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Inflammation and oxidative stress play an important part in the pathogenesis of focal cerebral ischemia/reperfusion (I/R) injury, resulting in neuronal death. The signaling pathways involved and the underlying mechanisms of these events are not fully understood. Chrysin, which is a naturally occurring flavonoid, exhibits various biological activities. In this study, we investigated the neuroprotective properties of chrysin in a mouse model of middle cerebral artery occlusion (MCAO). To this end, male C57/BL6 mice were pretreated with chrysin once a day for seven days and were then subjected to 1 h of middle cerebral artery occlusion followed by reperfusion for 24 h. Our data show that chrysin successfully decreased neurological deficit scores and infarct volumes, compared with the vehicle group. The increases in glial cell numbers and proinflammatory cytokine secretion usually caused by ischemia/reperfusion were significantly ameliorated by chrysin pretreatment. Moreover, chrysin also inhibited the MCAO-induced up-regulation of nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), compared with the vehicle. These results suggest that chrysin could be a potential prophylactic agent for cerebral ischemia/reperfusion (I/R) injury mediated by its anti-inflammatory and anti-oxidative effects.

One response to randomized trials like the International Subarachnoid Aneurysm Trial has been to adopt a \"coil first\" policy, whereby all aneurysms be considered for coiling, reserving surgery for unfavorable aneurysms or failed attempts. Surgical results with middle cerebral artery (MCA) aneurysms have been excellent, raising debate about the respective roles of surgical and endovascular therapy. To review our experience with MCA aneurysms managed with microsurgery as the treatment of first choice. Five hundred forty-three patients with 631 MCA aneurysms were managed with a \"clip first\" policy, with 115 patients (21.2%) referred from the Neurointerventional Radiology service and none referred from the Neurosurgical service for endovascular management. Two hundred eighty-two patients (51.9%) had ruptured aneurysms and 261 (48.1%) had unruptured aneurysms. MCA aneurysms were treated with clipping (88.6%), thrombectomy/clip reconstruction (6.2%), and bypass/aneurysm occlusion (3.3%). Complete aneurysm obliteration was achieved with 620 MCA aneurysms (98.3%); 89.7% of patients were improved or unchanged after therapy, with a mortality rate of 5.3% and a permanent morbidity rate of 4.6%. Good outcomes were observed in 92.0% of patients with unruptured and 70.2% with ruptured aneurysms. Worse outcomes were associated with rupture (P = .04), poor grade (P = .001), giant size (P = .03), and hemicraniectomy (P < .001). At present, surgery should remain the treatment of choice for MCA aneurysms. Surgical morbidity was low, and poor outcomes were due to an inclusive policy that aggressively managed poor-grade patients and complex aneurysms. This experience sets a benchmark that endovascular results should match before considering endovascular therapy an alternative for MCA aneurysms.

Lipohyalinotic degeneration (LD) and branch atheromatous disease (BAD) can contribute to subcortical infarctions in the lenticulostriate artery (LSA) territory. This study aimed to identify the association between the proximal and distal middle cerebral artery (MCA) diameter ratio and the two different pathomechanisms of LSA infarction. Patients with acute LSA infarctions categorized as small vessel occlusive disease were included. Demographic and clinical data, along with MCA geometrical variables, were collected. LD and BAD were differentiated based on the length of the infarction diameter and number of axial slices. The proximal/distal M1 diameter ratio was calculated. MCA geometrics between LD and BAD were compared. Independent factors associated with LD were investigated. Computational fluid dynamics (CFD) analysis was used to evaluate hemodynamic parameters. A total of 117 patients were included, of whom 64 (54.7%) and 53 (45.3%) were classified as BAD and LD, respectively. LD was associated with hypertension and favorable prognosis. MCA geometric variables revealed that LD had a higher proximal/distal M1 diameter ratio, indicating a potential distinguishing factor. Multivariate analysis confirmed the independent association between LD and the proximal/distal M1 diameter ratio. The proximal/distal M1 diameter ratio also showed a positive correlation with the number of ipsilesional lacunes. CFD analysis showed that the LD model had faster, greater blood influx into LSAs and higher wall shear stress and pressure gradient compared with the BAD model. This study suggests MCA geometry, particularly the proximal/distal M1 diameter ratio, may serve as an independent factor for identifying LD.

