Although physical exercise has been demonstrated to augment recovery of the post-stroke brain, the question of what level of exercise intensity optimizes neurological outcomes of post-stroke ...rehabilitation remains unsettled. In this study, we aim to clarify the mechanisms underlying the intensity-dependent effect of exercise on neurologic function, and thereby to help direct the clinical application of exercise-based neurorehabilitation. To do this, we used a well-established rat model of ischemic stroke consisting of cerebral ischemia induction through middle cerebral artery occlusion. Ischemic rats were subsequently assigned either to a control group entailing post-stroke rest, or to one of two exercise groups distinguished by the intensity of their accompanying treadmill regimens. After 24 h of reperfusion, exercise was initiated. Infarct volume, apoptotic cell death, and neurological defects were quantified in all groups at 3 days, and motor and cognitive function were tracked up to day 28. Additionally, Western blotting was used to assess the influence of our interventions on several proteins related to synaptogenesis and neuroplasticity (growth-associated protein 43, microtubule-associated protein, postsynaptic density-95, synapsin I, hypoxia inducible factor-1α, brain-derived neurotrophic factor, nerve growth factor, tyrosine kinase B, and cAMP response element binding protein). Our results were in equal parts encouraging and surprising. Both mild and intense exercise significantly decreased infarct volume, cell death, and neurological deficits. Motor and cognitive function, as determined using an array of tests such as beam balance, forelimb placing, and the Morris water maze, were also significantly improved by both exercise protocols. Interestingly, while an obvious enhancement of neuroplasticity proteins was shown in both exercise groups, mild exercise rats demonstrated a stronger effect on the expressions of Tau (p<0.01), brain-derived neurotrophic factor (p<0.01), and tyrosine kinase B (p<0.05). These findings contribute to the growing body of literature regarding the positive effects of both mild and intense long-term treadmill exercise on brain injury, functional outcome, and neuroplasticity. Additionally, the results may provide a base for our future study regarding the regulation of HIF-1α on the BDNF/TrkB/CREB pathway in the biochemical processes underlying post-stroke synaptic plasticity.
Cerebral venous thrombosis (CVT) is a rare type of venous thromboembolism (VTE). It is an important cause of stroke in young adults and children. Severe CVT, which is characterized by cerebral venous ...infarction or hemorrhage, seizures, or disturbance of consciousness, has more severe clinical manifestations and a worse prognosis. It is commonly believed that the onset of severe CVT gave credit to venous return disorder, with the underlying pathogenesis remaining unclear. There is increasing evidence suggesting that an inflammatory response is closely associated with the pathophysiology of severe CVT. Preclinical studies have identified the components of neuroinflammation, including microglia, astrocytes, and neutrophils. After CVT occurrence, microglia are activated and secrete cytokines (e.g., interleukin-1β and tumor necrosis factor-α), which result in a series of brain injuries, including blood-brain barrier disruption, brain edema, and cerebral venous infarction. Additionally, astrocytes are activated at the initial CVT stage and may interact with microglia to exacerbate the inflammatory response. The extent of cerebral edema and neutrophil recruitment increases temporally in the acute phase. Further, there are also changes in the morphology of inflammatory cells, expression of inflammatory mediators, and inflammatory pathway molecules with CVT progression. Lately, some clinical research suggested that some inflammation-related biomarkers are of great value in assessing the course, severity, and prognosis of severe CVT. Moreover, basic and clinical research suggested that anti-inflammatory therapy might hold promise in severe CVT. This study reviews the current literature regarding the involvement of inflammation in the pathophysiology and anti-inflammatory interventions of severe CVT, which would contribute to informing the pathophysiology mechanism and laying a foundation for exploring novel severe CVT therapeutic strategies.
This study aims to evaluate protective effects of brief repetitive bilateral arm ischemic preconditioning (BAIPC) on stroke recurrence in patients with symptomatic atherosclerotic intracranial ...arterial stenosis (IAS).
