The application and neuroprotective mechanisms of cerebral ischemic post-conditioning: A review.
Li Zhixing,Chen Hanlin,Lv Jinglei,Zhao Renliang
Brain research bulletin
Ischemic stroke is a serious cerebrovascular disease that leads to death and/or severe disability, and extensive research has been directed in search of appropriate treatment measures. One such potential treatment is the use of cerebral ischemic post-conditioning (IPostC), and its neuroprotective effects and controllability have been widely confirmed and validated. Numerous studies have indicated that cerebral IPostC can suppress the inflammatory reaction in ischemia reperfusion injury, improve cerebral circulation, reduce infarct volume, and promote both neurogenesis and angiogenesis. The neuroprotective mechanisms underlying IPostC have been systematically studied, but still need a comprehensive summary and a more exhaustive understanding. Continuing research has proposed further applications of IPostC, including remote ischemic post-conditioning, pharmacologic ischemic post-conditioning, and delayed ischemic post-conditioning. However, most studies of IPostC are performed on animal models, and clinical studies are scarce. Therefore, future studies will need to focus on increasing our understanding of neuroprotective mechanisms underlying cerebral IPostC as well as accelerating its clinical translation.
10.1016/j.brainresbull.2017.03.002
Effects of Remote Ischemic Conditioning on Cerebral Hemodynamics in Ischemic Stroke.
Qin Chen,Yan Xiuli,Jin Hang,Zhang Ruyi,He Yaode,Sun Xin,Zhang Yihe,Guo Zhen-Ni,Yang Yi
Neuropsychiatric disease and treatment
Ischemic stroke is one of the most common cerebrovascular diseases and is the leading cause of disability all over the world. It is well known that cerebral blood flow (CBF) is disturbed or even disrupted when ischemic stroke happens. The imbalance between demand and shortage of blood supply makes ischemic stroke take place or worsen. The search for treatments that can preserve CBF, especially during the acute phase of ischemic stroke, has become a research hotspot. Animal and clinical experiments have proven that remote ischemic conditioning (RIC) is a beneficial therapeutic strategy for the treatment of ischemic stroke. However, the mechanism by which RIC affects CBF has not been fully understood. This review aims to discuss several possible mechanisms of RIC on the cerebral hemodynamics in ischemic stroke, such as the improvement of cardiac function and collateral circulation of cerebral vessels, the protection of neurovascular units, the formation of gas molecules, the effect on the function of vascular endothelial cells and the nervous system. RIC has the potential to become a therapeutic treatment to improve CBF in ischemic stroke. Future studies are needed to highlight our understanding of RIC as well as accelerate its clinical translation.
10.2147/NDT.S231944
Chronic Remote Ischemic Conditioning Is Cerebroprotective and Induces Vascular Remodeling in a VCID Model.
Khan Mohammad Badruzzaman,Hafez Sherif,Hoda Md Nasrul,Baban Babak,Wagner Jesse,Awad Mohamed E,Sangabathula Hasith,Haigh Stephen,Elsalanty Mohammed,Waller Jennifer L,Hess David C
Translational stroke research
Vascular contributions to cognitive impairment and dementia (VCID) make up 50% of the cases of dementia. The purpose of this study was to determine the effect of chronic remote ischemic conditioning (C-RIC) on improving long-term (6 months) outcomes and cerebral blood flow (CBF) and collateral formation in a mouse model of VCID. Adult C57BL/6J male mice (10 weeks) were randomly assigned to four different groups: (1) sham-bilateral carotid artery stenosis (BCAS), (2) BCAS + sham RIC, (3) BCAS+C-RIC for 1 month (1MO), and (4) BCAS+C-RIC-4 months (4MO). CBF, cognitive impairment, and functional outcomes were performed up for 6 months after BCAS surgery. The expression of CD31, α-SMA, and myelin basic protein (MBP) was assessed by immunohistochemistry (IHC). Additional set of mice were randomized to sham, BCAS, and BCAS+C-RIC. The cerebrovascular angioarchitecture was studied with micro-CT. RIC therapy for either 1 or 4 months significantly improved CBF, new collateral formation, functional and cognitive outcomes, and prevented white matter damage. There was no difference between C-RIC for 1 or 4 months; IHC studies at 6 months showed an increase in brain CD31 and α-SMA expression indicating increased angiogenesis and MBP indicating preservation of white matter in animals receiving RIC. One month of daily RIC is as effective as 4 months of daily RIC in improving CBF, angiogenesis, and long-term functional outcomes (6 months) in a VCID model. This suggests that 1 month of RIC is sufficient to reduce cognitive impairment and induce beneficial cerebrovascular remodeling.