To compare the clinical outcomes among various infarct patterns and to investigate the associations between the morphological parameters of contralateral middle cerebral artery (cMCA) M segment and infarct patterns in ischemic stroke attributed to large vessel occlusion (LVO) in M segment caused by intracranial atherosclerotic disease (ICAD). Patients with stroke attributed to M -ICAD-LVO were enrolled. The infarct patterns were categorized into artery-to-artery embolism (AAE), large infarct, borderzone infarct (BZI), and perforating artery infarction (PAI). The morphological parameters of cMCA-M segment included proximal and distal diameter, arc, and chord length. The tortuosity index of cMCA-M segment was calculated by (arc length/chord length - 1) × 100%. A total of 171 participants were enrolled. Compared to AAE, the risk of poor outcome increased in BZI (odds ratio [OR] = 5.51, 95% confidence interval [CI] = 1.71-17.78, p = 0.004) and large infarct (OR = 10.92, 95% CI = 2.01-59.27, p = 0.006) and was comparable in PAI. The tortuosity index (OR = 2.85, 95% CI = 1.13-7.18, p = 0.026) and arc length (OR = 2.47, 95% CI = 1.02-5.97, p = 0.045) significantly increased in BZI than other three patterns. Participants other than BZI were categorized into large infarct (n = 32) and non-large-infarct (n = 46) groups, and the proximal diameter (OR = 0.22, 95% CI = 0.07-0.72, p = 0.012), arc length (OR = 0.88, 95% CI = 0.78-0.98, p = 0.018), and chord length (OR = 0.87, 95% CI = 0.77-0.995, p = 0.042) were associated with large infarct. For patients with M -ICAD-LVO, large infarct and BZI had poorer outcomes than PAI and AAE. The cMCA-M segment with elevated tortuosity and arc length was associated with BZI, whereas a thin and short M segment was correlated with large infarct in patients with a less tortuous cMCA trunk.

A great deal of attention has been paid to neuroprotective therapies for cerebral ischemic stroke. Our two recent clinical trials showed that ginsenoside Rd (Rd), a kind of monomeric compound extracted from Chinese herbs, Panax ginseng and Panax notoginseng , was safe and efficacious for the treatment of ischemic stroke. In this study, we conducted a pooled analysis of the data from 199 patients with acute ischemic stroke in the first trial and 390 in the second to reanalyze the efficacy and safety of Rd. Moreover, animal stroke models were carried out to explore the possible molecular mechanisms underlying Rd neuroprotection. The pooled analysis showed that compared with placebo group, Rd could improve patients’ disability as assessed by modified Rankin Scale (mRS) score on day 90 post-stroke and reduce neurologic deficits on day 15 or day 90 post-stroke as assessed by NIH Stroke Scale (NIHSS) and Barthel Index (BI) scores. For neuroprotective mechanisms, administration of Rd 4 h after stroke could inhibit ischemia-induced microglial activation, decrease the expression levels of various proinflammatory cytokines, and suppress nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IκBα) phosphorylation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear translocation. An in vitro proteasome activity assay revealed a significant inhibitory effect of Rd on proteasome activity in microglia. Interestingly, Rd was showed to have less side effects than glucocorticoid. Therefore, our study demonstrated that Rd could safely improve the outcome of patients with ischemic stroke, and this therapeutic effect may result from its capability of suppressing microglial proteasome activity and sequential inflammation.

Neuroinflammation immediately follows the onset of ischemic stroke in the middle cerebral artery. During this process, microglial cells are activated in and recruited to the penumbra. Microglial cells can be activated into two different phenotypes: M1, which can worsen brain injury; or M2, which can aid in long-term recovery. In this study, we contribute a summary of experimental data on microglial cell counts in the penumbra following ischemic stroke induced by middle cerebral artery occlusion (MCAO) in mice and compile available data sets into a single set suitable for time series analysis. Further, we formulate a mathematical model of microglial cells in the penumbra during ischemic stroke due to MCAO. Through use of global sensitivity analysis and Markov Chain Monte Carlo (MCMC)-based parameter estimation, we analyze the effects of the model parameters on the number of M1 and M2 cells in the penumbra and fit identifiable parameters to the compiled experimental data set. We utilize results from MCMC parameter estimation to ascertain uncertainty bounds and forward predictions for the number of M1 and M2 microglial cells over time. Results demonstrate the significance of parameters related to M1 and M2 activation on the number of M1 and M2 microglial cells. Simulations further suggest that potential outliers in the observed data may be omitted and forecast predictions suggest a lingering inflammatory response.

Background With the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as well as the number of individuals with vascular cognitive impairment/dementia (VCID). No specific FDA-approved treatments for VCID exist. Although clinical evidence supports that angiotensin receptor blockers (ARBs) prevent cognitive decline in older adults, whether ARBs have a similar effect on VCID after stroke is unknown. Moreover, these agents reduce BP, which is undesirable in the acute stroke period, so we believe that giving C21 in this acute phase or delaying ARB administration would enable us to achieve the neurovascular benefits without the risk of unintended and potentially dangerous, acute BP lowering. Methods The aim of our study was to determine the impact of candesartan (ARB) or compound-21 (an angiotensin type 2 receptor––AT2R––agonist) on long-term cognitive function post-stroke, in spontaneously hypertensive rats (SHRs). We hypothesized that AT2R stimulation, either directly with C21, or indirectly by blocking the angiotensin type 1 receptor (AT1R) with candesartan, initiated after stroke, would reduce cognitive impairment. Animals were subjected to a 60-min transient middle cerebral artery occlusion and randomly assigned to either saline/C21 monotherapy, for the full study duration (30 days), or given sequential therapy starting with saline/C21 (7 days) followed by candesartan for the remainder of the study (21 days). Outcome measures included sensorimotor/cognitive-function, amyloid-β determination, and histopathologic analyses. Results Treatment with RAS modulators effectively preserved cognitive function, reduced cytotoxicity, and prevented chronic-reactive microgliosis in SHRs, post-stroke. These protective effects were apparent even when treatment was delayed up to 7 days post-stroke and were independent of blood pressure and β-amyloid accumulation. Conclusion Collectively, our findings demonstrate that RAS modulators effectively prevent cognitive impairment after stroke, even when treatment is delayed.

