Pharmacological Inhibition of Epidermal Growth Factor Receptor Prevents Intracranial Aneurysm Rupture by Reducing Endoplasmic Reticulum Stress.

BACKGROUND: Multiple pathways and factors are involved in the rupture of intracranial aneurysms. The EGFR (epidermal growth factor receptor) has been shown to mediate inflammatory vascular diseases, including atherosclerosis and aortic aneurysm. However, the role of EGFR in mediating intracranial aneurysm rupture and its underlying mechanisms have yet to be determined. Emerging evidence indicates that endoplasmic reticulum (ER) stress might be the link between EGFR activation and the resultant inflammation. ER stress is strongly implicated in inflammation and apoptosis of vascular smooth muscle cells, both of which are key components of the pathophysiology of aneurysm rupture. Therefore, we hypothesized that EGFR activation promotes aneurysmal rupture by inducing ER stress. METHODS: Using a preclinical mouse model of intracranial aneurysm, we examined the potential roles of EGFR and ER stress in developing aneurysmal rupture. RESULTS: Pharmacological inhibition of EGFR markedly decreased the rupture rate of intracranial aneurysms without altering the formation rate. EGFR inhibition also significantly reduced the mRNA (messenger RNA) expression levels of ER-stress markers and inflammatory cytokines in cerebral arteries. Similarly, ER-stress inhibition also significantly decreased the rupture rate. In contrast, ER-stress induction nullified the protective effect of EGFR inhibition on aneurysm rupture. CONCLUSIONS: Our data suggest that EGFR activation is an upstream event that contributes to aneurysm rupture via the induction of ER stress. Pharmacological inhibition of EGFR or downstream ER stress may be a promising therapeutic strategy for preventing aneurysm rupture and subarachnoid hemorrhage.

Suppression of MALAT1 alleviates neurocyte apoptosis and reactive oxygen species production through the miR-499-5p/SOX6 axis in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH), a common devastating cerebrovascular accident, is a great threat to human health and life. Exploration of the potential therapeutic target of SAH is urgently needed. Previous studies showed that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes cell apoptosis in various diseases, while its role in SAH remains unclear. In our study, we established a mouse model of SAH and used the oxyhemoglobin (OxyHb) to induce neuronal injury in vitro. Interestingly, MALAT1 was found upregulated in brain tissues of SAH mice and OxyHb-stimulated neurons. In addition, knockdown of MALAT1 attenuated apoptosis and decreased reactive oxygen species (ROS) production in OxyHb-stimulated neurons. Mechanistically, we demonstrated that MALAT1 bound with miR-499-5p. Furthermore, our findings indicated that miR-499-5p bound to SOX6 3' untranslated region (UTR) and negatively regulated SOX6 mRNA and protein levels. Rescue assays suggested that SOX6 overexpression counteracted the effects of MALAT1 knockdown on neurocyte apoptosis, and ROS production in OxyHb-stimulated neurons. The in vivo assays indicated that knockdown of MALAT1 improved brain injury of SAH mice. Our study demonstrates that silencing of MALAT1 alleviates neurocyte apoptosis and reduces ROS production through the miR-499-5p/SOX6 axis after SAH injury.

Microsurgery versus embolization: different risk factors for short- and long- term outcomes of patients with ruptured aneurysms

Purpose: To evaluate the risk factors for poor outcomes after surgical and endovascular treatment of aneurysmal subarachnoid hemorrhage (aSAH). Methods: Patients with ≥ 18-years of age and aSAH were included, while patients who died within 12 h of admission or lost follow-up were excluded. All participants underwent standardized clinical and radiological assessment on admission and were reassessed at discharge and at 6-months follow-up using the Glasgow Outcome Scale (GOS). Results: Death at discharge was associated with female gender, anterior communication artery (ACoA) aneurysm location and presence of atherosclerotic plaque in the surgical group, and with age in the endovascular group. Both groups had clinical condition on follow-up associated with mFisher score on admission and hypertension. GOS on follow-up was also associated with presence of atherosclerotic plaque and multiple aneurysms in surgical group, and with age in endovascular group. Conclusions: Subjects treated surgically are prone to unfavorable outcomes if atherosclerotic plaques and multiple aneurysms are present. In patients with endovascular treatment, age was the main predictor of clinical outcome.

