Acute-Phase Plasma Pigment Epithelium-Derived Factor Predicting Outcomes after Aneurysmal Subarachnoid Hemorrhage in the Elderly.

Aneurysmal subarachnoid hemorrhage (SAH) has increased with the aging of the population, but the outcome for elderly SAH patients is very poor. Therefore, predicting the outcome is important for determining whether to pursue aggressive treatment. Pigment epithelium-derived factor (PEDF) is a matricellular protein that is induced in the brain, and the plasma levels could be used as a biomarker for the severity of metabolic diseases. This study investigated whether acute-phase plasma PEDF levels could predict outcomes after aneurysmal SAH in the elderly. Plasma samples and clinical variables were collected over 1-3 days, post-SAH, from 56 consecutive elderly SAH patients ≥75 years of age registered in nine regional stroke centers in Japan between September 2013 and December 2016. The samples and variables were analyzed in terms of 3-month outcomes. Acute-phase plasma PEDF levels were significantly elevated in patients with ultimately poor outcomes, and the cutoff value of 12.6 µg/mL differentiated 3-month outcomes with high sensitivity (75.6%) and specificity (80.0%). Acute-phase plasma PEDF levels of ≥12.6 µg/mL were an independent and possibly better predictor of poor outcome than previously reported clinical variables. Acute-phase plasma PEDF levels may serve as the first biomarker to predict 3-month outcomes and to select elderly SAH patients who should be actively treated.

Epidermal Growth Factor Receptor Mediates Neuronal Apoptosis After Subarachnoid Hemorrhage in Mice.

BACKGROUND: Early brain injury including neuronal apoptosis is a main contributor to neurological deterioration after subarachnoid hemorrhage (SAH). This study was aimed to investigate whether EGFR (epidermal growth factor receptor)/NFκB (nuclear factor-kappa B) inducing kinase (NIK)/NFκB (p65 and p50) pathway is involved in the neuronal apoptosis after SAH in mice. METHODS: C57BL/6 adult male mice underwent endovascular perforation SAH modeling or sham-operation (n=286), and 86 mild SAH mice were excluded. In experiment 1, vehicle or an EGFR inhibitor (632.0 ng AG1478) was administered intraventricularly at 30 minutes postmodeling. At 24 or 72 hours, after neurological score was tested, brain water content, double immunolabeling with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and a neuronal marker antimicrotubule-associated protein-2 antibody, Western blotting using whole tissue lysate or nuclear protein extraction of the left cortex, and immunohistochemistry for cleaved caspase-3, phosphorylated (p-) EGFR, NIK, p-NFκB p65, and NFκB p105/50 were evaluated. In experiment 2, after sham or SAH modeling, AG1478+vehicle or AG1478+4.0 ng EGF was administered intraventricularly. The brain was used for TUNEL staining and immunohistochemistry after 24-hour observation. RESULTS: SAH group showed deteriorated neurological score (P<0.01, Mann-Whitney U test), more TUNEL- and cleaved caspase-3-positive neurons (P<0.01, ANOVA), and higher brain water content (P<0.01, Mann-Whitney U test), and these observations were improved in SAH-AG1478 group. Western blotting showed that expression levels of p-EGFR, p-p65, p50, and nuclear-NIK were increased after SAH (P<0.05, ANOVA), and decreased by AG1478 administration. Immunohistochemistry revealed these molecules localized in degenerating neurons. EGF administration resulted in neurological deterioration, increased TUNEL-positive neurons, and activation of EGFR, NIK, and NFκB. CONCLUSIONS: Activated EGFR, nuclear-NIK, and NFκB expressions were observed in cortical degenerating neurons after SAH, and were decreased by administration of AG1478, associated with suppression of TUNEL- and cleaved caspase-3-positive neurons. EGFR/NIK/NFκB pathway is suggested to be involved in neuronal apoptosis after SAH in mice.

Inflammatory Skin Disease Causes Anxiety Symptoms Leading to an Irreversible Course.