A total of 68 consecutive cases with symptomatic IAS, diagnosed by imaging, were enrolled in this prospective and randomized study. All patients received standard medical management. Patients in the BAIPC group (n = 38) underwent 5 brief cycles consisting of bilateral upper limb ischemia followed by reperfusion. The BAIPC procedure was performed twice daily over 300 consecutive days. Incidence of recurrent stroke and cerebral perfusion status in BAIPC-treated patients were compared with the untreated control group (n = 30).
In the control group, incidence of recurrent stroke at 90 and 300 days were 23.3% and 26.7%, respectively. In the BAIPC group, incidence of recurrent stroke was reduced to 5% and 7.9% at 90 and 300 days (p < 0.01), respectively. The average time to recovery (modified Rankin Scale score 0-1) was also shortened by BAIPC. Cerebral perfusion status, measured by SPECT and transcranial Doppler sonography, improved remarkably in BAIPC-treated brain than in control (p < 0.01).
This study provides a proof-of-concept that BAIPC may be an effective way to improve cerebral perfusion and reduce recurrent strokes in patients with IAS. Further investigation of this therapeutic approach is warranted as some patients were excluded after randomization.
Many mammalian species naturally undergo hibernation, a process that is associated with drastic changes in metabolism and systemic physiology. Their ability to retain an undamaged central nervous ...system during severely reduced cerebral blood flow has been studied for possible therapeutic application in human ischemic stroke. By inducing a less extreme 'hibernation-like' state, it has been hypothesized that similar neuroprotective effects reduce ischemia-mediated tissue damage in stroke patients. This manuscript includes reviews and evaluations of: (1) true hibernation, (2) hibernation-like state and its neuroprotective characteristics, (3) the preclinical and clinical methods for induction of artificial hibernation (i.e., therapeutic hypothermia, phenothiazine drugs, and ethanol), and (4) the mechanisms by which cerebral ischemia leads to tissue damage and how the above-mentioned induction methods function to inhibit those processes.
Symptomatic intracranial arterial stenosis (SIAS) is very common in octo- and nonagenarians, especially in the Chinese population, and is likely the most common cause of stroke recurrence worldwide. ...Clinical trials demonstrate that endovascular treatment, such as stenting, may not be suitable for octogenarians with systemic diseases. Hence, less invasive methods for the octogenarian patients are urgently needed. Our previous study (unique identifier: NCT01321749) showed that repetitive bilateral arm ischemic preconditioning (BAIPC) reduced the incidence of stroke recurrence by improving cerebral perfusion (confirmed by single photon emission computed tomography and transcranial Doppler sonography) in patients younger than 80 years of age; however, the safety and effectiveness of BAIPC on stroke prevention in octo- and nonagenarians with SIAS are still unclear. The objective of this study was to evaluate the safety and effectiveness of BAIPC in reducing stroke recurrence in octo- and nonagenarian patients with SIAS. Fifty-eight patients with SIAS were enrolled in this randomized controlled prospective study for 180 consecutive days. All patients enrolled in the study received standard medical management. Patients in the BAIPC group (
n
= 30) underwent 5 cycles consisting of bilateral arm ischemia followed by reperfusion for 5 min each twice daily. Those in the control group (
n
= 28) underwent sham-BAIPC twice daily. Blood pressure, heart rate, local skin status, plasma myoglobin, and plasma levels of thrombotic and inflammatory markers were documented in both groups before beginning the study and for the first 30 days. Finally, the incidences of stroke recurrence and magnetic resonance imaging during the 180 days of treatment were compared. Compared with the control, BAIPC had no adverse effects on blood pressure, heart rate, local skin integrity, or plasma myoglobin, and did not induce cerebral hemorrhage in the studied cohort. BAIPC reduced plasma high sensitive C-reactive protein, interleukin-6, plasminogen activator inhibitor-1, leukocyte count, and platelet aggregation rate and elevated plasma tissue plasminogen activator (all
p
< 0.01). In 180 days, 2 infarctions and 7 transient ischemic attacks were observed in the BAIPC group compared with 8 infarctions and 11 transient ischemic attacks in the sham BAIPC group (
p
< 0.05). BAIPC may safely inhibit stroke recurrence, protect against brain ischemia, and ameliorate plasma biomarkers of inflammation and coagulation in octo- and nonagenarians with SIAS. A multicenter trial is ongoing.