Warning Signs in the Era of Unruptured Intracranial Aneurysms: Report on 2 Cases of Fatal Aneurysmal Hemorrhage.

INTRODUCTION: The timing of treatment remains unresolved for patients with unruptured intracranial aneurysms (UIAs) and headaches, particularly when the pain is short term, localized, and related to the aneurysm site. We lack evidence to support the notion that when a headache accompanies an aneurysm, it elevates the risk of rupture. RESULTS: We describe 2 cases of fatal subarachnoid hemorrhage in patients with a history of headache and known aneurysms. Both of these patients had good indications for treatment: a young age and an aneurysm >7 mm, and both were qualified for elective surgery. However, both patients died of fatal aneurysm ruptures before the planned surgery. CONCLUSION: These cases suggested that treatment should be started as soon as possible, when a UIA is diagnosed based on a short-term period of severe headaches or when a UIA is observed and then severe headaches appear. There is no straightforward guideline for treatment timing in these patients. However, in this era of UIAs, the significance of sentinel headaches should be reevaluated. Given the incidence of headaches in the general population and the very low risk of aneurysm rupture, there may be a tendency to neglect the role of headache as a possible warning sign.

MerTK inhibits the activation of the NLRP3 inflammasome after subarachnoid hemorrhage by inducing autophagy.

The NLR family pyrin domain-containing 3 (NLRP3) multiprotein complex is associated with neuroinflammation and poor prognosis after subarachnoid hemorrhage (SAH). Accumulating evidence shows that Mer tyrosine kinase (MerTK) alleviates inflammatory responses via a negative feedback mechanism. However, the contribution and function of MerTK in SAH remain to be determined. In this study, we explored the role of MerTK during microglial NLRP3 inflammasome activation and evaluated its contribution to the outcome of SAH in mice. Activating MerTK with growth arrest-specific 6 (Gas6) alleviated brain edema, neuronal degeneration and neurological deficits after SAH by regulating neuroinflammation. Gas6 did not change the mRNA levels of Nlrp3 or Casp1 but decreased the protein expression of NLRP3, cleaved caspase1 (p20), interleukin-1ß and interleukin-18. Furthermore, Gas6 increased the expression of Beclin1, the ratio of LC3-II/LC3-I and the level of autophagic flux. Inhibiting autophagy with 3-MA reversed the inhibition of NLRP3 inflammasome activation and diminished the neuroprotective effects of Gas6. Thus, MerTK activation may exert protective effects by limiting neuroinflammation and promoting neurological recovery after SAH via autophagy induction.

MiR-706 alleviates white matter injury via downregulating PKCα/MST1/NF-κB pathway after subarachnoid hemorrhage in mice.

Increasing numbers of patients with spontaneous subarachnoid hemorrhage(SAH) who recover from surgery and intensive care management still live with cognitive impairment after discharge, indicating the importance of white matter injury at the acute stage of SAH. In the present study, standard endovascular perforation was employed to establish an SAH mouse model, and a microRNA (miRNA) chip was used to analyze the changes in gene expression in white matter tissue after SAH. The data indicate that 17 miRNAs were downregulated, including miR-706, miR-669a-5p, miR-669p-5p, miR-7116-5p and miR-195a-3p, while 13 miRNAs were upregulated, including miR-6907-5p, miR-5135, miR-6982-5p, miR-668-5p, miR-8119. Strikingly, miR-706 was significantly downregulated with the highest fold change. Further experiments confirmed that miR-706 could alleviate white matter injury and improve neurological behavior, at least partially by inhibiting the PKCα/MST1/NF-κB pathway and the release of inflammatory cytokines. These results might provide a deeper understanding of the pathophysiological processes in white matter after SAH, as well as potential therapeutic strategies for the translational research.

Neuroprotective Effects of Early Brain Injury after Subarachnoid Hemorrhage in Rats by Calcium Channel Mediating Hydrogen Sulfide.