Intense itching significantly reduces the quality of life, and atopic dermatitis is associated with psychiatric conditions, such as anxiety and depression. Psoriasis, another inflammatory skin disease, is often complicated by psychiatric symptoms, including depression; however, the pathogenesis of these mediating factors is poorly understood. This study used a spontaneous dermatitis mouse model (KCASP1Tg) and evaluated the psychiatric symptoms. We also used Janus kinase (JAK) inhibitors to manage the behaviors. Gene expression analysis and RT-PCR of the cerebral cortex of KCASP1Tg and wild-type (WT) mice were performed to examine differences in mRNA expression. KCASP1Tg mice had lower activity, higher anxiety-like behavior, and abnormal behavior. The mRNA expression of S100a8 and Lipocalin 2 (Lcn2) in the brain regions was higher in KCASP1Tg mice. Furthermore, IL-1ß stimulation increased Lcn2 mRNA expression in astrocyte cultures. KCASP1Tg mice had predominantly elevated plasma Lcn2 compared to WT mice, which improved with JAK inhibition, but behavioral abnormalities in KCASP1Tg mice did not improve, despite JAK inhibition. In summary, our data revealed that Lcn2 is closely associated with anxiety symptoms, but the anxiety and depression symptoms caused by chronic skin inflammation may be irreversible. This study demonstrated that active control of skin inflammation is essential for preventing anxiety.

Neuroelectric Mechanisms of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) remains a challenging but very important condition, because DCI is preventable and treatable for improving functional outcomes after aneurysmal subarachnoid hemorrhage (SAH). The pathologies underlying DCI are multifactorial. Classical approaches to DCI focus exclusively on preventing and treating the reduction of blood flow supply. However, recently, glutamate-mediated neuroelectric disruptions, such as excitotoxicity, cortical spreading depolarization and seizures, and epileptiform discharges, have been reported to occur in high frequencies in association with DCI development after SAH. Each of the neuroelectric disruptions can trigger the other, which augments metabolic demand. If increased metabolic demand exceeds the impaired blood supply, the mismatch leads to relative ischemia, resulting in DCI. The neuroelectric disruption also induces inverted vasoconstrictive neurovascular coupling in compromised brain tissues after SAH, causing DCI. Although glutamates and the receptors may play central roles in the development of excitotoxicity, cortical spreading ischemia and epileptic activity-related events, more studies are needed to clarify the pathophysiology and to develop novel therapeutic strategies for preventing or treating neuroelectric disruption-related DCI after SAH. This article reviews the recent advancement in research on neuroelectric disruption after SAH.

Plasma Fibulin-5 Levels as an Independent Predictor of a Poor Outcome after an Aneurysmal Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is a poor-outcome disease with a delayed neurological exacerbation. Fibulin-5 (FBLN5) is one of matricellular proteins, some of which have been involved in SAH pathologies. However, no study has investigated FBLN5's roles in SAH. This study was aimed at examining the relationships between serially measured plasma FBLN5 levels and neurovascular events or outcomes in 204 consecutive aneurysmal SAH patients, including 77 patients (37.7%) with poor outcomes (90-day modified Rankin Scale 3-6). Plasma FBLN5 levels were not related to angiographic vasospasm, delayed cerebral ischemia, and delayed cerebral infarction, but elevated levels were associated with severe admission clinical grades, any neurological exacerbation and poor outcomes. Receiver-operating characteristic curves indicated that the most reasonable cut-off values of plasma FBLN5, in order to differentiate 90-day poor from good outcomes, were obtained from analyses at days 4-6 for all patients (487.2 ng/mL; specificity, 61.4%; and sensitivity, 62.3%) and from analyses at days 7-9 for only non-severe patient (476.8 ng/mL; specificity, 66.0%; and sensitivity, 77.8%). Multivariate analyses revealed that the plasma FBLN5 levels were independent determinants of the 90-day poor outcomes in both all patients' and non-severe patients' analyses. These findings suggest that the delayed elevation of plasma FBLN5 is related to poor outcomes, and that FBLN5 may be a new molecular target to reveal a post-SAH pathophysiology.

Tenascin-C in brain injuries and edema after subarachnoid hemorrhage: Findings from basic and clinical studies.

