Restoration Of Cerebral Perfusion Research Articles

Sinigrin improves cerebral ischaemia-reperfusion injury by inhibiting the TLR4 pathway-mediated oxidative stress.

Cerebral ischaemia-reperfusion (CIR) injury occurs in stroke patients after the restoration of cerebral perfusion. Sinigrin, a phytochemical found in cruciferous vegetables, exhibits strong antioxidant activity. This study investigated the role of sinigrin in oxidative stress using a CIR injury model. The effects of sinigrin were studied in middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation/reoxygenation (OGD/R)-injured SH-SY5Y cells. Sinigrin treatment improved brain injury and neurological deficits induced by MCAO surgery in rats. Sinigrin inhibited apoptosis in brain tissues and SH-SY5Y cells following OGD/R induction. Additionally, sinigrin elevated the levels of superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) while reducing malondialdehyde (MDA) levels. Furthermore, sinigrin inhibited the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signalling pathway. The anti-apoptotic and antioxidant activities of sinigrin in OGD/R-injured SH-SY5Y cells were reversed by TLR4 overexpression. In conclusion, sinigrin inhibits oxidative stress in CIR injury by suppressing the TLR4/MyD88 signalling pathway.

CGAS-STING pathway aggravates early cerebral ischemia-reperfusion injury in mice by activating NCOA4-mediated ferritinophagy

Stroke patients are often complicated by cerebral ischemia-reperfusion injury (CIRI) after the restoration of cerebral perfusion, and how to prevent CIRI at an early stage has received close attention. The imbalance of iron metabolism is one of the essential factors in the aggravation of CIRI, and NCOA4-mediated ferritinophagy, as a critical pathway to regulate iron metabolism, is expected to be an effective intervention target. We established a mouse model of cerebral ischemia-reperfusion (CIR) with NCOA4 silencing. We found that activation of NCOA4-mediated ferritinophagy atthe early stage of CIR mediated the onset of oxidative stress and contributed to autophagy and apoptosis, and eventually resulted in increased brain injury. This suggests that NCOA4-mediated ferritinophagy plays a vital role in early CIR and can be an effective target to prevent and treat CIRI. We next explored the upstream regulatory targets of NCOA4-mediated ferritinophagy. The previous evidence for the cGAS-STING pathway's importance during CIR and its strong relationship with autophagy attracted our attention. To investigate whether the cGAS-STING pathway regulates NCOA4-mediated ferritinophagy, we further administered a cGAS inhibitor to mice with CIR and overexpressed NCOA4. Along with the inhibition of the cGAS-STING pathway, ferritinophagy, oxidative stress, autophagy, and apoptosis were inhibited, and CIRI was ameliorated, which was attenuated by NCOA4 overexpression. In conclusion, our results suggest that activation of the cGAS-STING pathway exacerbates CIRI at the early stage of CIR, which may be achieved by mediating NCOA4-mediated ferritinophagy.

Protection against acute cerebral ischemia/reperfusion injury by QiShenYiQi via neuroinflammatory network mobilization

Cerebral ischemia/reperfusion injury (CI/RI) is a common feature of ischemic stroke, involving a period of impaired blood supply to the brain, followed by the restoration of cerebral perfusion through medical intervention. Although ischemia and reperfusion brain damage is a complex pathological process with an unclear physiological mechanism, more attention is currently focused on the neuroinflammatory response of an ischemia/reperfusion origin, and anti-inflammatory appears to be a potential therapeutic strategy following ischemic stroke. QiShenYiQi (QSYQ), a component-based Chinese medicine with Qi-tonifying and blood-activating property, has pharmacological actions of anti-inflammatory, antioxidant, mitochondrial protectant, anti-apoptosis, and antiplatelet aggregation. We have previously reported that the cardioprotective effect of QSYQ against ischemia/reperfusion injury is via improvement of mitochondrial functional integrity. In this research work, we aimed to investigate the possible mechanism involved in the neuroprotection of QSYQ in mice model of cerebral ischemia/reperfusion injury based on the inflammatory pathway. The cerebral protection was evaluated in the stroke mice after 24 h reperfusion by assessing the neurological deficit, cerebral infarction, brain edema, BBB functionality, and via histopathological assessment. TCM-based network pharmacology method was performed to establish and analyze compound-target-disease & function-pathway network so as to find the possible mechanism linking to the role of QSYQ in CI/RI. In addition, RT-qPCR was used to verify the accuracy of predicted signaling gene expression. As a result, improvement of neurological outcome, reduction of infarct volume and brain edema, a decrease in BBB disruption, and amelioration of histopathological alteration were observed in mice pretreated with QSYQ after experimental stroke surgery. Network pharmacology analysis revealed neuroinflammatory response was associated with the action of QSYQ in CI/RI. RT-qPCR data showed that the mice pretreated with QSYQ could significantly decrease IFNG-γ, IL-6, TNF-α, NF-κB p65, and TLR-4 mRNA levels and increase TGF-β1 mRNA level in the brain compared to the untreated mice after CI/RI (p < 0.05). In conclusion, our study indicated the cerebral protective effect of pretreatment with QSYQ against CI/RI, which may be partly related to its potential to the reduction of neuroinflammatory response in a stroke subject.