The present study explored the modulating apoptosis effect of hydrogen sulfide (H2S) in subarachnoid hemorrhage (SAH) rats and its exact mechanism. A rat SAH model established by intravascular puncturing was used for the present study. After giving NaHS (donor of H2S), an L-type calcium channel opener (Bay K8644), or a calcium channel agonist (nifedipine), the neurological function of the rats, associated pathological changes, and expression of apoptosis-related proteins (Bcl-2, Bax, and caspase-3) and microtubule-associated protein (MAP-2) were examined. The concentration of H2S and expression of cystathionine beta synthase in the hippocampus changed upon early brain injury (EBI) after SAH. Compared with the SAH group, the neurological function of the rats and microstructure observed by electron microscopy were better in the SAH + NaHS group and SAH + Bay K8644 group. It was observed that apoptosis was more obvious in the SAH group than in the control group and was alleviated in the SAH + NaHS group. Furthermore, the alleviating effect of NaHS was partially weakened by nifedipine, indicating that the effect of anti-apoptosis in H2S might be correlated with the calcium channel. The expression of Bax and caspase-3 was elevated, while the expression of Bcl-2 decreased in the SAH group but improved in the SAH + NaHS and SAH + Bay K8644 group. Compared with the SAH + NaHS group, the expression of pro-apoptotic proteins was higher in the SAH + NaHS + nifedipine group. Therefore, upon EBI following SAH, the H2S system plays an important neurological protective effect by modulating the function of the L-type calcium channel and inhibiting apoptosis.

Mast Cell Promotes the Development of Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Inflammation has emerged as a key component of the pathophysiology of intracranial aneurysms. Mast cells have been detected in human intracranial aneurysm tissues, and their presence was associated with intramural microhemorrhage and wall degeneration. We hypothesized that mast cells play a critical role in the development of aneurysmal rupture, and that mast cells can be used as a therapeutic target for the prevention of aneurysm rupture. METHODS: Intracranial aneurysms were induced in adult mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Aneurysm formation and rupture were assessed over 3 weeks. Roles of mast cells were assessed using a mast cell stabilizer (cromolyn), a mast cell activator (C48/80), and mice that are genetically lacking mature mast cells (KitW-sh/W-sh mice). RESULTS: Pharmacological stabilization of mast cells with cromolyn markedly decreased the rupture rate of aneurysms (80% versus 19%, n=10 versus n =16) without affecting the aneurysm formation. The activation of mast cells with C48/80 significantly increased the rupture rate of aneurysms (25% versus 100%, n=4 versus n=5) without affecting the overall rate of aneurysm formation. Furthermore, the genetic deficiency of mast cells significantly prevented aneurysm rupture (80% versus 25%, n=10 versus n=8, wild-type versus KitW-sh/W-sh mice). CONCLUSIONS: These results suggest that mast cells play a key role in promoting aneurysm rupture but not formation. Stabilizers of mast cells may have a potential therapeutic value in preventing intracranial aneurysm rupture in patients.

Clipping Versus Coiling in the Management of Unruptured Aneurysms with Multiple Risk Factors.

OBJECTIVE: We investigated the outcomes of patients with an unruptured intracranial aneurysm (UIA) and >2 risk factors concerning complications, obliteration rate, and other factors after surgical or endovascular treatment. METHODS: Coiling and clipping were compared in patients with UIAs treated in West China Hospital from January 2015 to May 2017. Patient survival, dependency, retreatment, complications, and other clinical outcome indexes were compared between the 2 groups. RESULTS: A total of 82 patients (92 aneurysms) had undergone treatment for UIAs with multiple risk factors. Of these 82 patients, 45 (54.9%) had undergone clipping and 37 (45.1%) had undergone coiling. No deaths were related to either treatment. Morbidity (modified Rankin scale score >2) at 1 year had developed in 1 of 45 and 1 of 37 patients in the clipping and coiling groups, without a statistically significant difference. Hospitalization >5 days (30 of 45 vs. 12 of 37; P < 0.05) was less frequent after coiling. The number of aneurysms with complete occlusion (48 of 51 vs. 33 of 41; P < 0.05) was greater in the surgical group. No differences in peritreatment complications were found in the surgical and endovascular groups (8 of 45 vs. 6 of 37; P > 0.05). CONCLUSIONS: In our study, clipping and coiling showed advantages for the treatment of UIAs with multiple risk factors. Surgical clipping of UIAs is achievable with a low rate of unfavorable outcomes and a high rate of complete obliteration for patients with multiple risk factors. However, endovascular treatment was also successful, with a shorter length of stay and low procedure-related morbidity. Additional randomized evidence are required to support the superior efficacy of clipping.