Subarachnoid hemorrhage (SAH) by a rupture of cerebral aneurysms remains the most devastating cerebrovascular disease. Early brain injury (EBI) is increasingly recognized to be the primary determinant for poor outcomes, and also considered to cause delayed cerebral ischemia (DCI) after SAH. Both clinical and experimental literatures emphasize the impact of global cerebral edema in EBI as negative prognostic and direct pathological factors. The nature of the global cerebral edema is a mixture of cytotoxic and vasogenic edema, both of which may be caused by post-SAH induction of tenascin-C (TNC) that is an inducible, non-structural, secreted and multifunctional matricellular protein. Experimental SAH induces TNC in brain parenchyma in rats and mice. TNC knockout suppressed EBI in terms of brain edema, blood-brain barrier disruption, neuronal apoptosis and neuroinflammation, associated with the inhibition of post-SAH activation of mitogen-activated protein kinases and nuclear factor-kappa B in mice. In a clinical setting, more severe SAH increases more TNC in cerebrospinal fluid and peripheral blood, which could be a surrogate marker of EBI and predict DCI development and outcomes. In addition, cilostazol, a selective inhibitor of phosphodiesterase type III that is a clinically available anti-platelet agent and is known to suppress TNC induction, dose-dependently inhibited delayed cerebral infarction and improved outcomes in a pilot clinical study. Thus, further studies may facilitate application of TNC as biomarkers for non-invasive diagnosis or assessment of EBI and DCI, and lead to development of a molecular target drug against TNC, contributing to the improvement of post-SAH outcomes.

Possible Involvement of Caspase-Independent Pathway in Neuronal Death After Subarachnoid Hemorrhage in Mice.

Early brain injury is now considered as an important cause of delayed neurological deterioration after aneurysmal subarachnoid hemorrhage (SAH), and neuronal apoptosis is one of the constituents of early brain injury. Caspase family is popular proteases in apoptotic pathways, but there also exist caspase-independent cell death pathways in many pathologic states. In this study, we investigated the ratio of caspase-related and caspase-unrelated neuronal deaths in a mice endovascular perforation SAH model. At 24 h after SAH, about half of neurons in the perforation-side cortex showed increased cleaved caspase-3 immunoreactivity. On the other hand, about half of cleaved caspase-3-immunonegative neurons showed abnormal morphology, suggesting that they were in the process of some sort of cell death in the absence of caspase-3 activity. These findings suggest that both caspase-dependent and caspase-independent signaling pathways may cause neuronal death after SAH.

Link Between Receptors That Engage in Developing Vasospasm After Subarachnoid Hemorrhage in Mice.

Vasospasm after subarachnoid hemorrhage (SAH) has been studied, but the mechanisms remain to be unveiled. Tenascin-C (TNC), which is a matricellular protein and reported to increase in spastic cerebral artery wall after SAH, is a ligand for both Toll-like receptor 4 (TLR4) and epidermal growth factor receptor (EGFR). Our previous studies suggested the involvement of TNC and these receptors in vasoconstriction or vasospasm after SAH. In this study, we investigated whether upregulation of TNC and TLR4 is observed and if an EGFR inhibitor has suppressive effects against them in a mice endovascular perforation SAH model. At 24 h after SAH, TNC and TLR4 expressions were widely observed in spastic cerebral arteries, and these expressions were suppressed by the administration of an EGFR inhibitor. From these results, EGFR inhibitors possibly suppress the expression of not only EGFR but also TLR4 at least partly through regulating TNC upregulation. More studies are needed to clarify the precise mechanisms linking these receptors.

Toll-Like Receptor 4 and Tenascin-C Signaling in Cerebral Vasospasm and Brain Injuries After Subarachnoid Hemorrhage.

Toll-like receptor 4 (TLR4) is expressed in various cell types in the central nervous system and exerts maximal inflammatory responses among the TLR family members. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of a cerebral aneurysm, and therefore its activation is reasonable as an initial step of cascades to brain injuries after aneurysmal subarachnoid hemorrhage (SAH). TLR4 activation induces tenascin-C (TNC), a representative of matricellular proteins that are a class of inducible, nonstructural, secreted, and multifunctional extracellular matrix glycoproteins. TNC is also an endogenous activator and inducer of TLR4, forming positive feedback mechanisms leading to more activation of the signaling transduction. Our studies have demonstrated that TLR4 as well as TNC are involved in inflammatory reactions, blood-brain barrier disruption, neuronal apoptosis, and cerebral vasospasm after experimental SAH. This article reviews recent understanding of TLR4 and TNC in SAH to suggest that the TLR4-TNC signaling may be an important therapeutic target for post-SAH brain injuries.