Reduced Hypoxic Tissue and Cognitive Improvement after Revascularization Surgery for Chronic Cerebral Ischemia

Background: Hypoxic but viable neural tissue is seen on 1-(2–¹⁸F-fluoro-1-[hydroxymethyl]ethoxy) methyl-2-nitroimidazole (¹⁸F-FRP170) positron emission tomography (PET) in patients with chronic cerebral ischemia with a combination of misery perfusion and moderately reduced oxygen metabolism. Cognitive function sometimes improves after revascularization surgery in patients with chronic cerebral ischemia. Objectives: We used brain perfusion single-photon emission computed tomography (SPECT) and ¹⁸F-FRP170 PET to determine whether hypoxic tissue was reduced following the restoration of cerebral perfusion after carotid endarterectomy (CEA) in patients with severe stenosis of the cervical internal carotid artery (ICA) and whether the reduction in hypoxic tissue was associated with cognitive improvement. Method: Eighteen patients with abnormally reduced cerebral blood flow (CBF) in the affected cerebral hemispheres on preoperative brain perfusion SPECT ­underwent CEA. They underwent ¹⁸F-FRP170 PET and neuropsychological tests preoperatively and 6 months postoperatively. Brain perfusion SPECT was also performed 6 months postoperatively. Regions of interest were placed in the bilateral middle cerebral artery territories on SPECT and PET images, and the ratio of values in the affected versus contralateral hemispheres was calculated. Results: The CBF ratio (p = 0.0006) and ¹⁸F-FRP170 ratio (p = 0.0084) were significantly increased and reduced, respectively, after surgery compared to the corresponding ratios before surgery. The difference in the ¹⁸F-FRP170 ratio (postoperative – preoperative value) was negatively correlated with the difference in the CBF ratio (ρ = –0.695; p = 0.0009). The difference in the ¹⁸F-FRP170 ratio was significantly lower in patients with postoperative improved cognition compared to that in those without (p = 0.0007). The area under the receiver operating characteristics curve for the difference in the ¹⁸F-FRP170 ratio for detecting postoperative improved cognition was significantly greater than that for the difference in the CBF ratio (difference between areas, 0.278; p = 0.0248). Conclusions: Hypoxic tissue is reduced following the restoration of cerebral perfusion with revascularization surgery in patients with severe atherosclerotic stenosis of the cervical ICA. The reduction in hypoxic tissue is associated with cognitive improvement in such patients.

Impaired functional recovery of endothelial colony-forming cells from moyamoya disease in a chronic cerebral hypoperfusion rat model.