Effect of Gastrodin on Early Brain Injury and Neurological Outcome After Subarachnoid Hemorrhage in Rats.

Gastrodin is a phenolic glycoside that has been demonstrated to provide neuroprotection in preclinical models of central nervous system disease, but its effect in subarachnoid hemorrhage (SAH) remains unclear. In this study, we showed that intraperitoneal administration of gastrodin (100 mg/kg per day) significantly attenuated the SAH-induced neurological deficit, brain edema, and increased blood-brain barrier permeability in rats. Meanwhile, gastrodin treatment significantly reduced the SAH-induced elevation of glutamate concentration in the cerebrospinal fluid and the intracellular Ca2+ overload. Moreover, gastrodin suppressed the SAH-induced microglial activation, astrocyte activation, and neuronal apoptosis. Mechanistically, gastrodin significantly reduced the oxidative stress and inflammatory response, up-regulated the expression of nuclear factor erythroid 2-related factor 2, heme oxygenase-1, phospho-Akt and B-cell lymphoma 2, and down-regulated the expression of BCL2-associated X protein and cleaved caspase-3. Our results suggested that the administration of gastrodin provides neuroprotection against early brain injury after experimental SAH.

Complications of endovascular treatment for acute ischemic stroke: Prevention and management.

Endovascular mechanical thrombectomy (MT) for the treatment of acute stroke due to large vessel occlusion has evolved significantly with the publication of multiple positive thrombectomy trials. MT is now a recommended treatment for acute ischemic stroke. Mechanical thrombectomy is associated with a number of intra-procedural or post-operative complications, which need to be minimized and effectively managed to maximize the benefits of thrombectomy. Procedural complications include: access-site problems (vessel/nerve injury, access-site hematoma and groin infection); device-related complications (vasospasm, arterial perforation and dissection, device detachment/misplacement); symptomatic intracerebral hemorrhage; subarachnoid hemorrhage; embolization to new or target vessel territory. Other complications include: anesthetic/contrast-related, post-operative hemorrhage, extra-cranial hemorrhage and pseudoaneurysm. Some complications are life-threatening and many lead to increased length of stay in intensive care and stroke units. Complications increase costs and delay the commencement of rehabilitation. Some may be preventable; the impact of others can be minimized with early detection and appropriate management. Both neurointerventionists and stroke specialists need to be aware of the risk factors, strategies for prevention, and management of these complications. With the increasing use of mechanical thrombectomy for the treatment of acute ischemic stroke, incidence and outcome of complications will need to be carefully monitored by stroke teams. In this narrative review, we examine the frequency of complications of MT in the treatment of acute ischemic stroke with an emphasis on periprocedural complications. Overall, from recent randomized controlled trials, the risk of complications with sequelae for patient from mechanical thrombectomy is ∼15%. We discuss the management of complications and identify areas with limited evidence, which need further research. Search strategy and selection criteria Relevant evidence was found by searches of Medline and Cochrane Library, reference list, cross-referencing and main journal content pages. Search terms included "brain ischemia", "acute ischemic stroke", "cerebral infarction" AND "mechanical thrombectomy", "endovascular therapy", "endovascular treatment", "endovascular embolectomy", "intra-arterial" AND "randomized controlled trial", "non-randomised trials", "observational studies" AND "complications", "procedural complications", "peri-procedural complications", "device-related complications", "management", "treatment", "outcome". The search included only human studies, and was limited to studies published in English between January 2014 and November 2016. The final reference list was selected on the basis of relevance to the topics covered in the Review. Guidelines for management of acute ischaemic stroke by the American Heart Association, the European Stroke Organisation, multi-disciplinary guidelines and the National Institute for Health and Care Excellence (NICE) were also reviewed.

