostomy (ETV) had the better therapeutic effect. Additionally, cerebrospinal fluid (CSF) diversion before radiotherapy or resection did not improve prognosis outcome, but it was necessary for patients with severe hydrocephalus. Logistical regression analysis indicated that age, lesion size, reoperation ratio, and intracranial complications were predictors of prognosis outcome. Conclusion: More attention should be paid to intracranial infections in pediatric patients with hydrocephalus secondary to pineal region lesions, and CSF diversion before radiotherapy or resection did not promote prognosis outcome, but it was necessary for patients with severe hydrocephalus. Age, lesion size, reoperation ratio, and intracranial complications may be the predictors of prognosis outcome. Most importantly, the surgical algorithm for pineal region lesions which was based on preoperatively diagnosis (non-germinoma and germinoma) is useful, especially for developing countries.

Activation of silent information regulator 1 exerts a neuroprotective effect after intracerebral hemorrhage by deacetylating NF-κB/p65.

Nuclear factor (NF)-κB-mediated neuroinflammation is an important mechanism of intracerebral hemorrhage (ICH)-induced neurotoxicity. Silent information regulator 1 (SIRT1) plays a multi-protective effect in a variety of diseases by deacetylating and inhibiting NF-κB/p65. However, the role of SIRT1 in brain damage following ICH remains unclear. We hypothesized that SIRT1 can protect against ICH-induced brain damage by inhibiting neuroinflammation through deacetylating NF-κB/p65. The ICH model was induced in vivo (with collagenase) and in vitro (with hemoglobin). Resveratrol and Ex527 were administered to activate or inhibit SIRT1, respectively. Western blot, immunohistochemistry, and immunofluorescence assays were performed to detect the expression of SIRT1 and p65. Enzyme-linked immunosorbent assays (ELISAs) were used to explore tumor necrosis factor (TNF)-α and interleukin (IL)-1ß release. The neurological score, brain water content, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and brain hemoglobin content were determined to evaluate the neuroprotective effect of SIRT1. SIRT1 expression was decreased, whereas the level of acetylated p65 (Ac-p65) was elevated after ICH in vivo. Moreover, hemoglobin treatment decreased the expression of SIRT1 in vitro. Activation of SIRT1 by resveratrol had a neuroprotective effect, along with decreased levels of Ac-p65, IL-1ß, TNF-α, and apoptosis after ICH. The effect of resveratrol was abolished by the SIRT1 inhibitor Ex527. Our results are consistent with the hypothesis that SIRT1 exerts a neuroprotective effect after ICH by deacetylating p65 to inhibit the NF-κB-dependent inflammatory response.

Inhibition of the Receptor for Advanced Glycation End-Products (RAGE) Attenuates Neuroinflammation While Sensitizing Cortical Neurons Towards Death in Experimental Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a threatening and devastating neurological insult with high mortality and morbidity rates. Despite considerable efforts, the underlying pathophysiological mechanisms are still poorly understood. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that has been implicated in various pathological conditions. We previously showed that RAGE was upregulated and may be involved in pathophysiology of SAH. In the current study, we investigated its potential role in SAH. We found that the upregulation of RAGE after SAH was NF-κB-dependent positive feedback regulation. Further, pharmacological inhibition of RAGE attenuated neuroinflammation, indicating a possible contributive role of RAGE in inflammation-associated brain injury after SAH. Conversely, however, inhibition of RAGE sensitized neurons, exacerbating cell death, which correlated with augmented apoptosis and diminished autophagy, suggesting that activation of RAGE may protect against SAH-induced neuronal injury. Furthermore, we demonstrate that inhibition of RAGE significantly reduced brain edema and improved neurological function at day 1 but not at day 3 post-SAH. Taken together, these results suggest that RAGE exerts dual role after SAH. Our findings also suggest caution should be exercised in setting RAGE-targeted treatment for SAH.

Increased Expression of Caspase-12 After Experimental Subarachnoid Hemorrhage.

