Aloe-emodin prevents nerve injury and neuroinflammation caused by ischemic stroke via PI3K/AKT/mTOR and NF-κB pathway

Ischemic stroke (IS) caused by cerebral arterial occlusion is the leading cause of global morbidity and mortality. Cellular oxidative stress and inflammation play a vital role in the pathological process...

Perioperative Dexmedetomidine attenuates brain ischemia reperfusion injury possibly via up-regulation of astrocyte Connexin 43

Background Astrocyte Connexin 43 (Cx43) is essential for the trophic and protective support of neurons during brain ischemia reperfusion (I/R) injury. It is believed that dexmedetomidine participates in Cx43-mediated effects. However, its mechanisms remained unclear. This study aims to address the relationship and regulation among them. Methods Adult male Sprague-Dawley rats were allocated to the 90-min right middle cerebral arterial occlusion with or without dexmedetomidine pretreatment (5 μg/kg). Neurological functions were evaluated and brain lesions, as well as inflammatory factors (IL-1β, IL-6, TNF-α), were assessed. Ischemic penumbral cortex was harvested to determine the expression of astrocyte Cx43. Primary astrocytes were cultured to evaluate the effect of dexmedetomidine on Cx43 after oxygen-glucose deprivation. Results Dexmedetomidine pretreatment attenuated neurological injury, brain lesions and expression of inflammatory factors (IL-1β, IL-6, TNF-α) after brain ischemia (P < 0.05). Astrocyte Cx43 was down-regulated by brain I/R injury, both in vivo and in vitro, which were reversed by dexmedetomidine (P < 0.05). This effect was mediated by the phosphorylation of Akt and GSK-3β. Further studies with LY294002 (PI3K inhibitor) or SB216763 (GSK-3β inhibitor) confirmed the effect of dexmedetomidine on astrocyte Cx43. Conclusions Perioperative dexmedetomidine administration attenuates neurological injury after brain I/R injury, possibly through up-regulation of astrocyte Cx43. Activation of PI3K-Akt-GSK-3β pathway might contribute to this protective effect.

Enhancing the Therapeutic Potential of CCL2-Overexpressing Mesenchymal Stem Cells in Acute Stroke

Although intravenous administration of mesenchymal stem cells (MSCs) is effective for experimental stroke, low engraftment and the limited functional capacity of transplanted cells are critical hurdles for clinical applications. C–C motif chemokine ligand 2 (CCL2) is associated with neurological repair after stroke and delivery of various cells into the brain via CCL2/CCR2 (CCL2 receptor) interaction. In this study, after CCL2-overexpressing human umbilical cord-derived MSCs (hUC-MSCs) were intravenously transplanted with mannitol in rats with middle cerebral arterial occlusion, we compared the differences between four different treatment groups: mannitol + CCL2-overexpressing hUC-MSCs (CCL2-MSC), mannitol + naïve hUC-MSCs (M-MSC), mannitol only, and control. At four-weeks post-transplantation, the CCL2-MSC group showed significantly better functional recovery and smaller stroke volume relative to the other groups. Additionally, we observed upregulated levels of CCR2 in acute ischemic brain and the increase of migrated stem cells into these areas in the CCL2-MSC group relative to the M-MSC. Moreover, the CCL2-MSC group displayed increased angiogenesis and endogenous neurogenesis, decreased neuro-inflammation but with increased healing-process inflammatory cells relative to other groups. These findings indicated that CCL2-overexpressing hUC-MSCs showed better functional recovery relative to naïve hUC-MSCs according to the increased migration of these cells into brain areas of higher CCR2 expression, thereby promoting subsequent endogenous brain repair.

Efficacy of Surgical Revascularizations in Young and Middle-aged Patients with Symptomatic Middle Cerebral Arterial Occlusion

Background: Treatments on middle cerebral arterial occlusions (MCAO) remain controversial. This study aims at investigating efficacies of surgical revascularizations in young and middle-aged patients (aged 18-65 y) with symptomatic MCAO, and making comparisons between surgical procedures.Methods: From a seven-year prospective consecutive registry, 115 cases were enrolled in this study. Patient individually received medical therapy alone (medical group, n=64) and medical therapy plus direct or indirect revascularization (surgical group, n=51). The secondary ischemic events (SIE) was defined as the primary outcome. SIE incidences and SIE-free survival rates were compared between groups. Risk factors were analyzed using the Cox regression analysis.Results: During a follow-up of 42.7 months on average, SIE occurred in 11cases of medical group and 10 cases of surgical group. SIE incidences were indifferent between groups (surgical:medical = 19.6%:17%, P=0.810, 95%CI 0.455-3.034). SIE incidences were 29.4% and 0% in direct revascularization subgroup and indirect revascularization subgroup, respectively. Indirect revascularization induced a higher SIE-free survival rate than direct revascularization (Log-rank P=0.015) and medical therapy (Log-rank P=0.044). An age>43y, with concomitant intracerebral arterial stenosis, and hyperlipidaemia history were correlated to the occurrence of SIE, while presences of compensatory arteries and taking antihypertensive drugs reduced risks of SIE.Conclusions: Indirect revascularization plus medical therapy was suggested to be more effective on SIE prevention than both medical treatments alone and direct revascularization plus medical therapy in young and middle aged patients with symptomatic MCAO. Direct revascularization was not recommended, for its similar efficacy to medical therapy alone.