Seizures and Epilepsy following Subarachnoid Hemorrhage: A Review on Incidence, Risk Factors, Outcome and Treatment

The mortality rates of subarachnoid hemorrhage (SAH) average 51%, and survivors frequently experience acute and long-term neurological conditions, including seizures and epilepsy. The incidence of post SAH-related seizures and epilepsy, its risk factors, outcomes and management are controversial. The present paper aims to discuss these aspects, to provide the pros and cons of different management options of this condition. A review on PubMed was performed encompassing the incidence of seizures and epilepsy following SAH, the risk factors for its occurrence, its related outcomes, and treatment. The incidence of seizures and epilepsy following SAH varies widely in the literature (from 6 to 26%). Some possible risk factors were identified, such as middle cerebral artery (MCA) aneurysm, Hunt and Hess grade III, aneurysm clipping, thick subarachnoid clot, intracerebral hemorrhage, rebleeding, ischemic brain infarction, Fisher grade III or IV, acute hydrocephalus, hypertension history and poorWorld Federation of Neurosurgical Societies (WFNS) grade. Nevertheless, these relations are frequently uncertain. Also, it appears that the outcome of patients who suffered SAH is worsened by seizures. Given these uncertainties, the need for antiepileptic drug (AED) prophylaxis, the choice of the best drug and dose, as well as the duration of the treatment are controversial topics. However, some recommendations based on low quality evidence are reasonable to be adopted. These include considering AED prophylaxis when a seizure occur after SAH, considering routine long-term AED prophylaxis in specific populations, considering electroencephalogram (EEG) monitoring, and avoiding phenytoin prescription. That is, an individualized approach appears to be the best option, since there is no high-quality evidence.

ErbB4 protects against neuronal apoptosis via activation of YAP/PIK3CB signaling pathway in a rat model of subarachnoid hemorrhage.

Neuronal apoptosis is a central pathological process in subarachnoid hemorrhage (SAH)-induced early brain injury. Previous studies indicated that ErbB4 (EGFR family member v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4) is essential for normal development and maintenance of the nervous system. In this study, we explored the neuroprotective effects of ErbB4 and its downstream YAP (yes-associated protein)/PIK3CB signaling pathway in early brain injury after SAH in a rat model using the endovascular perforation method. Rats were neurologically evaluated with the Modified Garcia Scale and beam balance test at 24h and 72h after SAH. An ErbB4 activator Neuregulin 1ß1 (Nrg 1ß1), ErbB4 siRNA and YAP siRNA were used to explore this pathway. The expression of p-ErbB4 and YAP was significantly increased after SAH. Multiple immunofluorescence labeling experiments demonstrated that ErbB4 is mainly expressed in neurons. Activation of ErbB4 and its downstream signals improved the neurological deficits after SAH and significantly reduced neuronal cell death. Inhibition of ErbB4 reduced YAP and PIK3CB expression, and aggravated cell apoptosis. YAP knockdown reduced the PIK3CB level and eliminated the anti-apoptotic effects of ErbB4 activation. These findings indicated that ErbB4 plays a neuroprotective role in early brain injury after SAH, possibly via the YAP/PIK3CB signaling pathway.

Netrin-1 Preserves Blood-Brain Barrier Integrity Through Deleted in Colorectal Cancer/Focal Adhesion Kinase/RhoA Signaling Pathway Following Subarachnoid Hemorrhage in Rats.

