Acute Stage Of Cerebral Ischemia Research Articles

Feasibility of Catalpol Intranasal Administration and Its Protective Effect on Acute Cerebral Ischemia in Rats via Anti-Oxidative and Anti-Apoptotic Mechanisms.

PurposeCatalpol is the main active component of Rehmannia glutinosa, which has a variety of pharmacological activities, including anti-inflammatory and anti-oxidative effects. This study investigates the feasibility of catalpol intranasal administration and its protective effect on acute cerebral ischemia in rats via anti-oxidative and anti-apoptotic mechanisms.Patients and MethodsThis study investigates the method of catalpol intranasal administration to evaluate the nasal mucosal toxicity, brain targeting and pharmacokinetics of catalpol. The protective effect of catalpol of intranasal administration on stroke-induced brain injury in rats and its mechanisms on oxidative stress pathway Nrf2/HO-1 and apoptosis were also investigated using middle cerebral artery occlusion (MCAO).ResultsThe results showed that catalpol intranasal administration was safe and feasible with no hemolysis, no bad effect on the maxillary ciliary movement of bullfrog. After intranasal administration, the brain targeting index (DTI) of catalpol was greater than 1, which indicated that catalpol had good brain targeting after intranasal administration. The bioavailability of catalpol administered intranasally was higher than that of in plasma. In MACO model, catalpol intranasal administration could significantly reduce cerebral infarction volume, neurological dysfunction and brain edema. In addition, catalpol intranasal administration can also reduce the brain cell’s occurrence of apoptosis, promote the expression of Bcl-2 protein and inhibit the expression of Bax protein, reduce oxidative stress damage via up-regulating expression of Nrf2 and HO-1, increasing the activities of SOD and decreasing the activities of MDA.ConclusionCollectively, catalpol intranasal administration has good safety, stability and brain targeting. It can effectively protect the brain injury of the rat model of acute cerebral ischemia and provide the possibility of drug administration in the acute stage of cerebral ischemia, especially before entering the hospital.

Loss of neuronal CD200 contributed to microglial activation after acute cerebral ischemia in mice

CD200 has been proved to play a role in immuno-inflammatory reaction. However, little information is available on CD200 in the acute stage of cerebral ischemia. We investigated the association between neuronal death and expression of CD200, and explored the relationship between CD200 and microglia in cerebral ischemic mice. Firstly, localization of CD200 expression in the normal brain tissue was detected by immunofluorescent assay. Then, focal cerebral ischemia was induced in mice by permanent middle cerebral artery occlusion (pMCAO) and then cortical tissues were collected at 6, 12, 24 and 48 h after surgery. Changes of CD200 and neuron-specific enolase (NSE) after pMCAO were assessed by western blotting. Meanwhile flow cytometry analysis was implemented to analyze the death of cortical cells. Results of these two parts were analyzed by Pearson correlation analysis. To further study, intracerebroventricular (ICV) injection of recombinant CD200 (rCD200) protein was carried out immediately after pMCAO. Iba-1 was measured by western blotting to evaluate activation of microglia, and inflammatory cytokines including IL-1β, TNF-α and IL-10 were tested by enzyme-linked immuno sorbent assay (ELISA). The results showed that CD200 was expressed in neurons and was not observed on mircroglia in cortex of normal mice. Expression of CD200 was decreased within 48 h after pMCAO, with a concomitant decrease of NSE expression. The rate of neuronal cell death was approximately around 30% and statistical analysis revealed a negative correlation between level of CD200 and the rate of neuronal death. Compared with control, exogenous rCD200 reduced expressions of Iba-1, IL-1β, TNF-α and IL-10. Taking together, our results demonstrated that loss of CD200 was caused by neuronal death and was one of contributing factors in microglial activation after cerebral ischemia. ICV injection of rCD200 protein could suppress activation of microglia in vivo.