Interspecies variability and poor clinical translation from rodent studies indicate that large gyrencephalic animal stroke models are urgently needed. We present a proof-of-principle study describing an alternative animal model of malignant infarction of the middle cerebral artery (MCA) in the common pig and illustrate some of its potential applications. We report on metabolic patterns, ionic profile, brain partial pressure of oxygen (PtiO2), expression of sulfonylurea receptor 1 (SUR1), and the transient receptor potential melastatin 4 (TRPM4). A 5-hour ischemic infarct of the MCA territory was performed in 5 2.5-to-3-month-old female hybrid pigs (Large White x Landrace) using a frontotemporal approach. The core and penumbra areas were intraoperatively monitored to determine the metabolic and ionic profiles. To determine the infarct volume, 2,3,5-triphenyltetrazolium chloride staining and immunohistochemistry analysis was performed to determine SUR1 and TRPM4 expression. PtiO2 monitoring showed an abrupt reduction in values close to 0 mmHg after MCA occlusion in the core area. Hourly cerebral microdialysis showed that the infarcted tissue was characterized by reduced concentrations of glucose (0.03 mM) and pyruvate (0.003 mM) and increases in lactate levels (8.87mM), lactate-pyruvate ratio (4202), glycerol levels (588 μM), and potassium concentration (27.9 mmol/L). Immunohistochemical analysis showed increased expression of SUR1-TRPM4 channels. The aim of the present proof-of-principle study was to document the feasibility of a large animal model of malignant MCA infarction by performing transcranial occlusion of the MCA in the common pig, as an alternative to lisencephalic animals. This model may be useful for detailed studies of cerebral ischemia mechanisms and the development of neuroprotective strategies.

Transient middle cerebral artery occlusion (tMCAO) model is widely used to mimic human focal ischemic stroke in order to study ischemia/reperfusion brain injury in rodents. In tMCAO model, intraluminal suture technique is widely used to achieve ischemia and reperfusion. However, variation of infarct volume in this model often requires large sample size, which hinders the progress of preclinical research. Our previous study demonstrated that infarct volume was related to the success of reperfusion although the reason remained unclear. The aim of present study is to explore the relationship between focal thrombus formation and model reproducibility with respect to infarct volume. We hypothesize that suture-induced thrombosis causes infarct volume variability due to insufficient reperfusion after suture withdrawal. Seventy-two adult male CD-1 mice underwent 90 minutes of tMCAO with or without intraperitoneal administration of heparin. Dynamic synchrotron radiation microangiography (SRA) and laser speckle contrast imaging (LSCI) were performed before and after tMCAO to observe the cerebral vascular morphology and to measure the cerebral blood flow in vivo. Infarct volume and neurological score were examined to evaluate severity of ischemic brain injury. We found that the rate of successful reperfusion was much higher in heparin-treated mice compared to that in heparin-free mice according to the result of SRA and LSCI at 1 and 3 hours after suture withdrawal (p<0.05). Pathological features and SRA revealed that thrombus formed in the internal carotid artery, middle cerebral artery or anterior cerebral artery, which blocked reperfusion following tMCAO. LSCI showed that cortical collateral circulation could be disturbed by thrombi. Our results demonstrated that suture-induced thrombosis was a critical element, which affects the success of reperfusion. Appropriate heparin management provides a useful approach for improving reproducibility of reperfusion model in mice.

Background/Aims: Calcium-permeable ionotropic NMDAR-mediated hyperactivity is regarded as the critical factor in modulating the development of ischaemic stroke. Recently, there has been increasing interest in preventing post-stroke neuronal death by focusing on intervening in the function of subpopulations of NMDARs and their downstream signalling. Geniposide, an iridoid glycoside, has been found to have cytoprotective functions in various conditions. However, it is still unclear whether and how geniposide affects neuronal insult under experimental stroke. Methods: We demonstrate that dose-dependent geniposide significantly decreased the infarct volume in tMCAO models. Results: A medium level of geniposide improved anti-apoptotic functions and inhibited BBB leakage/haemorrhage via elevating GluN2A-containing NMDAR expression in tMCAO rats. Importantly, these effects could be eliminated by co-treatment of geniposide with the GluN2A antagonist NVP but not the GluN2B inhibitor ifenprodil. Moreover, geniposide’s protection was due to the enhancement of GluN2A-dependent survival signals, including pAKT, pERK and PSD-95. Conclusion: The results suggest that geniposide protects neurons against post-ischaemic neurovascular injury through the activation of GluN2A/AKT/ERK pathways. As a very promising natural agent, geniposide may be a future therapeutic for stroke patients.