Current Neurovascular Research - Volume 13, Issue 4, 2016

Despite advances in imaging techniques and detailed examinations to determine the etiology of a stroke, the cause still remains undetermined in about one fourth of all ischemic strokes. The aim of this prospective study was to determine whether perfusion magnetic resonance imaging (MRI) can differentiate cardioembolic stroke from large artery atherosclerosis (LAA). We recruited 17 cardioembolic stroke and 22 LAA stroke patients, who were classified according to the Trial of Org 10172 in Acute Stroke Treatment and underwent perfusion MRI within 24 hours after the onset of stroke. The patients with cardioembolic stroke had more severe initial stroke severity and larger volumes of initial and final infarct compared to those with LAA stroke. Receiver operating characteristic curve analysis showed that the ratio of time to maximum of the residual curve (TΚmaxΚ) volume for a 2-, 3-, 4- or 5-s lag over TΚmaxΚ volume for a 8s lag all had excellent area under the curve values (> 0.9) to predict cardioembolic stroke. After adjusting for initial National Institute of Health Stroke Scale scores, a threshold of 3.73 for (TΚmaxΚ > 4s volume)/(TΚmaxΚ > 8s volume) had the highest odds ratio to predict cardioembolic stroke (p=0.012; odds ratio: 58.5; 95% confident interval: 2.5-1391.1), with 87.5% sensitivity and 94.4% specificity. In conclusion, perfusion MRI could be a reliable tool to identify cardioembolic stroke with its lower collateral. This is important as it could be used to reveal the exact mechanism and provide supportive evidence to classify a stroke.

Fingolimod (FTY720) reduces infarct volume and improves neurological deficits in different rodent stroke models by modulating inflammatory and immune processes. However, studies on FTY720 regarding its non-immunological efficacy on ischemic cerebral tissue are sparse. Here we investigated whether FTY720 has cytoprotective and restorative properties following ischemic stroke in mice. Male mice received FTY720 (1mg/kg) or a vehicle solution intraperitoneally immediately prior to transient middle cerebral artery occlusion (tMCAO; 30 min.) and 48 hours thereafter. Infarct volume was determined on T2-weighted magnetic resonance images on day 1 and 7 after tMCAO. Motor function was assessed by the ladder rung walking test using a foot fault score. Specific immunostainings were performed to quantify neuronal density, astrocytic reactivity, microvascular density and expression of synaptophysin in the cortical perilesional area on consecutive brain slices. The amount of brain-derived neurotrophic factor (BDNF) was examined using ELISA analyses. FTY720 treatment significantly reduced infarct volumes and motor deficits compared to controls. Neuronal survival, astrogliosis as well as synaptogenesis and BDNF expression in the penumbra of the infarcted cortex did not significantly differ between the treatment groups. Taken together, our data support the hypothesis that the key mode of FTY720 action in stroke is the reduction of microvascular thrombosis and not a direct effect at the neurovascular unit (NVU).

Stroke patients with carotid disease have a high risk of recurrence of disease. By measuring cerebral blood flow volume (BFV) using extracranial duplex technique for clinical estimation of intracranial collaterals, we aimed to investigate the relationship between the presence of intracranial collaterals and stroke recurrence in stroke patients with carotid disease. Consecutive stroke patients indicated for carotid duplex ultrasound investigations in our hospital were recruited during three years’ period. Carotid stenosis was diagnosed as ≥50% stenosis and extracranial arterial BFV was measured by using color velocity imaging quantification ultrasound (CVIQ) software. Presence of intracranial collateral flow was defined as a blood flow volume of either ≥370 mL/min in common carotid artery or ≥120 mL/min in vertebral artery. Univariate and multivariate analyses were performed to determine the independent predictors of recurrent stroke. One hundred and twelve stroke patients (19.1%) with ≥50% carotid stenosis were recruited from consecutive ischemic stroke patients. During a mean follow-up of 28.6±13.1 months, recurrent stroke was recorded in 32 (28.6%) out of the total recruited patients. Estimated by blood flow volume measured by CVIQ, the patients with intracranial collateral flow had a lower rate of recurrent stroke than those without (9.5% vs. 33%, P=0.032). After adjusting for potential confounders, the presence of CVIQ-estimated intracranial collateral flow was an independent protector of recurrent stroke (OR, 0.169; 95% CI, 0.034- 0.842; P=0.03). It could be concluded that blood supply through intracranial collateral flow estimated by CVIQ technique may protect stroke patients with carotid stenosis from suffering recurrent stroke.