Modified Citrus Pectin Prevents Blood-Brain Barrier Disruption in Mouse Subarachnoid Hemorrhage by Inhibiting Galectin-3.

Background and Purpose- Plasma levels of galectin-3-a matricellular protein-are increased after aneurysmal subarachnoid hemorrhage (SAH), but the functional significance remains undetermined. This study was conducted to evaluate whether modified citrus pectin (MCP; galectin-3 inhibitor) prevents post-SAH early brain injury, focusing on blood-brain barrier disruption. Methods- C57BL/6 male adult mice (n=251) underwent sham or filament perforation SAH modeling, followed by a random intracerebroventricular injection of vehicle or drug at 30 minutes post-modeling. First, vehicle-treated and 0.8, 4, 16, or 32 µg MCP-treated mice were assessed by neuroscore and brain water content at 24 and 48 hours post-modeling. Second, Evans blue extravasation, Western blotting, coimmunoprecipitation and immunostaining were performed in vehicle-treated or 4 µg MCP-treated mice at 24 hours post-modeling. Third, vehicle or R-galectin-3 (recombinant galectin-3) was administered to SAH mice simultaneously with vehicle or MCP, and neuroscore and Evans blue extravasation were evaluated at 24 hours post-modeling. Fourth, vehicle or R-galectin-3 was administered to MCP-treated SAH mice at 24 hours, and neuroscore and IgG immunostaining were evaluated at 48 hours post-SAH. Results- Among tested dosages, 4 µg MCP showed the best neuroprotective effects as to preventing neurological impairments and brain edema at 24 to 48 hours post-SAH. Four micrograms MCP attenuated post-SAH blood-brain barrier disruption and galectin-3 upregulation in brain capillary endothelial cells, associated with inactivation of ERK (extracellular signal-related kinase) 1/2, STAT (signal transducer and activator of transcription)-3, and MMP (matrix metalloproteinase)-9, and the consequent preservation of a tight junction protein ZO-1 (zonula occludens-1). Coimmunoprecipitation assay demonstrated physical interactions between galectin-3 and TLR (Toll-like receptor) 4. R-galectin-3 blocked the neuroprotective effects of MCP. Conclusions- MCP prevents post-SAH blood-brain barrier disruption possibly by inhibiting galectin-3, of which the mechanisms may include binding to TLR4 and activating ERK1/2, STAT-3, and MMP-9. This study suggests galectin-3 to be a novel therapeutic target against post-SAH early brain injury.

Role of Periostin in Early Brain Injury After Subarachnoid Hemorrhage in Mice.

BACKGROUND AND PURPOSE: A matricellular protein tenascin-C is implicated in early brain injury after experimental subarachnoid hemorrhage (SAH). This study first evaluated the role of another matricellular protein periostin and the relationships with tenascin-C in post-SAH early brain injury. METHODS: Wild-type (n=226) and tenascin-C knockout (n=9) C57BL/6 male adult mice underwent sham or filament perforation SAH modeling. Vehicle, anti-periostin antibody, or recombinant periostin was randomly administrated by an intracerebroventricular injection at 30 minutes post-modeling. Neuroscores, SAH grading, brain water content, immunostaining, and Western blotting were blindly evaluated at 24 to 48 hours post-SAH. RESULTS: Periostin was induced in brain capillary endothelial cells and neurons at 24 hours post-SAH. Anti-periostin antibody improved post-SAH neurobehavior, brain edema, and blood-brain barrier disruption associated with downregulation of tenascin-C, inactivation of p38, extracellular signal-related kinase 1/2 and matrix metalloproteinase-9, and subsequent preservation of zona occludens-1. Recombinant periostin aggravated post-SAH brain edema and tenascin-C induction. Tenascin-C knockout prevented post-SAH neurobehavioral impairments and periostin induction. CONCLUSIONS: Periostin may cause post-SAH early brain injury through activating downstream signaling pathways and interacting with tenascin-C, providing a novel approach for the treatment of early brain injury.

Vascular Endothelial Growth Factor in Brain Edema Formation After Subarachnoid Hemorrhage.

Vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of brain edema formation after experimental subarachnoid hemorrhage (SAH). In this study, we evaluated the effect of anti-VEGF antibody neutralization on brain edema formation after experimental SAH in mice. Mice underwent sham operation or filament puncture SAH and were assigned to sham, SAH + vehicle, or SAH + anti-VEGF antibody groups. Vehicle or anti-VEGF antibody was administrated by an intracerebroventricular injection at 30 min post-SAH. After 24 h of SAH modeling, neurological score was recorded to evaluate neurobehavioral functions, brain water content was calculated to assess the level of brain edema, and immunohistochemistry of immunoglobulin (Ig) G was performed to evaluate the permeability of the blood-brain barrier (BBB). Anti-VEGF antibody significantly ameliorated neurological score and brain edema after SAH compared with the SAH + vehicle group. Immunohistochemistry showed that post-SAH IgG extravasation in brain tissue was suppressed by anti-VEGF antibody. This study suggests that VEGF is involved in brain edema formation after SAH, and that anti-VEGF antibody can decrease BBB permeability, suppress brain edema formation, and improve functional outcome after 24 h of SAH.

The Role of Matricellular Proteins in Brain Edema after Subarachnoid Hemorrhage.

Accumulated evidence suggests that blood-brain barrier disruption or brain edema is an important pathologic manifestation for poor outcome after aneurysmal subarachnoid hemorrhage. Many molecules may be involved, acting simultaneously or at different stages during blood-brain barrier disruption via multiple independent or interconnected signaling pathways. Matricellular protein is a class of nonstructural, secreted, and multifunctional extracellular matrix proteins, which potentially mediates brain edema formation. This study reviews the role of osteopontin and tenascin-C, representatives of matricellular proteins, in the context of brain edema formation after subarachnoid hemorrhage in both clinical and experimental settings.

[Distribution of Pain and Numbness in Patients with Cervical Spine Disorders].

PURPOSE: To elucidate the distribution of improved pain and numbness after cervical decompression surgery in patients with cervical spine disorders. METHODS: This study included 4 men and 5 women aged 45 to 71 years(mean 58 years)presenting with radiculopathy and 50 men and 17 women aged 35 to 88 years(mean 66 years)presenting with myelopathy. RESULTS: All 9 patients with radiculopathy presented with neck pain, and 3 presented with cervical angina. Among the patients with myelopathy, 2 presented with headache, 2 with onion-skin facial pain, 29 with neck pain, 8 with truncal pain, 7 with low back pain, 4 with numbness below the T4 dermatomal area, 1 with penile pain, 61 with arm pain, 49 with leg pain, and 2 without pain or numbness. Patients with myelopathy presenting with preoperative neck and arm pain had significantly better recovery rates compared to patients without such pain. CONCLUSION: Patients with cervical spine disorders present with pain and numbness in various areas. Preoperative neck pain and arm pain are indicators for better recovery in patients with myelopathy.

Vasoconstrictive effect of tenascin-C on cerebral arteries in rats.

BACKGROUND AND PURPOSE: The authors have reported that tenascin-C (TNC), a matricellular protein, is induced after subarachnoid hemorrhage (SAH), associated with cerebral vasospasm. In this study, we examined whether TNC alone causes cerebral vasospasm-like constriction of the intracranial internal carotid arteries (ICAs) in rats, focusing on the p38 mitogen-activated protein kinase (MAPK)-mediated mechanisms. METHODS: First, we injected 10 µg of TNC into the cisterna magna of healthy rats and studied morphologically whether TNC caused constriction of the left ICA at 24-72 h after administration. Second, we examined the effect of SB203580 (a p38 MAPK inhibitor) on the vessel diameter of the left ICA in healthy rats at 24 h. Third, we evaluated the effect of SB203580 on TNC-induced constriction of the left ICA in healthy rats at 24 h. RESULTS: TNC significantly induced cerebral vasospasm-like angiographic constriction of the left ICAs, which continued at least for 72 h. SB203580 itself had no effect on the diameter of normal ICAs, but abolished the TNC-induced vasoconstrictive effect on the left ICA. CONCLUSION: These findings show that TNC causes left ICA constriction via activation of p38 MAPK, resembling post-SAH vasospasm, and suggest the possible involvement of TNC in the pathogenesis of cerebral vasospasm.