Infiltration and persistence of lymphocytes during late-stage cerebral ischemia in middle cerebral artery occlusion and photothrombotic stroke models

BackgroundEvidence suggests that brain infiltration of lymphocytes contributes to acute neural injury after cerebral ischemia. However, the spatio-temporal dynamics of brain-infiltrating lymphocytes during the late stage after cerebral ischemia remains unclear.MethodsC57BL/6 (B6) mice were subjected to sham, photothrombosis, or 60-min transient middle cerebral artery occlusion (MCAO) procedures. Infarct volume, neurodeficits, production of reactive oxygen species (ROS) and inflammatory factors, brain-infiltrating lymphocytes, and their activation as well as pro-inflammatory cytokine IFN-γ production were assessed. Brain-infiltrating lymphocytes were also measured in tissue sections from post-mortem patients after ischemic stroke by immunostaining.ResultsIn mice subjected to transient MCAO or photothrombotic stroke, we found that lymphocyte infiltration persists in the ischemic brain until at least day 14 after surgery, during which brain infarct volume significantly diminished. These brain-infiltrating lymphocytes express activation marker CD69 and produce proinflammatory cytokines such as IFN-γ, accompanied with a sustained increase of reactive oxygen species (ROS) and inflammatory cytokines release in the brain. In addition, brain-infiltrating lymphocytes were observed in post-mortem brain sections from patients during the late stage of ischemic stroke.ConclusionOur results demonstrate that brain-infiltration of lymphocytes persists after the acute stage of cerebral ischemia, facilitating future advanced studies to reveal the precise role of lymphocytes during late stage of stroke.

Metabolite changes in the ipsilateral and contralateral cerebral hemispheres in rats with middle cerebral artery occlusion.

Cerebral ischemia not only causes pathological changes in the ischemic areas but also induces a series of secondary changes in more distal brain regions (such as the contralateral cerebral hemisphere). The impact of supratentorial lesions, which are the most common type of lesion, on the contralateral cerebellum has been studied in patients by positron emission tomography, single photon emission computed tomography, magnetic resonance imaging and diffusion tensor imaging. In the present study, we investigated metabolite changes in the contralateral cerebral hemisphere after supratentorial unilateral ischemia using nuclear magnetic resonance spectroscopy-based metabonomics. The permanent middle cerebral artery occlusion model of ischemic stroke was established in rats. Rats were randomly divided into the middle cerebral artery occlusion 1-, 3-, 9- and 24-hour groups and the sham group. 1H nuclear magnetic resonance spectroscopy was used to detect metabolites in the left and right cerebral hemispheres. Compared with the sham group, the concentrations of lactate, alanine, γ-aminobutyric acid, choline and glycine in the ischemic cerebral hemisphere were increased in the acute stage, while the concentrations of N-acetyl aspartate, creatinine, glutamate and aspartate were decreased. This demonstrates that there is an upregulation of anaerobic glycolysis (shown by the increase in lactate), a perturbation of choline metabolism (suggested by the increase in choline), neuronal cell damage (shown by the decrease in N-acetyl aspartate) and neurotransmitter imbalance (evidenced by the increase in γ-aminobutyric acid and glycine and by the decrease in glutamate and aspartate) in the acute stage of cerebral ischemia. In the contralateral hemisphere, the concentrations of lactate, alanine, glycine, choline and aspartate were increased, while the concentrations of γ-aminobutyric acid, glutamate and creatinine were decreased. This suggests that there is a difference in the metabolite changes induced by ischemic injury in the contralateral and ipsilateral cerebral hemispheres. Our findings demonstrate the presence of characteristic changes in metabolites in the contralateral hemisphere and suggest that they are most likely caused by metabolic changes in the ischemic hemisphere.

Bumetanide promotes neural precursor cell regeneration and dendritic development in the hippocampal dentate gyrus in the chronic stage of cerebral ischemia.

Bumetanide has been shown to lessen cerebral edema and reduce the infarct area in the acute stage of cerebral ischemia. Few studies focus on the effects of bumetanide on neuroprotection and neurogenesis in the chronic stage of cerebral ischemia. We established a rat model of cerebral ischemia by injecting endothelin-1 in the left cortical motor area and left corpus striatum. Seven days later, bumetanide 200 µg/kg/day was injected into the lateral ventricle for 21 consecutive days with a mini-osmotic pump. Results demonstrated that the number of neuroblasts cells and the total length of dendrites increased, escape latency reduced, and the number of platform crossings increased in the rat hippocampal dentate gyrus in the chronic stage of cerebral ischemia. These findings suggest that bumetanide promoted neural precursor cell regeneration, dendritic development and the recovery of cognitive function, and protected brain tissue in the chronic stage of ischemia.