OBJECTIVEEndothelial colony-forming cells (ECFCs) isolated from pediatric patients with moyamoya disease (MMD) have demonstrated decreased numbers and defective functioning in in vitro experiments. However, the function of ECFCs has not been evaluated using in vivo animal models. In this study, the authors compared normal and MMD ECFCs using a chronic cerebral hypoperfusion (CCH) rat model.METHODSA CCH rat model was made via ligation of the bilateral common carotid arteries (2-vessel occlusion [2-VO]). The rats were divided into three experimental groups: vehicle-treated (n = 8), normal ECFC-treated (n = 8), and MMD ECFC-treated (n = 8). ECFCs were injected into the cisterna magna. A laser Doppler flowmeter was used to evaluate cerebral blood flow, and a radial arm maze test was used to examine cognitive function. Neuropathological examinations of the hippocampus and agranular cortex were performed using hematoxylin and eosin and Luxol fast blue staining in addition to immunofluorescence with CD31, von Willebrand factor, NeuN, myelin basic protein, glial fibrillary acidic protein, and cleaved caspase-3 antibodies.RESULTSThe normal ECFC-treated group exhibited improvement in the restoration of cerebral perfusion and in behavior compared with the vehicle-treated and MMD ECFC-treated groups at the 12-week follow-up after the 2-VO surgery. The normal ECFC-treated group showed a greater amount of neovasculogenesis and neurogenesis, with less apoptosis, than the other groups.CONCLUSIONSThese results support the impaired functional recovery of MMD ECFCs compared with normal ECFCs in a CCH rat model. This in vivo study suggests the functional role of ECFCs in the pathogenesis of MMD.

Emergent Endovascular Management of Long-Segment and Flow-Limiting Carotid Artery Dissections in Acute Ischemic Stroke Intervention with Multiple Tandem Stents.

Although most cervical dissections are managed medically, emergent endovascular treatment may become necessary in the presence of intracranial large-vessel occlusions, flow-limiting and long-segment dissections with impending occlusion, and/or hypoperfusion-related ischemia at risk of infarction. We investigated the role of emergent endovascular stenting of long-segment carotid dissections in the acute ischemic stroke setting. We retrospectively studied long-segment carotid dissections requiring stent reconstruction with multiple tandem stents (≥3 stents) and presenting with acute (<12 hours) ischemic stroke symptoms (NIHSS score, ≥4). We analyzed patient demographics, vascular risk factors, clinical presentations, imaging/angiographic findings, technical procedures/complications, and clinical outcomes. Fifteen patients (mean age, 51.5 years) with acute ischemic stroke (mean NIHSS score, 15) underwent endovascular stent reconstruction for vessel and/or ischemic tissue salvage. All carotid dissections presented with >70% flow limiting stenosis and involved the distal cervical ICA with a minimum length of 3.5 cm. Carotid stent reconstruction was successful in all patients with no residual stenosis or flow limitation. Nine patients (60%) harbored intracranial occlusions, and 6 patients (40%) required intra-arterial thrombolysis/thrombectomy, achieving 100% TICI 2b-3 reperfusion. Two procedural complications were limited to thromboembolic infarcts from in-stent thrombus and asymptomatic hemorrhagic infarct transformation (7% morbidity, 0% mortality). Angiographic and ultrasound follow-up confirmed normal carotid caliber and stent patency, with 2 cases of <20% in-stent stenosis. Early clinical improvement resulted in a mean discharge NIHSS score of 6, and 9/15 (60%) patients achieved a 90-day mRS of ≤2. Emergent stent reconstruction of long-segment and flow-limiting carotid dissections in acute ischemic stroke intervention is safe and effective, with favorable clinical outcomes, allowing successful thrombectomy, vessel salvage, restoration of cerebral perfusion, and/or prevention of recurrent thromboembolic stroke.

126 * EXTRA-ANATOMIC REVASCULARISATION FOR DISTAL OCCLUSION OF THE LEFT OR RIGHT COMMON CAROTID ARTERY IN ACUTE TYPE A AORTIC DISSECTION WITH CEREBRAL MALPERFUSION