Clinical Trial Registration:
www.clinicaltrials.gov
, unique identifier: NCT01570231.
While it is well-known that pre-stroke exercise conditioning reduces the incidence of stroke and the development of comorbidities, it is unclear whether post-stroke exercise conditioning is also ...neuroprotective. The present study investigated whether exercise postconditioning (PostE) induced neuroprotection and elucidated the involvement of SIRT1 regulation on the ROS/ER stress pathway. Adult rats were subjected to middle cerebral artery occlusion (MCAO) followed by either: (1) resting; (2) mild exercise postconditioning (MPostE); or (3) intense exercise postconditioning (IPostE). PostE was initiated 24 h after reperfusion and performed on a treadmill. At 1 and 3 days thereafter, we determined infarct volumes, neurological defects, brain edema, apoptotic cell death through measuring pro- (BAX and Caspase-3) and anti-apoptotic (Bcl-2) proteins, and ER stress through the measurement of glucose-regulated protein 78 (GRP78), inositol-requiring 1α (IRE1α), protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), Caspase-12, and SIRT1. Proteins were measured by Western blot. ROS production was detected by flow cytometry.Compared to resting rats, both MPostE and IPostE significantly decreased brain infarct volumes and edema, neurological deficits, ROS production, and apoptotic cell death. MPostE further increased Bcl-2 expression and Bcl-2/BAX ratio as well as BAX and Caspase-3 expressions and ROS production (*
< 0.05). Both PostE groups saw decreases in ER stress proteins, while MPostE demonstrated a further reduction in GRP78 (***
< 0.001) and Caspase-12 (*
< 0.05) expressions at 1 day and IRE1α (**
< 0.01) and CHOP (*
< 0.05) expressions at 3 days. Additionally, both PostE groups saw significant increases in SIRT1 expression.In this study, both mild and intense PostE levels induced neuroprotection after stroke through SIRT1 and ROS/ER stress pathway. Additionally, the results may provide a base for our future study regarding the regulation of SIRT1 on the ROS/ER stress pathway in the biochemical processes underlying post-stroke neuroprotection. The results suggest that mild exercise postconditioning might play a similar neuroprotective role as intensive exercise and could be an effective exercise strategy as well.
Unilateral jugular stenosis is easily mistaken as jugular hypoplasia for their similar jugular appearances. This study aimed to propose a scheme to differentiate acquired internal jugular ...vein stenosis (IJVS) from congenital jugular variation through two case examples.
We presented a dynamic evolution process of the IJVS formation, through a case of a 17-year-old female with paroxysmal nocturnal hemoglobinuria (PNH)-associated right internal jugular venous thrombosis (IJVT), which resulted in post-thrombotic IJVS in the rare context of rapid recanalization. Meanwhile, we compared her images with images of a 39-year-old healthy male with hypoplastic IJV to determine the differences between the acquired IJVS and congenital dysplasia.
Based on the first case, we noticed the whole formative process of acquired IJVS from nothing to something. Meantime, we found that acquired IJVS was surrounded by abnormal corkscrew collaterals as imaged on contrast-enhanced magnetic resonance venography (CE-MRV), and the ipsilateral jugular foramen (JF) was normal-sized as displayed on computer tomography (CT). Conversely, jugular hypoplasia was with ipsilateral stenotic JF and without serpentine collaterals.
JF morphology and venous collaterals may be deemed as surrogate identifiers to distinguish acquired unilateral IJVS from jugular hypoplasia.