Vascular dementia is the highly devastating neurodegenerative disorder after Alzheimer’s disease (AD) and mainly found in aged people but the effectual therapeutic target is still not there. Chronic cerebral hypoperfusion (CCH) has been broadly found in vascular dementia (VaD) patients. CCH is thought to link with neurodegenerative disorders and their subsequent cognitive deteriorate on. This study has been framed to examine the role of a selective agonist of cannabinoid receptor type 2(CB2); 1-phenylisatin in CCH induced VaD. Permanent bilateral common carotid arteries ligation or two vessels occlusion (2VO) technique was used to induce CCH in rats. 2VO animals have shown significant impairment in learning-memory (Morris water maze) and in executive functioning (Attentional set-shifting test). These animals have shown a considerable reduction in brain oxidative stress (thiobarbituric reactive acid substance-TBARS; glutathione-GSH; catalase-CAT and superoxide dismutase-SOD), mitochondrial dysfunction (complexes I, II, IV) with a significant enhancement in cholinergic activity- AChE and brain infarct size2,3,5-triphenylterazolium chloride staining (TTC staining). Animals treated with 2VO have also demonstrated a considerable augmentation in brain edema (water content). Oral administration of 1-phenylisatin has significantly recuperated 2VO induced impairment in learning-memory, an increase in TBARS, GSH, CAT, SOD, mitochondrial activity with a significant reduction in AChE activity and brain damage. Administration of 1- phenylisatin has also reported recovering brain edema in these animals. These results indicate that 2VO induced CCH in rats, which was attenuated with the treatment of 1-phenylisatin. Hence, it may be suggested that modulation of cannabinoid receptor may provide benefits in CCH as cognitive impairment and VaD. Therefore, selective agonists of CB2 receptors may be a potential research target for the alleviation of VaD.

Elevated alkaline phosphatase (ALP) levels are associated with cerebral small vascular diseases, such as silent brain infarction and cerebral white matter hyperintensity (cWMH), but few prospective data are available for cerebral microbleeds (CMBs). The aim of the study was to investigate associations between serum ALP levels and CMBs in acute ischemic stroke patients with atrial fibrillation and/or rheumatic heart disease. This prospective study involved consecutively recruited acute ischemic stroke patients with atrial fibrillation and/or rheumatic heart disease treated at two large tertiary care hospitals in southwestern China. We used logistic regression to examine the relationships between ALP levels and CMBs. Of 128 patients (56 males; mean age, 68 years) included, 71 (55.5%) patients had CMBs. Compared with the first tertile of ALP concentration, participants in the third tertile were 3.59 times more likely to have multi-CMBs (≥2) [95% confidence interval (CI): 1.21-10.71; P = 0.02] after adjusting for age, gender, smoking habits, drinking habits, ALT (alanine transaminase) levels, AST (aspartate transaminase) levels, renal impairment and cWMH.

Oxaliplatin is a widely used chemotherapeutic agent that induces both acute and chronic peripheral neuropathy. Based on previous research indicating that estrogen replacement may attenuate some forms of pain in ovariectomized animals, we examined the effects of 17β-estradiol in OXAIPN. We discovered that local cold exposure induces an abnormal vascular response in both acute and chronic models of OXAIPN (oxaliplatin-induced peripheral neuropathy) that may be used as an easy and non-invasive method to predict which patients may be susceptible to the development of severe, chronic OXAIPN. Neuropathy was induced by injection of oxaliplatin on the first two days for the short-term OXAIPN group and twice a week for 3 weeks for the long-term OXAIPN group. Local cold-induced vascular responses were recorded in the presence or absence of subcutaneously injected transient receptor potential ankyrin 1 (TRPA1) antagonist HC033031 or transient receptor potential melastatin 8 (TRPM8) antagonist AMTB using laser Doppler flowmetry. Both short-term and long-term OXAIPN groups exhibited abnormal local cold-induced vascular responses, characterized by initial vasodilation followed by vasoconstriction. Local blockade of TRPA1 or TRPM8 receptors attenuated the initial vasodilation. Changes in release of calcitonin gene related peptide (CGRP) and nitric oxide (NO) metabolites due to local cold exposure at the hind paw were also involved. Administration of 17β-estradiol resulted in an anti-nociceptive effect and attenuating abnormal vasodilation.