N-acetylaspartate decrease in acute stage of ischemic stroke: a perspective from experimental and clinical studies.

N-acetylaspartate (NAA) appears in a prominent peak in proton magnetic resonance spectroscopy ((1)H-MRS) of the brain. Exhibition by NAA of time-dependent attenuation that reflects energy metabolism during the acute stage of cerebral ischemia makes this metabolite a unique biomarker for assessing ischemic stroke. Although magnetic resonance (MR) imaging is a powerful technique for inspecting the pathological changes that occur during ischemic stroke, biomarkers that directly reflect the drastic metabolic changes associated with acute-stage ischemia are strongly warranted for appropriate therapeutic decision-making in daily clinical settings. In this review, we provide a brief overview of NAA metabolism and focus on the use of attenuation in NAA as a means for assessing the pathophysiological changes that occur during the acute stage of ischemic stroke.

Residual high-grade stenosis after recanalization of extracranial carotid occlusion in acute ischemic stroke.

Residual stenosis after recanalization of an acute symptomatic extracranial occlusion of the internal carotid artery (ICA) might be an indication for carotid endarterectomy. We evaluated the proportion of residual high-grade stenosis (≥70%, near occlusions not included) on follow-up imaging in a consecutive series of patients with an acute symptomatic occlusion of the extracranial ICA. We included patients participating in the Dutch Acute Stroke Study (DUST), who had an acute symptomatic occlusion of the extracranial ICA that was diagnosed on computed tomographic angiography within 9 hours after onset of neurological symptoms. Follow-up imaging of the carotid artery had to be available within 7 days after admission. Of the 1021 patients participating in DUST between May 2009 and May 2013, an acute symptomatic occlusion of the extracranial ICA was found in 126 (12.3%) patients. Follow-up imaging was available in 86 (68.3%) of these patients. At follow-up, a residual stenosis of <30% was found in 15 (17.4%; 95% confidence interval, 10.8-26.9) patients, a 30% to 49% stenosis in 3 (3.5%; 95% confidence interval, 0.8-10.2) patients, a 50% to 69% stenosis in 2 (2.3%; 95% confidence interval, 0.1-8.6) patients, and a ≥70% stenosis in 14 (16.3%; 95% confidence interval, 9.8-25.6) patients. A near or persistent occlusion was present in the remaining 52 (60.5%) patients. A residual high-grade stenosis of the extracranial ICA occurs in 1 of 6 patients with a symptomatic occlusion in the acute stage of cerebral ischemia. Because this may have implications for secondary prevention, we recommend follow-up imaging in these patients within a week after the event. http://www.clinicaltrials.gov. Unique identifier: NCT00880113.

Long-term expression of periostin during the chronic stage of ischemic stroke in mice

Periostin is an extracellular matrix glycoprotein and has various cellular effects. Previously, we demonstrated the neuroprotective effects of periostin during the acute stage of cerebral ischemia. However, its expression during the chronic stage remains unknown. Herein, we examined the expression of full-length periostin (periostin 1; Pn1) and its splicing variant lacking exon 17 (periostin 2; Pn2) during the 28 days following transient middle cerebral artery occlusion in mice. Real-time reverse transcription-PCR showed that the expression of Pn2 was dramatically upregulated between days 3 and 28, and the highest expression was observed on day 7. The expression of Pn1 was also increased, but delayed compared with Pn2. Immunohistochemistry showed that periostin was weakly expressed in reactive astrocytes in the peri-infarct region and in microglia/macrophages in infarct regions, on days 3 and 7. Periostin was also expressed around CD31-positive cells in both the peri-infarct and the sub-ventricular zone (SVZ) on days 3 and 7. SOX-2 positive cells, which are neural stem cells, also expressed periostin on day 7. The highest periostin immunoreactivity that occurred co-localized with collagen I and fibronectin in the peri-infarct region between days 7 and 28. Thus, the expression pattern of periostin mRNA was dependent on the splicing variant, and it continued to be expressed up to 28 days after cerebral ischemia. As periostin was expressed in various cells, such as reactive astrocytes/microglia, fibroblasts and neuronal progenitor cells, periostin might be associated with pathophysiology in post-ischemic inflammation and neurogenesis.