Objectives: Immediate restoration of cerebral perfusion in patients with acute aortic dissection type A (AADA) is crucial but may be aggravated if distal occlusion of the left (LCCA) or right common carotid artery (RCCA) is present. Methods: Between May 2007 and July 2013, 16 out of 313 conventionally operated AADA patients (median age 60.5; range 23–80) suffered from concomitant severe cerebral malperfusion with distal occlusion of the LCCA (n = 9) or RCCA (n = 8). AADA repair comprised hemi- (n = 9) or total (n = 7) arch replacement in combination with aortic valve repair (n = 6) or replacement (n = 5), root replacement (n = 9) and CABG (n = 1). Extra-anatomic carotid-to-aortic bypass was performed prior to circulatory arrest (n = 13) to allow for unilateral selective cerebral perfusion, or during the procedure if persisting malperfusion was suspected by near-infrared spectroscopy (NIRS) or Doppler (n = 3). Results: Mean ICU stay was 17.6 ± 21.1 days. Re-thoracotomy for haemorrhage (n = 1) or cardiac tamponade (n = 3) was performed in 4 patients. Postoperative complications comprised respiratory insufficiency with prolonged ventilation (n = 7), renal failure with temporary/permanent dialysis (n = 5) and persisting visceral malperfusion (n = 2) requiring stent grafting (n = 1) or intestinal resection (n = 1). Stroke with permanent sensory or motor deficits (PND) was diagnosed in 6 (37.5%) patients. Temporary neurological deficits were seen in 10 (62.5%) individuals, including 4 patients with PND. Hospital (n = 1) and 1-year (n = 3) mortality rates were 6.3% and 25.0%. Conclusion: Extra-anatomic bypass for distal LCCA or RCCA occlusion presents a valuable bail-out technique to restore cerebral perfusion during AADA repair, potentially reducing the increased incidence of neurological complications in patients with cerebral malperfusion.

E-047 Endovascular management of long segment carotid and vertebral artery dissections with multiple overlapping stents

IntroductionCarotid or vertebral artery dissections account for approximately 20% of strokes in young adults1. Optimal anticoagulation treatment is currently the standard therapy. Endovascular management of such lesions becomes necessary in...

Immediate Regression of Leukoaraiosis after Carotid Artery Revascularization

Background: Leukoaraiosis (LA) affects cognition after stroke and reversal of LA may improve cognitive performance. We aimed to determine the impact of cerebral perfusion and circle of Willis (CoW) flow patterns on the extent of LA after carotid artery revascularization. Methods: LA was scored on fluid-attenuated inversion recovery magnetic resonance (MR) images at the levels of the centrum semiovale and frontal horns in both cerebral hemispheres of 62 contiguous patients (men/women = 38/24, mean age = 63.2 ± 8.4 years, range 44–82) before and after unilateral carotid artery revascularization. The pre- and poststenting differences in LA scores, CoW flow pattern on MR angiography, and MR perfusion parameters were analyzed. Results: The total LA score decreased from 9.87 ± 0.65 to 8.33 ± 0.72 after stenting (p = 0.03). The CoW was complete in 21 subjects and incomplete in 41 subjects. The incomplete CoW group had a higher preoperative LA load and higher cerebral interhemispheric asymmetry index, both of which decreased significantly postoperatively. Conclusions: CoW anomalies may contribute to LA in patients with carotid artery stenosis, and restoration of cerebral perfusion by carotid artery revascularization can reduce LA severity.

Carotid shunt provides cerebral protection during emergency coronary artery bypass grafting in a patient with bilateral high grade carotid stenosis: a case report

BackgroundManagement of patients with co-existent coronary and carotid disease is a controversial and challenging issue. The risk for stroke after coronary artery bypass grafting (CABG) in patients with hemodynamically significant carotid stenosis is up to 30%. In these patients a common practice is to proceed first with the restoration of cerebral perfusion and then perform the coronary revascularization. The rationale is that this strategy will reduce perioperative neurological morbidity and mortality. However, what happens when the carotid procedure is acutely complicated by cardiac instability which necessitates the interruption of the carotid procedure?Case reportWe describe a case of a patient with unstable angina and high grade asymptomatic bilateral carotid stenosis who underwent emergency combined CABG and carotid endarterectomy (CEA). Due to hemodynamic instability, ST-T changes, hypotension and bradycardia, upon completion of endarterectomy we placed a carotid shunt and the patient was put on cardiopulmonary bypass through median sternotomy. After triple CABG (duration of 90 minutes) we concluded the interrupted CEA procedure with primary closure of the carotid arteriotomy with the shunt in place. The postoperative course was uneventful and the patient was discharged after a week. In extreme cases with bilateral severe carotid stenosis and coronary artery disease where the carotid procedure should be interrupted, we suggest the use of carotid shunt which can provide adequate cerebral perfusion giving time to cardiac surgeon to perform the life saving cardiac procedure first.

