Cerebral Stroke Model Research Articles

Intranasal Application of Diluted Saline Alleviates Ischemic Brain Injury in Association with Suppression of Vasopressin Neurons

Plain Language SummaryNeuroendocrine disorders during cerebral stroke are a major etiology of ischemic brain injury that occurs following the occlusion of the cerebral artery. A hypothalamic neuropeptide, antidiuretic hormone or vasopressin (VP), is a key neuroendocrine factor in ischemic brain injury. To identify the way to reduce the overly produced VP following the stroke, this study used a rat model of cerebral stroke and tested the effects of intranasal application/drops of low concentration saline-0.09% NaCl (IAL) on VP neuronal activity that determines VP secretion. The results revealed for the first time that IAL inhibition of stroke-evoked VP neuronal activation and its associated brain damage is related to IAL inhibition of ischemia-evoked astrocytic process retraction around VP neurons and increase in excitatory inputs on VP neurons from the mitral cells in the activated olfactory bulb in the ischemic side. Similar but weaker effects also occurred at oxytocin neurons that co-exist with VP neurons but exert neural protective effects. These findings highlight that IAL (or commercially available purified water?) inhibition of VP neuronal activity may provide a simply available protective strategy in the early stage of cerebral stroke after further clinical trials.

SSOCT/A reveals cerebrovascular activity during ischemic stroke in zebrafish

Using swept-source optical coherence tomography/angiography (SSOCT/A), we present a non-invasive examination of the zebrafish brain to comprehend the vasculature and altering cellular dynamics in the cerebral stroke model. Reduced or blocked blood flow to the brain during an ischemic stroke eventually results in cell death from a lack of oxygen and nutrients. SSOCT is used to examine ischemic stroke's aberrant/anomalous blood flow features using phase variance and the Doppler method. The SSOCT speckle-contrast technique is used to track the ensuing cell demise. Fast acquisition times, reduced motion artefacts, label-free viewing, and non-invasive testing are all features of the SSOCT approach for disease surveillance.

Cerebroprotective effects of khellin: validation through computational studies in a bilateral common carotid artery occlusion/reperfusion (BCCAO/R) model

ABSTRACT This study investigates the molecular interactions between khellin and nitric oxide synthase, which plays a significant role in the pathophysiology of acute ischemic stroke. Molecular docking, dynamic simulation, and in vivo approaches were used to explore these interactions, revealing that khellin has a superior binding affinity for nitric oxide synthase compared to its co-crystallized ligand. The cerebroprotective effect of khellin was evaluated in a rat model of cerebral stroke induced by bilateral common carotid artery occlusion and reperfusion (BCCAO/R), and the results showed that khellin treatment significantly decreased infarct size, increased antioxidant levels, decreased oxidative stress, and improved EEG function. Histological analysis also revealed increased pyramidal cell layer thickness and reduced apoptosis in the hippocampus. These findings suggest that khellin may be a promising therapeutic agent for cerebral ischemia by targeting the nitric oxide synthase-nitric oxide pathway.

Smurf2-Mediated Ubiquitination of FOXO4 Regulates Oxygen-glucose Deprivation/Reperfusion-induced Pyroptosis of Cortical Neurons.

Smad ubiquitination regulatory factor 2 (Smurf2) has been observed to alleviate ischemia-reperfusion injury. This study sought to explore the molecular mechanism of Smurf2-mediated forkhead box O4 (FOXO4) ubiquitination in oxygen-glucose deprivation/ reperfusion (OGD/R)-induced pyroptosis of cortical neurons. Human cortical neurons (HCN-2) were subjected to OGD/R to establish a cell model of cerebral stroke. Smurf2, FOXO4, and doublecortin domain containing 2 (DCDC2) expressions were determined by RT-qPCR and Western blot. LDH release, pyroptosis-related proteins NLRP3, GSDMD-N, and cleaved-caspase-3, as well as inflammatory factors IL-1β and IL-18, were assessed by LDH assay kit, Western blot, and ELISA. The ubiquitination level of FOXO4 was determined by ubiquitination assay. The bindings of Smurf2 to FOXO4 and FOXO4 to DCDC2 were testified by Co-IP, ChIP, and dual-luciferase assays. Rescue experiments were designed to validate the role of FOXO4/DCDC2 in the pyroptosis of HCN-2 cells. Smurf2 was weakly expressed, while FOXO4 and DCDC2 were prominently expressed in OGD/R-treated HCN-2 cells. Smurf2 overexpression promoted LDH release, reduced NLRP3, GSDMD-N, and cleaved-caspase-3 proteins, and decreased IL-1β and IL-18 concentrations. Sumrf2 improved the ubiquitination level of FOXO4 to downregulate its protein level. FOXO4 is bound to the DCDC2 promoter to facilitate its transcription. Overexpression of FOXO4 or DCDC2 reversed the inhibition of Smurf2 overexpression on pyroptosis of OGD/Rtreated HCN-2 cells. Smurf2 overexpression facilitated the ubiquitination of FOXO4 to reduce its protein level, thereby suppressing DCDC2 transcription and restricting OGD/R-induced pyroptosis of cortical neurons.

Untargeted metabonomic analysis of a cerebral stroke model in rats: a study based on UPLC-MS/MS.