Anti-Apoptotic Effects of AMPA Receptor Antagonist Perampanel in Early Brain Injury After Subarachnoid Hemorrhage in Mice.

This study was aimed to investigate if acute neuronal apoptosis is induced by activation of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors (AMPARs) and inhibited by a clinically available selective AMPAR antagonist and antiepileptic drug perampanel (PER) in subarachnoid hemorrhage (SAH), and if the mechanisms include upregulation of an inflammation-related matricellular protein periostin. Sham-operated and endovascular perforation SAH mice randomly received an administration of 3 mg/kg PER or the vehicle intraperitoneally. Post-SAH neurological impairments and increased caspase-dependent neuronal apoptosis were associated with activation of AMPAR subunits GluA1 and GluA2, and upregulation of periostin and proinflammatory cytokines interleukins-1ß and -6, all of which were suppressed by PER. PER also inhibited post-SAH convulsion-unrelated increases in the total spectral power on video electroencephalogram (EEG) monitoring. Intracerebroventricularly injected recombinant periostin blocked PER's anti-apoptotic effects on neurons. An intracerebroventricular injection of a selective agonist for GluA1 and GluA2 aggravated neurological impairment, neuronal apoptosis as well as periostin upregulation, but did not increase the EEG total spectral power after SAH. A higher dosage (10 mg/kg) of PER had even more anti-apoptotic effects compared with 3 mg/kg PER. Thus, this study first showed that AMPAR activation causes post-SAH neuronal apoptosis at least partly via periostin upregulation. A clinically available AMPAR antagonist PER appears to be neuroprotective against post-SAH early brain injury through the anti-inflammatory and anti-apoptotic effects, independent of the antiepileptic action, and deserves further study.

Cilostazol May Improve Outcomes Even in Patients with Aneurysmal Subarachnoid Hemorrhage Aged 75 Years and Older: Multicenter Cohort Study and Propensity Score-Matched Analyses.

BACKGROUND: The opportunities to treat elderly patients with aneurysmal subarachnoid hemorrhage (aSAH) are increasing globally, but the outcome remains poor. This study seeks to investigate treatment-related factors that can modify functional outcomes in patients with aSAH aged ≥75 years. METHODS: A total of 202 patients with aSAH aged ≥75 years prospectively enrolled in 9 primary stroke centers from 2013 to 2021 were retrospectively analyzed. Clinical variables including treatments for hydrocephalus, angiographic vasospasm, and delayed cerebral ischemia were compared between patients with good (modified Rankin Scale [mRS] score 0-2) and poor (mRS score 3-6) outcomes at 90 days from onset, followed by multivariate analyses to find independent outcome determinants. A modifiable treatment-related variable was evaluated after propensity score matching with adjustments for age, sex, pre-onset mRS score, aSAH severity, and treatment modality. RESULTS: More than half of patients showed World Federation of Neurological Societies grades IV-V on admission. Univariate analyses showed that advanced age, worse pre-onset mRS score, more severe neurologic status on admission, higher modified Fisher grade on admission computed tomography scans, and acute and chronic hydrocephalus were associated with poor outcomes. In contrast, administration of a phosphodiesterase type III inhibitor, cilostazol, was associated with good outcomes in both univariate (P = 0.036) and multivariate analyses (adjusted odds ratio, 0.305; 95% confidence interval, 0.097-0.955; P = 0.042). Propensity score matching analyses showed that patients treated with cilostazol had better outcomes (P = 0.016) with fewer incidences of delayed cerebral infarction (P = 0.008). CONCLUSIONS: Even in patients with aSAH aged ≥75 years, cilostazol administration may lead to better outcomes by suppressing the development of delayed cerebral infarction.