O.609 Tactics in the treatment of anterior cranial fossa fractures

Cerebral ischemia/reperfusion injury (CI/RI) is a common feature of ischemic stroke, involving a period of impaired blood supply to the brain, followed by the restoration of cerebral perfusion through medical intervention. Although ischemia and reperfusion brain damage is a complex pathological process with an unclear physiological mechanism, more attention is currently focused on the neuroinflammatory response of an ischemia/reperfusion origin, and anti-inflammatory appears to be a potential therapeutic strategy following ischemic stroke. QiShenYiQi (QSYQ), a component-based Chinese medicine with Qi-tonifying and blood-activating property, has pharmacological actions of anti-inflammatory, antioxidant, mitochondrial protectant, anti-apoptosis, and antiplatelet aggregation. We have previously reported that the cardioprotective effect of QSYQ against ischemia/reperfusion injury is via improvement of mitochondrial functional integrity. In this research work, we aimed to investigate the possible mechanism involved in the neuroprotection of QSYQ in mice model of cerebral ischemia/reperfusion injury based on the inflammatory pathway. The cerebral protection was evaluated in the stroke mice after 24 h reperfusion by assessing the neurological deficit, cerebral infarction, brain edema, BBB functionality, and via histopathological assessment. TCM-based network pharmacology method was performed to establish and analyze compound-target-disease & function-pathway network so as to find the possible mechanism linking to the role of QSYQ in CI/RI. In addition, RT-qPCR was used to verify the accuracy of predicted signaling gene expression. As a result, improvement of neurological outcome, reduction of infarct volume and brain edema, a decrease in BBB disruption, and amelioration of histopathological alteration were observed in mice pretreated with QSYQ after experimental stroke surgery. Network pharmacology analysis revealed neuroinflammatory response was associated with the action of QSYQ in CI/RI. RT-qPCR data showed that the mice pretreated with QSYQ could significantly decrease IFNG-γ, IL-6, TNF-α, NF-κB p65, and TLR-4 mRNA levels and increase TGF-β1 mRNA level in the brain compared to the untreated mice after CI/RI (p < 0.05). In conclusion, our study indicated the cerebral protective effect of pretreatment with QSYQ against CI/RI, which may be partly related to its potential to the reduction of neuroinflammatory response in a stroke subject.

P.140 Diagnostic difficulties and atypical clinical manifestation of Wegener's granulomatosis

Cerebral ischemia/reperfusion injury (CI/RI) is a common feature of ischemic stroke, involving a period of impaired blood supply to the brain, followed by the restoration of cerebral perfusion through medical intervention. Although ischemia and reperfusion brain damage is a complex pathological process with an unclear physiological mechanism, more attention is currently focused on the neuroinflammatory response of an ischemia/reperfusion origin, and anti-inflammatory appears to be a potential therapeutic strategy following ischemic stroke. QiShenYiQi (QSYQ), a component-based Chinese medicine with Qi-tonifying and blood-activating property, has pharmacological actions of anti-inflammatory, antioxidant, mitochondrial protectant, anti-apoptosis, and antiplatelet aggregation. We have previously reported that the cardioprotective effect of QSYQ against ischemia/reperfusion injury is via improvement of mitochondrial functional integrity. In this research work, we aimed to investigate the possible mechanism involved in the neuroprotection of QSYQ in mice model of cerebral ischemia/reperfusion injury based on the inflammatory pathway. The cerebral protection was evaluated in the stroke mice after 24 h reperfusion by assessing the neurological deficit, cerebral infarction, brain edema, BBB functionality, and via histopathological assessment. TCM-based network pharmacology method was performed to establish and analyze compound-target-disease & function-pathway network so as to find the possible mechanism linking to the role of QSYQ in CI/RI. In addition, RT-qPCR was used to verify the accuracy of predicted signaling gene expression. As a result, improvement of neurological outcome, reduction of infarct volume and brain edema, a decrease in BBB disruption, and amelioration of histopathological alteration were observed in mice pretreated with QSYQ after experimental stroke surgery. Network pharmacology analysis revealed neuroinflammatory response was associated with the action of QSYQ in CI/RI. RT-qPCR data showed that the mice pretreated with QSYQ could significantly decrease IFNG-γ, IL-6, TNF-α, NF-κB p65, and TLR-4 mRNA levels and increase TGF-β1 mRNA level in the brain compared to the untreated mice after CI/RI (p < 0.05). In conclusion, our study indicated the cerebral protective effect of pretreatment with QSYQ against CI/RI, which may be partly related to its potential to the reduction of neuroinflammatory response in a stroke subject.