BACKGROUND: Netrin-1 (NTN-1) has been established to be a novel intrinsic regulator of blood-brain barrier (BBB) maintenance. This study was carried out to investigate the potential roles of exogenous NTN-1 in preserving BBB integrity after experimental subarachnoid hemorrhage (SAH) as well as the underlying mechanisms of its protective effects. METHODS AND RESULTS: A total of 309 male Sprague-Dawley rats were subjected to an endovascular perforation model of SAH. Recombinant NTN-1 was administered intravenously 1 hour after SAH induction. NTN-1 small interfering RNA or Deleted in Colorectal Cancer small interfering RNA was administered intracerebroventricular at 48 hours before SAH. Focal adhesion kinase inhibitor was administered by intraperitoneal injection at 1 hour prior to SAH. Neurological scores, brain water content, BBB permeability, RhoA activity, Western blot, and immunofluorescence staining were evaluated. The expression of endogenous NTN-1 and its receptor Deleted in Colorectal Cancer were increased after SAH. Administration of exogenous NTN-1 significantly reduced brain water content and BBB permeability and ameliorated neurological deficits at 24 and 72 hours after SAH. Exogenous NTN-1 treatment significantly promoted phosphorylated focal adhesion kinase activation and inhibited RhoA activity, as well as upregulated the expression of ZO-1 and Occludin. Conversely, depletion of endogenous NTN-1 aggravated BBB breakdown and neurological impairments at 24 hours after SAH. The protective effects of NTN-1 at 24 hours after SAH were also abolished by pretreatment with Deleted in Colorectal Cancer small interfering RNA and focal adhesion kinase inhibitor. CONCLUSIONS: NTN-1 treatment preserved BBB integrity and improved neurological functions through a Deleted in Colorectal Cancer/focal adhesion kinase/RhoA signaling pathway after SAH. Thus, NTN-1 may serve as a promising treatment to alleviate early brain injury following SAH.

Reduction in Autophagy by (-)-Epigallocatechin-3-Gallate (EGCG): a Potential Mechanism of Prevention of Mitochondrial Dysfunction After Subarachnoid Hemorrhage.

Mitochondrial dysfunction and subsequent autophagy, which are common features in central nervous system (CNS) disorders, were found to contribute to neuronal cell injury after subarachnoid hemorrhage (SAH). (-)-Epigallocatechin-3-gallate (EGCG), the main biological active of tea catechin, is well known for its beneficial effects in the treatment of CNS diseases. Here, the ability of EGCG to rescue cellular injury and mitochondrial function following the improvement of autophagic flux after SAH was investigated. As expected, EGCG-protected mitochondrial function depended on the inhibition of cytosolic Ca2+ concentration ([Ca2+]i) influx via voltage-gated calcium channels (VGCCs) and, consequently, mitochondrial Ca2+ concentration ([Ca2+]m) overload via mitochondrial Ca2+ uniporter (MCU). The attenuated [Ca2+]i and [Ca2+]m levels observed in the EGCG-treated group likely lessened oxyhemoglobin (OxyHb)-induced mitochondrial dysfunction, including mitochondrial membrane potential depolarization, mitochondrial membrane permeability transition pore (mPTP) opening, reactive oxygen species (ROS), and cytochrosome c (cyt c) releasing. Subsequently, EGCG can restore the disrupted autophagy flux after SAH both at the initiation and formation stages by regulating Atg5, LC3B, and Becn-1 (Beclin-1) mRNA expressions. Thus, precondition EGCG resulted in autophagosomes and more autolysosomes compared with SAH group. As a result, EGCG pre-treatment increased the neurological score and decreased cell death. This study suggested that the mitochondrial dysfunction and abnormal autophagy flux synergistically contribute to SAH pathogenesis. Thus, EGCG can be regarded as a new pharmacological agent that targets both mitochondria and altered autophagy in SAH therapy.

[Japanese Guidelines for the Management of Stroke 2015: overview of the chapter on Subarachnoid Hemorrhage].

After an interval of 6 years, the Japanese Guidelines for the Management of Stroke were revised in 2015 in accordance with recent advances in clinical knowledge. The chapter on subarachnoid hemorrhage includes new and revised recommendations for diagnosis, treatment selection, and management of vasospasm. The chapter on diagnosis recommends re-examination of vascular images at regular intervals in cases in which cerebral aneurysm was not detected on the first examination. The section dealing with treatment selection for cerebral aneurysmal emphasizes that the method for aneurysm obliteration should be selected based on consultation with both surgical and endovascular specialists. The role of triple-H therapy(i.e., induced hypertension, hypervolemia, and hemodilution) has changed from a preventive measure to a treatment option for symptomatic cerebral vasospasm.