Plasma SPARC Elevation in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

Matricellular proteins have been implicated in pathologies after subarachnoid hemorrhage (SAH). To find a new therapeutic molecular target, the present study aimed to clarify the relationships between serially measured plasma levels of a matricellular protein, secreted protein acidic and rich in cysteine (SPARC), and delayed cerebral ischemia (DCI) in 117 consecutive aneurysmal SAH patients with admission World Federation of Neurological Surgeons (WFNS) grades I-III. DCI developed in 25 patients with higher incidences of past history of hypertension and dyslipidemia, preoperative WFNS grade III, modified Fisher grade 4, spinal drainage, and angiographic vasospasm. Plasma SPARC levels were increased after SAH, and significantly higher in patients with than without DCI at days 7-9, and in patients with VASOGRADE-Yellow compared with VASOGRADE-Green at days 1-3 and 7-9. However, there were no relationships between plasma SPARC levels and angiographic vasospasm. Receiver-operating characteristic curves differentiating DCI from no DCI determined the cut-off value of plasma SPARC ≥ 82.1 ng/ml at days 7 - 9 (sensitivity, 0.800; specificity, 0.533; and area under the curve, 0.708), which was found to be an independent determinant of DCI development in multivariate analyses. This is the first study to show that SPARC is upregulated in peripheral blood after SAH, and that SPARC may be involved in the development of DCI without angiographic vasospasm in a clinical setting.

Effects of New-Generation Antiepileptic Drug Prophylaxis on Delayed Neurovascular Events After Aneurysmal Subarachnoid Hemorrhage.

Neuroelectric disruptions such as seizures and cortical spreading depolarization may contribute to the development of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). However, effects of antiepileptic drug prophylaxis on outcomes remain controversial in SAH. The authors investigated if prophylactic administration of new-generation antiepileptic drugs levetiracetam and perampanel was beneficial against delayed neurovascular events after SAH. This was a retrospective single-center cohort study of 121 consecutive SAH patients including 56 patients of admission World Federation of Neurological Surgeons grades IV - V who underwent aneurysmal obliteration within 72 h post-SAH from 2013 to 2021. Prophylactic antiepileptic drugs differed depending on the study terms: none (2013 - 2015), levetiracetam for patients at high risks of seizures (2016 - 2019), and perampanel for all patients (2020 - 2021). The 3rd term had the lowest occurrence of delayed cerebral microinfarction on diffusion-weighted magnetic resonance imaging, which was related to less development of DCI. Other outcome measures were similar among the 3 terms including incidences of angiographic vasospasm, computed tomography-detectable delayed cerebral infarction, seizures, and 3-month good outcomes (modified Rankin Scale 0 - 2). The present study suggests that prophylactic administration of levetiracetam and perampanel was not associated with worse outcomes and that perampanel may have the potential to reduce DCI by preventing microcirculatory disturbances after SAH. Further studies are warranted to investigate anti-DCI effects of a selective α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist perampanel in SAH patients in a large-scale prospective study.

Inhibition of AMPA (α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate) Receptor Reduces Acute Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice.

Activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) is thought to cause acute brain injury, but the role remains poorly understood in subarachnoid hemorrhage (SAH). This study was conducted to evaluate if AMPAR activation induces acute blood-brain barrier (BBB) disruption after SAH. C57BL/6 male adult mice (n = 117) underwent sham or filament perforation SAH modeling, followed by a random intraperitoneal injection of vehicle or two dosages (1 mg/kg or 3 mg/kg) of a selective noncompetitive AMPAR antagonist perampanel (PER) at 30 min post-modeling. The effects were evaluated by mortality, neurological scores, and brain water content at 24-48 h and video electroencephalogram monitoring, immunostaining, and Western blotting at 24 h post-SAH. PER significantly suppressed post-SAH neurological impairments, brain edema, and BBB disruption. SAH developed epileptiform spikes without obvious convulsion, which were also inhibited by PER. Western blotting showed that the expression of AMPAR subunits GluA1 and GluA2 was unchanged after SAH, but they were significantly activated after SAH. PER prevented post-SAH activation of GluA1/2, associated with the suppression of post-SAH induction of tenascin-C, a causative mediator of post-SAH BBB disruption. Meanwhile, an intracerebroventricular injection of a subtype-selective GluA1/2 agonist augmented the activation of GluA1/2 and the induction of tenascin-C in brain capillary endothelial cells and aggravated post-SAH BBB disruption without increases in epileptiform spikes. Neurological impairments and brain edema were not correlated with the occurrence of epileptiform spikes. This study first showed that AMPAR plays an important role in the development of post-SAH BBB disruption and can be a novel therapeutic target against it.