In-vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO.

Cerebral ischemia provokes tissue damage by two major patho-physiological mechanisms. Direct cell necrosis is induced by diminished access of neurons and glia to essential nutrients such as glucose and oxygen leading to energy failure. A second factor of cellular loss is related to the activation of immune-competent cells within and around the primary infarct. While granulocytes and presumably monocytes are linked to the no-reflow phenomenon, activated microglia cells and monocytes can release cytotoxic substrates, which cause delayed cell death. As a consequence the infarct volume will increase, despite restoration of cerebral perfusion. In the past, visualization of immune competent cells was only possible by histological analysis of post-mortem tissue. However, contrast agents based on small particles of iron oxide are known to accumulate in organs rich in cells with phagocytotic function. These particles can be tracked in vivo by MRI methods based on their relaxation properties. In the present study, the spatio-temporal distribution of USPIO particles was monitored in a rat model of transient cerebral infarction using T1- and T2-weighted MRI sequences. USPIO were detected in vessels at 24 h after administration. At later time points specific accumulation of USPIO was observed within the infarcted hemisphere, with maximal signal enhancement on day 2. Their detectability based on T1-contrast disappeared between day 4 and day 7. Immuno-histochemically (IHC) stains confirmed the presence of macrophages, presumably blood-derived monocytes within areas of T1 signal enhancement. Direct visualization of iron-burdened macrophages by IHC was only possible later than day 3 after occlusion.

Microsurgical approach for experimental ischaemia

Sudden occlusion of the middle cerebral artery (MCA) is one of the common strokes in humans which causes ischaemic brain damage and neurological deficit. Although a number of experimental approaches to produce MCA occlusion were performed using larger animals such as monkeys and cats, MCA occlusion in rats which was originally devised in Glasgow (Tamura et al., 1981) provided a useful means to investigate the pathophysiology of focal cerebral ischaemia particularly when combined with the autoradiographic techniques because of the reduced requirement of expensive radioisotopes in small animals. Through a subtemporal craniectomy under the operative microscope, the trunk of MCA was exposed. There was an important tiny arterial branch called lenticulostriate artery which arose from the very proximal part of the MCA and supplied circulation to the caudate nucleus. The circulatory and neuropathological consequences were quite different whether or not this artery was involved. The “proximal” occlusion which involved both the MCA and the lenticulostriate artery produced ischaemia and ischaemic brain damage in both cortex and the caudate nucleus, whereas the “distal” occlusion without occluding the lenticulostriate artery produced only cortical damage. Since the sites of occlusion for both types were so close, a careful microsurgical technique was required. The neuropathological consequence was found much more consistent and severe in proximal occlusion. Several autoradiographic investigations were carried out to investigate cerebral blood flow using (14C)-iodoantipyrine, cerebral glucose metabolism using (14C)-2-deoxyglucose, blood-brain barrier permeability using (14C)-aminoisobutyric acid and protein synthesis using (14C)-leucine. Heterogeneous alterations were found in each of the autoradiographic indices but these could be well correlated with a combined use of enzyme histochemistry for glycogen phosphorylase which could delineate the lesion. A greater interest was focused on the areas outside .the irreversibly damaged ischaemic core which were not yet dead and potentially salvageable. The autoradiographic investigations showed that this was an area with a metabolic activation through an enhanced anaerobic glycolysis. A model of reversible ischaemia was also established by utilizing a snare ligature in the trunk of the MCA. It was found that a short period of ischaemia for 30 minutes caused prolonged derangement in local cerebral circulation even after initial full restoration of cerebral perfusion. In conclusion, a small animal model of focal cerebral ischaemia can provide a sound basis for the study of ischaemic pathophysiology in the brain when a careful microsurgical technique is used.