Convincing evidences have proved that apoptosis plays a vital role in the pathogenesis of early and delayed brain injury following subarachnoid hemorrhage (SAH). Recently, a novel caspase-12-mediated apoptotic pathway has been reported to be induced by excess endoplasmic reticulum (ER) stress. Extensive protein damage occurs after SAH, which may trigger ER stress-associated apoptotic pathway. Thus, we hypothesized that caspase-12, as the major molecular marker of this novel apoptotic pathway, may be activated and involved in the pathogenesis of apoptotic injury after SAH. This study sought to investigate the changes of caspase-12 expressions in both in vitro and in vivo SAH models. Western blot analysis found significantly increased protein expressions of both pro- and active forms of caspase-12 after SAH. Quantitative real-time PCR and immunohistochemistry assays confirmed elevated caspase-12 level after SAH in vivo. Further, double immunofluorescence staining revealed obvious caspase-12 over-expression in both cortical neurons and astrocytes. Moreover, immunofluorescent co-staining in vivo demonstrated that neural cells with high immunoreactivity of caspase-12 also expressed caspase-3, and dual-immunofluorescent staining for caspase-12 and TUNEL in vitro showed that TUNEL-positive cells were more likely to exhibit higher caspase-12 immunoreactivity, indicating a potential contribution of caspase-12 activation to apoptosis in SAH. Collectively, our results showed significant upregulation of caspase-12 expression after experimental SAH. These findings also offer important implications for further investigations of the therapeutic potential of caspase-12 associated apoptosis in SAH.

Inhibition of SENP3 by lentivirus induces suppression of apoptosis in experimental subarachnoid hemorrhage in rats.

BACKGROUND: Subarachnoid hemorrhage (SAH) is one of the life-threatening diseases with high morbidity and mortality rates. SUMO-specific proteases 3 (SENP3), a member of the small ubiquitin-like modifier specific protease family, was identified as an isopeptidase that deconjugates SUMOylation (The covalent modification by SUMO) of modified protein substrates. It is reported that SUMO-2/3 conjugation, a member of SUMOylation, presented neuroprotection. The study aimed to evaluate the expression of SENP3 and to explore its potential role in SAH. MATERIALS AND METHODS: A total of 108 Sprague Dawley (SD) rats were randomly divided into 2 parts experiment and 9 subgroups (part 1:Sham group, SAH group, SAH+NAC group, SAH+vehicle group; part 2: Sham group, SAH group, SAH+lv-SENP3 group, SAH+lv-null group, SAH+NS group). 7 days before SAH, lentivirus was administrated into rats׳ left lateral ventricle to down-regulate SENP3. Experimental SAH was imitated by injection with 0.3ml nonheparinized autoblood into the prechiasmatic cistern. MDA levels, SOD activities, and GSH contents were detected to evaluate oxidative stress level. SENP3 and cleaved caspase 3 were detected by western blot, apoptosis was observed by TUNEL staining. RESULTS: High oxidative stress level following SAH induced rising of SENP3. And inhibition of SENP3 by lentivirus induces suppression of apoptosis in experimental subarachnoid hemorrhage in rats. CONCLUSION: When SENP3 accumulated by high oxidative stress, caspase 3 activated subsequently. And it leads to more severe apoptosis than physiological.

Expression and Cell Distribution of SENP3 in Brain Tissue After Traumatic Brain Injury in Mice: A Pilot Study.

SUMO-specific proteases 3 (SENP3) is a member of the small ubiquitin-like modifier-specific protease family and deconjugates SUMO2/3 from protein substrates. To date, the expression and function of SENP3 in traumatic brain injury (TBI) are unclear. The present study examined dynamic changes in SENP3 expression in the cerebral cortex and in its cellular localization, using an acute TBI model in adult mice. SENP3 expression was examined at 3, 6, 12, 24 h, 3, and 5 days after TBI using Western Blot analysis and quantitative real-time PCR. Immunohistochemistry and immunofluorescence were examined to detect SENP3 localization. Western Blot indicated that SENP3 protein levels gradually increased from 3 h after TBI and peaked at 24 h. Quantitative real-time PCR demonstrated a gradual increase in SENP3 expression, which peaked 12 h after TBI and declined subsequently. Immunohistochemical staining demonstrated that SENP3-positive cells were observed in both the sham and 24 h post-TBI groups. However, robust expression of SENP3 was seldom observed in the sham group, while it was notably enhanced after TBI. Furthermore, immunofluorescence results revealed that the expression of SENP3 increased more significantly in neurons at day 1 after TBI compared with sham group and less significantly in astrocytes and microglia. Moreover, the SENP3-positive cells that were co-expressed with NeuN also expressed caspase-3, indicating a potential correlation between SENP3 and apoptosis after TBI. Collectively, our results showed obvious up-regulation of SENP3 expression in the brain after TBI, especially in the neurons. However, the full role of SENP3 and its therapeutic potential in TBI needs further investigation.

IL-33 expression in the cerebral cortex following experimental subarachnoid hemorrhage in rats.