An apoE-derived mimic peptide, COG1410, alleviates early brain injury via reducing apoptosis and neuroinflammation in a mouse model of subarachnoid hemorrhage.

This study investigated the neuroprotective effects of COG1410, an apoliporotein E (apoE)-derived mimic peptide, against early brain injury (EBI) after subarachnoid hemorrhage (SAH). SAH was induced in C57BL/6J mice (n=68) by endovascular perforation. Mice received intravenous injection of COG1410 (2mg/kg) or equal volume of vehicle (saline). The mortality rate, neurological score, rotarod latencies, cell apoptosis, microglial activation, pro-inflammatory cytokines production and protein levels of apoptotic and inflammatory markers were assessed at 24h after sham operation or SAH. Results showed that COG1410 alleviated the neurological deficits associated with SAH. Compared with vehicle treatment group, the number of apoptotic cells and activated microglia decreased significantly in the COG1410 treated group. COG1410 enhanced Akt activation and suppressed caspase-3 cleavage. The imbalance of Bax and Bcl-2 induced by SAH was regulated by COG1410. Additionally, COG1410 attenuated cytokines production of IL-1ß, IL-6 and TNF-α and suppressed the activation of JNK/c-Jun and NF-κB. Taken together, COG1410 protected against EBI via reducing apoptosis and neuroinflammation, through mechanisms that involve the regulation of apoptotic signaling and microglial activation. COG1410 is a potential neuroprotective agent for SAH treatment.

[INSULIN-LIKE GROWTH FACTOR 1 UNDER CONDITIONS OF THE BRAIN VASCULAR DISEASES.]

The system insulin-like growth factors (IGF) occupies an important place in the development and growth of the central nervous system (CNS). Gene expression of insulin-like growth factor I (IGF-1) and IGF-1 receptor are represented in all parts of the brain and are heavily concentrated in the cerebral vessels. IGF-1 is involved in neuro-, angiogenesis, in the stimulation of cell proliferation, and repair responses to damage for both the central and peripheral nervous system. IGF- 1 exerts antioxidant, anti-inflammatory and protective effects on the CNS. The review discusses the importance and the role of IGF-I in vascular diseases of the brain, in particular, aneurysms, the ischemic stroke, the aneurysmal subarachnoid hemorrhage, as well as neuroprotection.

[De novo cerebral aneurysms].

OBJECTIVE: To substantiate the reasonability and duration of angiographic follow-up of patients operated on for cerebral aneurysms to rule out de novo aneurysm formation. MATERIAL AND METHODS: The results of angiographic examination (cerebral angiography and SCT angiography) of 43 patients with cerebral aneurysms operated on at the Burdenko Neurosurgical Institute in 1995-2012 are analyzed. The follow-up duration varied from 1 to 14 years after surgery (mean duration, 5 years). Patients' age ranged from 14 to 56 years. RESULTS: Control angiographic examination showed that de novo aneurysms were formed in 7 (16.2%) patients. A total of 8 de novo aneurysms were detected (in one case there were two aneurysms formed). All aneurysms, both the previously operated and the de novo ones, were located in the anterior part of the circle of Willis. De novo aneurysms were clipped in 5 cases; the cavity of the de novo aneurysm was occluded with spirals in one case. One patient with a small aneurysm of the middle cerebral artery refused surgery. Neither lethal nor unfavorable outcomes were recorded. CONCLUSIONS: The patient groups with the high risk of de novo aneurysm formation are as follows: 1) young smokers with hypertension; 2) patients who developed clinical signs of the disease when being young; 3) patients subjected to proximal exclusion of the main artery; and 4) patients with multiple and familial forms of the pathology. Dynamic angiographic follow-up (SCT angiography or magnetic resonance angiography) for 1-3 years is recommended for these patients.