The effect of age and cerebral ischemia on diffusion-weighted proton MR spectroscopy of the human brain.

DW-MRS is a promising tool for the noninvasive identification of the cellular response to cerebral ischemia. To date, the potential confounding effects of aging and the stage of ischemia are unknown. We, therefore, examined the cross-sectional effects of age and different stages of cerebral ischemia on the diffusion of brain metabolites. The ADCs of 3 major metabolites, including Cho, Cr, and NAA were measured by DW-MRS in healthy younger (n = 26, 24 ± 2.2 years of age) and older (n = 17, 63 ± 7.0 years of age) adults, as well as in patients with acute (n = 7, 57 ± 4.0 years of age) and subacute (n = 12, 62 ± 7.8 years of age) cerebral ischemia. Compared with younger adults, healthy older adults presented with significantly reduced ADC values of NAA (P = .000052), Cr (P = .000018), and Cho (P = .00075). Meanwhile, the ADC values of NAA (F(2,36) = 6.057, P = .006), Cr (F(2,36) = 5.634, P = .008), and Cho (F(2,36) = 8.167, P = .001) were significantly different among the acute cerebral ischemia group, subacute cerebral ischemia group, and healthy older controls. These metabolites decreased in the acute stage of cerebral ischemia but increased in the subacute stage, compared with age-matched controls. The effect of age should be considered when analyzing diffusion of cerebral metabolites with DW-MRS. Our observations also suggest that metabolite diffusion data may be used to reveal changes in the intracellular environment, depending on the pathologic status of ischemia.

Vascular endothelial growth factor in cerebral ischemia

Vascular endothelial growth factor (VEGF) is involved in many central nervous system disorders, including stroke, and confers neuroprotection in cerebral ischemia. In this Mini-Review, we examine in detail the in vitro and in vivo evidence for the role of VEGF in cerebral ischemia. VEGF is a therapeutic mediator for cerebral ischemia because of its angiogenic and neuroprotective effects. However, several studies indicate that the delivery route and the timing of VEGF delivery seem to determine the outcome of VEGF therapy after an ischemic insult. In the acute stage of cerebral ischemia, the effect of VEGF is considered controversial. Therefore, further work is necessary to identify a suitable therapeutic regime prior to phase II/III clinical trials. In addition, recent studies indicate that VEGF enhances neurogenesis after ischemia. Therefore, further investigation is necessary to clarify the exact role of VEGF in neurogenesis.

Visualization of Clot Composition in Ischemic Stroke

See related article, page 1237–1243 Sudden occlusion of a brain artery by a blood clot represents the pivotal event in ischemic stroke. Consequently, most of the therapeutic effort during the acute stage of cerebral ischemia aims at resolving the thrombus to restore blood flow. Because the clot is the primary target of thrombolytic therapy, the definition of clot characteristics that are associated with successful vessel recanalization could help to identify patients at risk and stratify treatment decisions. One promising approach is to visualize the thrombotic vessel by noninvasive imaging techniques. Indeed, early vessel signs indicative for occlusive clots have been described in ischemic stroke such as the hyperdense middle cerebral artery sign (HMCAS) on CT or blooming artifact (BA) on specific MRI sequences and their presence was shown to be associated with lower recanalization rates and worse outcomes.1,2 However, little is known about the histological basis, that is, clot composition, underlying the occurrence of these surrogate markers. The interesting question …

Thin-Section Diffusion-Weighted Imaging of the Infratentorium in Patients With Acute Cerebral Ischemia Without Apparent Lesion on Conventional Diffusion-Weighted Imaging