We recently revealed that p.H157Y (rs2234255), a rare coding variant of triggering receptor expressed on myeloid cells 2 gene (TREM2), was associated with Alzheimer’s disease (AD) susceptibility in Han Chinese. Contrastingly, although p.H157Y was previously identified in both AD cases and controls by several sequencing studies, no association of this variant with disease susceptibility was reported. To gain a credible conclusion on the association between p.H157Y and AD risk, a meta-analysis involving 7,102 cases and 7,408 controls was conducted. Our results indicated that p.H157Y was associated with an increased risk of AD (OR=3.65, 95% CI: 1.61-8.28; P=0.002), further establishing TREM2 as an important susceptibility gene for this disease.

Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that modulates N-methyl-D-aspartate (NMDA) receptor activity by binding to several different 5-HT receptor subtypes. In the present study, we used whole-cell patch-clamp recordings in transverse slice preparations to test the role of 5-HT receptors in modulating the NMDA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex. We found that the NMDA receptor-mediated component of mEPSCs could be potentiated by exogenously applied 5-HT. Similar results were obtained by exogenously applied 5-CT or 8-OH-DPAT (the 5-HTΚ1AΚ and 5-HT7 receptor agonist). A specific antagonist for the 5-HTΚ7Κ receptor, SB-269970, completely blocked the increase in NMDA receptor-mediated component of mEPSCs by 5-CT or 8- OH-DPAT. Moreover, the selective 5-HTΚ1AΚ receptor antagonist, WAY-100135, displayed no influence on the enhancement in NMDA receptor-mediated component of mEPSCs by 5-CT or 8-OHDPAT. These results indicated that the increase in NMDA receptor-mediated component of mEPSCs by 5-HT in layer II/III pyramidal neurons of the young rat visual cortex requires activation of 5-HTΚ7Κ receptors, but not 5-HTΚ1AΚ receptors. These observations might be clinically relevant to schizophrenia and Alzheimer's disease (AD), where enhancing NMDA receptor-mediated neurotransmission is considered to be a promising strategy for treatment of these diseases.

Life expectancy continues to increase throughout the world, but is accompanied by a rise in the incidence of non-communicable diseases. As a result, the benefits of an increased lifespan can be limited by aging-related disorders that necessitate new directives for the development of effective and safe treatment modalities. With this objective, the mechanistic target of rapamycin (mTOR), a 289-kDa serine/threonine protein, and its related pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), proline rich Akt substrate 40 kDa (PRAS40), AMP activated protein kinase (AMPK), Wnt signaling, and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), have generated significant excitement for furthering novel therapies applicable to multiple systems of the body. Yet, the biological and clinical outcome of these pathways can be complex especially with oversight of cell death mechanisms that involve apoptosis and autophagy. Growth factors, and in particular erythropoietin (EPO), are one avenue under consideration to implement control over cell death pathways since EPO can offer potential treatment for multiple disease entities and is intimately dependent upon mTOR signaling. In experimental and clinical studies, EPO appears to have significant efficacy in treating several disorders including those involving the developing brain. However, in mature populations that are affected by aging-related disorders, the direction for the use of EPO to treat clinical disease is less clear that may be dependent upon a number of factors including the understanding of mTOR signaling. Continued focus upon the regulatory elements that control EPO and mTOR signaling could generate critical insights for targeting a broad range of clinical maladies.