10.1007/s12975-017-0555-1
Enhancing cerebral perfusion with external counterpulsation after ischaemic stroke: how long does it last?
Xiong Li,Lin Wenhua,Han Jinghao,Chen Xiangyan,Leung Thomas,Soo Yannie,Wong Ka Sing
Journal of neurology, neurosurgery, and psychiatry
OBJECTIVE:External counterpulsation (ECP) is a non-invasive method used to augment cerebral perfusion in ischaemic stroke. We aimed to investigate time-course effects on blood pressure elevation and cerebral blood flow augmentation induced by ECP in ischaemic stroke. METHODS:Patients with acute unilateral ischaemic stroke and large artery occlusive disease were recruited to receive 35 daily 1 h ECP treatment sessions. Serial transcranial Doppler monitoring of bilateral middle cerebral arteries was performed on days 3, 5, 7, 10, 14, 21, 28 and 35 after stroke onset. Flow velocity changes before, during and after ECP and continuous beat-to-beat blood pressure data were recorded. The cerebral augmentation index (CAI) is the increase in the percentage of the middle cerebral artery mean flow velocity during ECP compared with baseline. RESULTS:The CAI in patients with stroke was significantly higher on the ipsilateral side and on the contralateral side on day 3 (ipsilateral CAI, 9.3%; contralateral CAI, 7.2%), day 5 (7.0%; 6.7%), day 7 (6.8%; 6.0%), day 10 (6.0%; 5.1%), day 14 (4.7%; 2.6%) and day 21 (4.1%; 2.2%) after stroke onset than that in controls (-2.0%) (all p<0.05). There was a significant trend of decreasing CAI on the ipsilateral and contralateral sides over time after a stroke. Differences in the percentage increase in the mean blood pressure did not change significantly over time in patients with stroke. CONCLUSIONS:Blood pressure elevation persists throughout ECP treatment, which consists of 35 sessions. However, cerebral blood flow augmentation may last at least 3 weeks and then appears to return to baseline 1 month after acute stroke onset.
10.1136/jnnp-2014-309842
Quantification of Serial Cerebral Blood Flow in Acute Stroke Using Arterial Spin Labeling.
Harston George W J,Okell Thomas W,Sheerin Fintan,Schulz Ursula,Mathieson Phil,Reckless Ian,Shah Kunal,Ford Gary A,Chappell Michael A,Jezzard Peter,Kennedy James
Stroke
BACKGROUND AND PURPOSE:Perfusion-weighted imaging is used to select patients with acute ischemic stroke for intervention, but knowledge of cerebral perfusion can also inform the understanding of ischemic injury. Arterial spin labeling allows repeated measurement of absolute cerebral blood flow (CBF) without the need for exogenous contrast. The aim of this study was to explore the relationship between dynamic CBF and tissue outcome in the month after stroke onset. METHODS:Patients with nonlacunar ischemic stroke underwent ≤5 repeated magnetic resonance imaging scans at presentation, 2 hours, 1 day, 1 week, and 1 month. Imaging included vessel-encoded pseudocontinuous arterial spin labeling using multiple postlabeling delays to quantify CBF in gray matter regions of interest. Receiver-operator characteristic curves were used to predict tissue outcome using CBF. Repeatability was assessed in 6 healthy volunteers and compared with contralateral regions of patients. Diffusion-weighted and T2-weighted fluid attenuated inversion recovery imaging were used to define tissue outcome. RESULTS:Forty patients were included. In contralateral regions of patients, there was significant variation of CBF between individuals, but not between scan times (mean±SD: 53±42 mL/100 g/min). Within ischemic regions, mean CBF was lowest in ischemic core (17±23 mL/100 g/min), followed by regions of early (21±26 mL/100 g/min) and late infarct growth (25±35 mL/100 g/min; ANOVA P<0.0001). Between patients, there was marked overlap in presenting and serial CBF values. CONCLUSIONS:Knowledge of perfusion dynamics partially explained tissue fate. Factors such as metabolism and tissue susceptibility are also likely to influence tissue outcome.
10.1161/STROKEAHA.116.014707
Control of cerebral ischemia with magnetic nanoparticles.
Nature methods
The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.
10.1038/nmeth.4105
Silent infarcts in sickle cell disease occur in the border zone region and are associated with low cerebral blood flow.