Subarachnoid hemorrhage (SAH) is a pervasive and devastating condition in which inflammatory and apoptotic pathways contribute to poor outcome. Interleukin-33 (IL-33) plays a crucial role in the inflammatory and apoptotic pathways through binding of the transmembrane ST2 receptor. This study investigated the expression and cellular localization of IL-33 in the cerebral cortex after SAH in order to clarify the role of IL-33 after SAH. Sprague-Dawley rats were randomly divided into sham and SAH groups and evaluated 2, 6, and 12 h and 1, 2, 3, and 5 days after the surgery, with SAH animals subjected to prechiasmatic cistern SAH. IL-33 expression was measured by western blot analysis, real-time PCR, immunohistochemistry, and immunofluorescence. The mRNA levels of tumor necrosis factor (TNF)-α and IL-1ß were also assessed. The expression of IL-33, IL-1ß, and TNF-α was markedly elevated in the SAH as compared to the sham group; IL-33 was mainly localized in neurons and astrocytes and not microglia after SAH. Moreover, a significant positive association was observed between IL-33 and IL-1ß expression. These findings indicate that IL-33 might play an important role in the inflammatory response following SAH.

Necroptosis, a novel type of programmed cell death, contributes to early neural cells damage after spinal cord injury in adult mice.

BACKGROUND: Necroptosis is an emerging programmed necrosis other than traditional necrosis and apoptosis. Until recently, there have not been studies that have investigated a relationship between necroptosis and pathogenesis of cell death after spinal cord injury (SCI). OBJECTIVE: To investigate whether necroptosis takes part in the early pathophysiological processes of traumatic SCI in mice. METHODS: Female ICR mice were randomized equally into three groups: the sham, the vehicle-treated + SCI group, and the Nec-1-treated + SCI group. To induce SCI, the mice were subjected to a laminectomy at T9 and compression with a vascular clip. After mice were sacrificed 24 hours post-SCI, propidium iodide (PI)-positive cells were detected using in vivo PI labeling. Morphological analyses were performed by hematoxylin and eosin staining and Nissl staining. The samples were evaluated for apoptosis by the in situ TUNEL assay. The expression of caspase-3 was assessed by western blot. Locomotor behavior of hindlimb was evaluated by BMS (Basso mouse scale) score at 1, 3, 5, 7, and 14 days post-injury. RESULTS: Compared with dimethyl sulfoxide -treated mice, necrostatin-1-treated mice showed decreased PI-positive cells (P < 0.05), alleviated tissue damage, more surviving neuron at 24 hours after SCI (P < 0.05), and improved functional recovery from days 7 to 14 (P < 0.05). Necrostatin-1 did not reduce the expression of caspase-3 and the number of TUNEL-positive cells at 24 hours after SCI (P > 0.05). CONCLUSIONS: Necroptosis contributes to necroptotic cell death and influences functional outcome after SCI in adult mice. The inhibition of necroptosis by necrostatin-1 may have therapeutic potential for patients with SCI.

Ghrelin alleviates early brain injury after subarachnoid hemorrhage via the PI3K/Akt signaling pathway.

Early brain injury (EBI) plays a key role in the pathogenesis of subarachnoid hemorrhage (SAH). Although the neuroprotective effects of ghrelin have been demonstrated in several studies, whether ghrelin reduces EBI after SAH remains unknown. In this study, we hypothesized that treatment with ghrelin would attenuate EBI after SAH, and that this protection would be mediated, at least in part, by activation of the PI3K/Akt signaling pathway. Adult male Sprague-Dawley rats (n=100) were randomly divided into the following groups: control group (n=20), SAH group (n=20), SAH+vehicle group (n=20), SAH+ghrelin group (n=20) and SAH+ghrelin+LY294002 group (n=20). The rats were injected with autologous blood (0.3mL) into the prechiasmatic cistern to induce SAH. Ghrelin (80µg/kg, IP), or an equal volume of vehicle, was administered immediately after surgery. The PI3K inhibitor, LY294002, was applied to manipulate the proposed pathway. Mortality, neurological scores, brain edema, cell apoptosis, and the expression of p-Akt, and cleaved caspase-3 proteins were assayed after 24h SAH. Ghrelin significantly improved neurological function and reduced neuronal apoptosis and brain edema at 24h after SAH. The level of p-Akt, expressed mainly in neurons, was markedly up-regulated. Additionally, the level of cleaved caspase-3 was decreased by ghrelin treatment. The beneficial effects of ghrelin in SAH rats were partially suppressed by LY294002. These results demonstrate that ghrelin may reduce EBI after SAH, via a mechanism involving the PI3K/Akt signaling pathway.