False-negative diffusion-weighted (DW) imaging findings are often encountered during the acute stage of cerebral ischemia. The types of acute ischemia most likely to be missed by conventional DW imaging, and the utility of additional thin-section DW imaging of the infratentorium were investigated in 192 consecutive patients admitted within 24 hours of the onset of ischemic symptoms. If 6-mm section DW imaging at admission showed no obvious lesion, additional 3-mm section DW imaging of the infratentorium was performed. Six-mm section DW imaging failed to demonstrate ischemic lesion in 32 patients; 18 patients with transient ischemic attack (TIA), 13 with infratentorial infarction, and one with supratentorial infarction. Three-mm section DW imaging revealed the ischemic lesions in 12 of these 32 patients. Most patients with negative 6-mm section DW imaging findings at admission suffered from either infratentorial infarction or TIA. If 6-mm section DW imaging shows no ischemic lesion, 3-mm section DW imaging of the infratentorium is considered to be useful for detection of the lesion.

Impact of Stroke Subtype on Blood Pressure Course During the Acute Stage of Cerebral Ischemia

To the Editor: We read with interest the recent article by Toyoda and colleagues investigating the acute blood pressure (BP) course using consecutive manual BP recordings among patients with different ischemic stroke (IS) subtypes and determining which baseline factors contribute to BP changes during the acute stroke stage.1 The authors concluded that during the first 6 days of hospitalization the BP course varied widely according to stroke subtypes with lacunar and atherothrombotic patients having higher BP values than the other ischemic stroke subtypes. They also reported that pre-existing hypertension and poorly controlled diabetes mellitus were associated with the acute systolic and diastolic BP …

Prognostic Value of Hyperintense Vessel Signals on Fluid-Attenuated Inversion Recovery Sequences in Acute Cerebral Ischemia

Background: Fluid-attenuated inversion recovery (FLAIR) sequences may reveal hyperintense vessel signals (HVS) at the acute stage of cerebral ischemia. The aim of this study was to test the hypothesis that HVS are associated with a worse outcome. Methods: We included 30 consecutive patients admitted within 12 h after onset of hemispheric cerebral ischemia. The outcome was assessed with the modified Rankin Scale at month 1. Results: Proximal HVS were present in 9 patients and distal HVS in 16. All patients with proximal occlusions on time-of-flight sequences had distal HVS on FLAIR. Patients with poor outcome at month 1 (modified Rankin Scale 3–6) more frequently had had HVS on MRI (12/13 vs. 4/17; p< 0.001). Conclusion: Distal HVS found on FLAIR sequences within 12 h of acute cerebral ischemia are associated with a worse 1-month outcome.

Antithrombotic agents’ use in patients with atrial fibrillation and acute cerebral ischemia

although trials suggest a benefit of aspirin, and not of anticoagulation (AC), in the acute stage of cerebral ischemia associated with atrial fibrillation (AF), many neurologists still use heparin. to evaluate how antithrombotic agents were used at the acute stage of cerebral ischemia in AF patients after the publication of trials and guidelines. we reviewed the charts of all patients with AF who were admitted between 1996 and 2002 as primary care patients, within 48 hours after onset of an ischemic stroke (IS) or transient ischemic attacks (TIAs). We recorded the first antithrombotic treatment prescribed at admission. in 763 consecutive patients (42% men; median age 79 years), the use of AC on admission decreased over time from 70% to 22% (p<0.001), while antiplatelet agents increased from 27% to 78% (p<0.001). Patients who received AC were more likely to be younger, to have a Barthel index >60, no hemorrhagic changes, and to have been admitted in 1996 or 1997. Results were similar between patients with IS and TIAs and in patients who were not under AC before. In patients who were under oral AC before, AC use at admission did not decline over time (p=0.366). there was a clear decrease in AC use during the study period, except in patients who were already under AC before, and in TIA patients.