Blood
Silent cerebral infarcts (SCIs) are associated with cognitive impairment in sickle cell anemia (SCA). SCI risk factors include low hemoglobin and elevated systolic blood pressure; however, mechanisms underlying their development are unclear. Using the largest prospective study evaluating SCIs in pediatric SCA, we identified brain regions with increased SCI density. We tested the hypothesis that infarct density is greatest within regions in which cerebral blood flow is lowest, further restricting cerebral oxygen delivery in the setting of chronic anemia. Neuroradiology and neurology committees reached a consensus of SCIs in 286 children in the Silent Infarct Transfusion (SIT) Trial. Each infarct was outlined and coregistered to a brain atlas to create an infarct density map. To evaluate cerebral blood flow as a function of infarct density, pseudocontinuous arterial spin labeling was performed in an independent pediatric SCA cohort. Blood flow maps were aligned to the SIT Trial infarct density map. Mean blood flow within low, moderate, and high infarct density regions from the SIT Trial were compared. Logistic regression evaluated clinical and imaging predictors of overt stroke at 3-year follow-up. The SIT Trial infarct density map revealed increased SCI density in the deep white matter of the frontal and parietal lobes. A relatively small region, measuring 5.6% of brain volume, encompassed SCIs from 90% of children. Cerebral blood flow was lowest in the region of highest infarct density ( < .001). Baseline infarct volume and reticulocyte count predicted overt stroke. In pediatric SCA, SCIs are symmetrically located in the deep white matter where minimum cerebral blood flow occurs.
10.1182/blood-2018-04-841247
External counterpulsation augments blood pressure and cerebral flow velocities in ischemic stroke patients with cerebral intracranial large artery occlusive disease.
Lin Wenhua,Xiong Li,Han Jinghao,Leung Thomas Wai Hong,Soo Yannie Oi Yan,Chen Xiangyan,Wong Ka Sing Lawrence
Stroke
BACKGROUND AND PURPOSE:External counterpulsation (ECP) is a novel noninvasive method used to improve the perfusion of vital organs, which may benefit ischemic stroke patients. We hypothesized that ECP may augment cerebral blood flow of ischemic stroke patients via induced hypertension. METHODS:We recruited ischemic stroke patients with cerebral intracranial large artery occlusive disease and healthy elderly controls into this study. Bilateral middle cerebral arteries of subjects were monitored using transcranial Doppler. Flow velocity changes before, during, and after ECP were, respectively, recorded for 3 minutes while continuous beat-to-beat blood pressure data were recorded. Cerebral augmentation index was the increase in percentage of middle cerebral artery mean flow velocity during ECP compared with baseline. Transcranial Doppler data were analyzed based on ipsilateral or contralateral to the infarct side. RESULTS:ECP significantly increased mean blood pressure of stroke patients and controls. During ECP, middle cerebral artery mean flow velocities of stroke patients increased on both ipsilateral and contralateral sides when compared with baseline (ipsilateral cerebral augmentation index, 9.64%; contralateral cerebral augmentation index, 9%; both P<0.001), but there was no increase in difference between the 2 sides when compared with each other. Mean flow velocities of controls did not change under ECP. After ECP, blood pressure and flow velocity of stroke patients returned to baseline level. CONCLUSIONS:ECP provides a new method of cerebral blood flow augmentation in ischemic stroke by elevation of blood pressure. Flow augmentation induced by ECP suggests the improvement of cerebral perfusion and collateral supply from infarct ipsilateral and contralateral sides.
10.1161/STROKEAHA.112.659144
Transient Aortic Occlusion Augments Collateral Blood Flow and Reduces Mortality During Severe Ischemia due to Proximal Middle Cerebral Artery Occlusion.
Ramakrishnan Gomathi,Dong Bin,Todd Kathryn G,Shuaib Ashfaq,Winship Ian R
Translational stroke research
Cerebral collateral circulation provides alternative vascular routes for blood to reach ischemic tissues during stroke. Collateral therapeutics attempt to augment flow through these collateral channels to reduce ischemia and brain damage during acute ischemic stroke. Transient aortic occlusion (TAO) has pre-clinical data suggesting that it can augment collateral blood flow and clinical data suggesting a benefit for patients with moderate cortical strokes. By diverting blood from the periphery towards the cerebral circulation, TAO has the potential to augment primary collateral flow at the circle of Willis and thereby improve outcome even during large, hemispheric strokes. Using proximal middle and anterior cerebral artery occlusion in rats, we demonstrate that TAO reduces mortality and improves collateral blood flow in severely ischemic animals. As such, TAO may be an effective therapy to reduce early mortality during severe ischemia associated with proximal occlusions.
10.1007/s12975-015-0443-5