To demonstrate the role of the rate-limiting and ATP-dependent gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK) in oxidative and lactic stress and the effect of phenothiazine on PCK after ...stroke, a total of 168 adult male Sprague Dawley rats (3 months old, 280–300 g) underwent 2-h intraluminal middle cerebral artery occlusion (MCAO) and reperfusion for 6, 24, 48 h, or 7 days. Phenothiazine (chlorpromazine and promethazine (C+P)) (8 mg/kg) and 3-mercaptopicolinic acid (3-MPA, a PCK inhibitor, 100 μM) were administered at reperfusion onset. The effects of phosphoenolpyruvate, 3-MPA, or PCK knockdown were studied in neuronal cultures subjected to oxygen/glucose deprivation. Reactive oxygen species, lactate, phosphoenolpyruvate (PEP; a gluconeogenic product), mRNA, and protein of total PCK, PCK-1, and PCK-2 increased after MCAO and oxygen–glucose deprivation (OGD). Oxaloacetate (a gluconeogenic substrate) decreased, while PEP and glucose were increased, suggesting reactive gluconeogenesis. These changes were attenuated by phenothiazine, 3-MPA, or PCK shRNA. PCK-1 and -2 existed primarily in neurons, while the effects of ischemic stroke on the PCK expression were seen predominately in astrocytes. Thus, phenothiazine reduced infarction and oxidative/lactic stress by inhibiting PCKs, leading to functional recovery.
Background. Cerebrovascular disease (CVD) is recognized as the leading cause of permanent disability worldwide. Depressive disorders are associated with increased incidence of CVD. The goal of this ...study was to establish a chronic restraint stress (CRS) model for mice and examine the effect of stress on cerebrovascular inflammation and oxidative stress responses. Methods. A total of forty 6-week-old male C57BL/6J mice were randomly divided into the CRS and control groups. In the CRS group (n=20), mice were placed in a well-ventilated Plexiglas tube for 6 hours per day for 28 consecutive days. On day 29, open field tests (OFT) and sucrose preference tests (SPT) were performed to assess depressive-like behaviors for the two groups (n=10/group). Macrophage infiltration into the brain tissue upon stress was analyzed by measuring expression of macrophage marker (CD68) with immunofluorescence in both the CRS and control groups (n=10/group). Cerebral microvasculature was isolated from the CRS and controls (n=10/group). mRNA and protein expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), and macrophage chemoattractant protein-1 (MCP-1) in the brain vessels were measured by real-time PCR and Western blot (n=10/group). Reactive oxygen species (ROS), hydrogen peroxide (H2O2), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activities were quantified by ELISA to study the oxidative profile of the brain vessels (n=10/group). Additionally, mRNA and protein expressions of NOX subunits (gp91phox, p47phox, p67phox, and p22phox) in the cerebrovascular endothelium were analyzed by real-time PCR and Western blot (n=10/group). Results. CRS decreased the total distances (p<0.05) and the time spent in the center zone in OFT (p<0.001) and sucrose preference test ratio in SPT (p<0.01). Positive ratio of CD68+ was increased with CRS in the entire region of the brain (p<0.001), reflecting increased macrophage infiltration. CRS increased the expression of inflammatory factors and oxidative stress in the cerebral microvasculature, including TNF-α (p<0.001), IL-1β (p<0.05), IL-6 (p<0.05), VCAM-1 (p<0.01), MCP-1 (p<0.01), ROS (p<0.001), and H2O2 (p<0.001). NADPH oxidase (NOX) was activated by CRS (p<0.01), and mRNA and protein expressions of NOX subunits (gp91phox, p47phox, p67phox, and p22phox) in brain microvasculature were found to be increased. Conclusions. To our knowledge, this is the first study to demonstrate that CRS induces depressive stress and causes inflammatory and oxidative stress responses in the brain microvasculature.
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