Correction of cerebral ischemia in low-resistant animals with an antistress drug Deltaran

Deltaran decreased the amplitude of EEG slow waves and restored neuronal reactivity after carotid artery occlusion in Wistar rats sensitive to cerebral ischemia. Deltaran had no effect on local cerebral blood flow. This drug increased blood supply to a unit of neuronal activity in the brain of intact animals during the acute stage of cerebral ischemia, provided 100% survival rate of rats with cerebral ischemia, and prevented the development of neurological symptoms in survivors. Animal experiments proved the possibility of correcting cerebral ischemia with antistress drug Deltaran.

1145 Antithrombotic agents use in patients with atrial fibrillation at the acute stage of cerebral ischemia

1145 Antithrombotic agents use in patients with atrial fibrillation at the acute stage of cerebral ischemia

Motor evoked potentials following transcranial magnetic stimulation after middle cerebral artery and/or basilar artery occlusions in rats.

To clarify the significance of motor evoked potentials following transcranial magnetic stimulation (MMEPs) in acute stage of cerebral ischemia, MMEPs were recorded in rats with the right middle cerebral artery (MCA) and/or the basilar (BA) artery occlusions. MMEPs from bilateral forelimb muscle and regional cerebral blood flow (rCBF) of the pons were recorded simultaneously. After MCA occlusion, the amplitudes of MMEPs from left forelimb were increased up to approximately 184-221% of the pre-ischemic value for 60 min, though the latencies were unchanged. On the other hand, in the rats of BA occlusion and both BA and MCA occlusion groups, MMEPs amplitudes were decreased to 8-25% of the pre-ischemic value for 60 min. Pontine rCBF was decreased to 28-44% in both groups. As a mechanism of the facilitation of MMEPs after MCA occlusion, the affection of the inhibitory mechanism between the cerebral cortex and the generator of MMEPs by MCA occlusion is speculated.

Predicting the pathological fate of focal cerebral ischemia using 1H-magnetic resonance spectroscopic imaging

To clarify regional difference in 1H magnetic resonance spectral changes in the acute stage of focal cerebral ischemia, and to assess whether any correlation exists between spectral changes in acute stage and pathological outcome in the chronic stage, we measured the non-volume selected 1H-MRSI serially in the acute stage of focal ischemia in rat brain and correlated histopathological findings. The focal ischemia was induced by intraluminal MCA thread occlusion. After induction of focal ischemia, 1H-MR Spectroscopic Images (MRSI) were taken serially up to 10 h after the occlusion. NAA in the peri-ischemic area was maintained. On the other hand, the decline of NAA in the ischemic lesion was linear and drastic during the first 10 h after MCA occlusion, and the rates of decline of NAA concentrations up to 10 h after induction of ischemia, calculated with linear regression, were 0.44 m mol/kg/h in the ischemic core and 0.29 m mol/kg/h in the ischemic rim ( p<0.05). Lactate accumulated significantly in all three areas. Decreasing depth of NAA during the acute stage of cerebral ischemia identifies the formation of the ischemic core and can be used as a predictor for histological outcome.

Cerebral blood flow index image as a simple indicator for the fate of acute ischemic lesion.

To evaluate the feasibility of utilizing cerebral blood flow (CBF) index images, we attempted to investigate 1) whether CBF index images can reveal the resulting infracted area, 2) whether the CBF index can correlate other modality (SPECT). DWI and DPI were obtained in 17 patients within 12 hours of stroke onset and follow up MRI. On three DPI delivered images, namely relative regional cerebral blood volume (rrCBV), uncorrected mean transit time (MTTu) and CBF index images, correlations between initial lesion volume of and follow up infarction volume of three images and rCBF images delivered with singular value decomposition (SVD) methods were assessed. Then 99mTc-ECD SPECT was taken immediately after MRI to correlate to MRI data. Among the three images, lesion volume of CBF index images against follow up infarct volume had the highest correlation (r = 0.995) to a linear fit and the slope was closest to 1.0 (0.91) and had identical accuracy to the regression coefficient of rCBF images. CBF index well correlated to SPECT delivered CBF. CBF index images can accurately predict final infarct volume. Evaluating CBF index images together with DWI can guide the initial assessment in the acute stage of cerebral ischemia.