Efficacy of Surgical Revascularizations in Young and Middle-aged Patients with Symptomatic Middle Cerebral Arterial Occlusion

Background: Treatments on middle cerebral arterial occlusions (MCAO) remain controversial. This study aims at investigating efficacies of surgical revascularizations in young and middle-aged patients (aged 18-65 y) with symptomatic MCAO, and making comparisons between surgical procedures.Methods: From a seven-year prospective consecutive registry, 115 cases were enrolled in this study. Patient individually received medical therapy alone (medical group, n=64) and medical therapy plus direct or indirect revascularization (surgical group, n=51). The secondary ischemic events (SIE) was defined as the primary outcome. SIE incidences and SIE-free survival rates were compared between groups. Risk factors were analyzed using the Cox regression analysis.Results: During a follow-up of 42.7 months on average, SIE occurred in 11cases of medical group and 10 cases of surgical group. SIE incidences were indifferent between groups (surgical:medical = 19.6%:17%, P=0.810, 95%CI 0.455-3.034). SIE incidences were 29.4% and 0% in direct revascularization subgroup and indirect revascularization subgroup, respectively. Indirect revascularization induced a higher SIE-free survival rate than direct revascularization (Log-rank P=0.015) and medical therapy (Log-rank P=0.044). An age>43y, with concomitant intracerebral arterial stenosis, and hyperlipidaemia history were correlated to the occurrence of SIE, while presences of compensatory arteries and taking antihypertensive drugs reduced risks of SIE.Conclusions: Indirect revascularization plus medical therapy was more effective on SIE prevention than both medical treatments alone and direct revascularization plus medical therapy in young and middle aged patients with symptomatic MCAO. Direct revascularization was not recommended, for its similar efficacy to medical therapy alone.

Measurement of cerebrovascular reserve by multimodal imaging for cerebral arterial occlusion or stenosis patients: protocol of a prospective, randomized, controlled clinical trial

Background Cerebrovascular reactivity (CVR), index of cerebral hemodynamics, might guide the treatment of ischemic stroke. However, the previous studies that the therapeutic strategy of stroke mainly depends on the degree of vascular stenosis with steady-state vascular parameters, such as cerebral blood flow, and CVR factors are not under consideration. Measurement of CVR by multimodal image might improve the prognosis for ischemic stroke. Methods/design The study is a prospective, randomized, paralleled controlled clinical trial to examine the multimodal image evaluation for CVR. A total of 66 eligible patients will be recruited from Renji hospital, Shanghai Jiaotong University School of Medicine. The patients will be categorized based on CVR into two subgroups as follows: CVR>10% group and CVR<10% group. And the patients will be randomly assigned to medical management, percutaneous transluminal angioplasty and stenting, and intracranial and extra-cranial bypass groups in a 1:1:1 ratio. The primary end point is all adverse events and ipsilateral stroke recurrence at 6, 12, 24 months after the management. The secondary outcomes include the CVR, the National Institute of Health stroke scale and the Modified Rankin Scale at 6, 12, 24 months. Discussion Measurement of cerebrovascular reserve by multimodal image is recommended by most recent studies to guide the treatment of ischemic stroke, and thus its efficacy and evaluation accuracy need to be established in randomized controlled settings. This prospective, randomized, paralleled controlled registry study, together with other ongoing studies, will present more evidence for optimal individualized accurate treatment of ischemic stroke.

Measurement of cerebrovascular reserve by multimodal image for cerebral arterial occlusion or stenosis patients: study protocol of a randomized paralleled controlled trial

Background Cerebrovascular reactivity (CVR), index of cerebral hemodynamics, might guide the treatment of ischemic stroke. However, the previous studies that the therapeutic strategy of stroke mainly depends on the degree of vascular stenosis with steady-state vascular parameters, such as cerebral blood flow, and CVR factors are not under consideration. Measurement of CVR by multimodal image might improve the prognosis for ischemic stroke. Methods/design The study is a prospective, randomized, paralleled controlled clinical trial to examine the multimodal image evaluation for CVR. A total of 66 eligible patients will be recruited from Renji hospital, Shanghai Jiaotong University School of Medicine. The patients will be categorized based on CVR into two subgroups as follows: CVR>10% group and CVR<10% group. And the patients will be randomly assigned to medical management, percutaneous transluminal angioplasty and stenting, and intracranial and extra-cranial bypass groups in a 1:1:1 ratio. The primary end point is all adverse events and ipsilateral stroke recurrence at 6, 12, 24 months after the management. The secondary outcomes include the CVR, the National Institute of Health stroke scale and the Modified Rankin Scale at 6, 12, 24 months. Discussion Measurement of cerebrovascular reserve by multimodal image is recommended by most recent studies to guide the treatment of ischemic stroke, and thus its efficacy and evaluation accuracy need to be established in randomized controlled settings. This prospective, randomized, paralleled controlled registry study, together with other ongoing studies, will present more evidence for optimal individualized accurate treatment of ischemic stroke.