Brain tissue damage caused by ischemic stroke can trigger changes in the body's metabolic response, and understanding the changes in the metabolic response of the gut after stroke can contribute to research on poststroke brain function recovery. Despite the increase in international research on poststroke metabolic mechanisms and the availability of powerful research tools in recent years, there is still an urgent need for poststroke metabolic studies. Metabolomic examination of feces from a cerebral ischemia-reperfusion rat model can provide new insights into poststroke metabolism and identify key metabolic pathways, which will help reveal diagnostic and therapeutic targets as well as inspire pathophysiological studies after stroke. We randomly divided 16 healthy adult pathogen-free male Sprague-Dawley (SD) rats into the normal group and the study group, which received middle cerebral artery occlusion/reperfusion (MCAO/R). Ultra-performance liquid chromatography-tandem mass spectrometry (UPLCMS/MS) was used to determine the identities and concentrations of metabolites across all groups, and filtered high-quality data were analyzed for differential screening and differential metabolite functional analysis. After 1 and 14 days of modeling, compared to the normal group, rats in the study group showed significant neurological deficits (p < 0.001) and significantly increased infarct volume (day 1: p < 0.001; day 14: p = 0.001). Mass spectra identified 1,044 and 635 differential metabolites in rat feces in positive and negative ion modes, respectively, which differed significantly between the normal and study groups. The metabolites with increased levels identified in the study group were involved in tryptophan metabolism (p = 0.036678, p < 0.05), arachidonic acid metabolism (p = 0.15695), cysteine and methionine metabolism (p = 0.24705), and pyrimidine metabolism (p = 0.3413), whereas the metabolites with decreased levels were involved in arginine and proline metabolism (p = 0.15695) and starch and sucrose metabolism (p = 0.52256). We determined that UPLC-MS/MS could be employed for untargeted metabolomics research. Moreover, tryptophan metabolic pathways may have been disordered in the study group. Alterations in the tryptophan metabolome may provide additional theoretical and data support for elucidating stroke pathogenesis and selecting pathways for intervention.

Resistance to Degradation of Silk Fibroin Hydrogels Exposed to Neuroinflammatory Environments.

Central nervous system (CNS) diseases represent an extreme burden with significant social and economic costs. A common link in most brain pathologies is the appearance of inflammatory components that can jeopardize the stability of the implanted biomaterials and the effectiveness of therapies. Different silk fibroin scaffolds have been used in applications related to CNS disorders. Although some studies have analyzed the degradability of silk fibroin in non-cerebral tissues (almost exclusively upon non-inflammatory conditions), the stability of silk hydrogel scaffolds in the inflammatory nervous system has not been studied in depth. In this study, the stability of silk fibroin hydrogels exposed to different neuroinflammatory contexts has been explored using an in vitro microglial cell culture and two in vivo pathological models of cerebral stroke and Alzheimer's disease. This biomaterial was relatively stable and did not show signs of extensive degradation across time after implantation and during two weeks of in vivo analysis. This finding contrasted with the rapid degradation observed under the same in vivo conditions for other natural materials such as collagen. Our results support the suitability of silk fibroin hydrogels for intracerebral applications and highlight the potentiality of this vehicle for the release of molecules and cells for acute and chronic treatments in cerebral pathologies.

Model of small-focal ischemic cerebral infarction as a basis for the development of new methods of stroke therapy

Background. Among the existing experimental models of cerebral stroke in large animals, there is no possibility to create a focal brain infarction of limited volume, which would provide an opportunity to evaluate both the endogenous potential of neuroregeneration and to establish the effectiveness of new drugs on postischemic brain remodeling.&#x0D; Aim. Development of a method for modeling small-focal ischemic infarction of the cerebral cortex in a mini-pig.&#x0D; Material and methods. The study used mature female mini-pigs of the Vietnamese fold-bellied breed. Two-level occlusion of the great vessels was performed by ligation of the right common carotid artery and subsequent cauterization of the distal branches of the middle cerebral artery. In the postoperative period, the survival rate of animals and neurological deficit were assessed. On the 7th day, the animals were taken out of the experiment, the brain was isolated from the cranial box. Macroscopic and microscopic examinations included analysis of the localization and area of cerebral infarction, as well as morphological changes in the infarcted and peri-infarcted areas of the cerebral cortex.&#x0D; Results. With a 100% survival rate of experimental animals on the 3rd day after the operation, a neurological examination revealed violations of skin sensitivity and muscle tone in the hind and fore limbs, which partially recovered a week after the onset of ischemic stroke. Macroscopic examination of the brain on the 7th day after the operation visually revealed a small-focal ischemic cerebral infarction in the parietal lobe of the left hemisphere. Histological analysis of the cerebral cortex revealed a wedge-shaped necrotic focus of ischemic injury. In the peri-infarction region of the brain, reactive tissue changes with preserved nerve cells, mostly without visible damage, were found.&#x0D; Conclusion. The developed two-level method of stroke modeling in a mini pig induces ischemic cerebral infarction of limited volume in the parietal lobe; non-critical histological changes in the peri-infarct area and a slight neurological deficit suggest the possibility of using this model to develop new methods of stroke therapy.

Echinacoside Alleviates Cognitive Impairment in Cerebral Ischemia Rats through α 7nAChR-Induced Autophagy.

To evaluate the effect of echinacoside (ECH) on cognitive dysfunction in post cerebral stroke model rats. The post stroke cognitive impairment rat model was created by occlusion of the transient middle cerebral artery (MCAO). The rats were randomly divided into 3 groups by a random number table: the sham group (sham operation), the MCAO group (received operation for focal cerebral ischemia), and the ECH group (received operation for focal cerebral ischemia and ECH 50 mg/kg per day), with 6 rats in each group. The infarct volume and spatial learning were evaluated by triphenyl tetrazolium chloride staining and Morris water maze. The expression of α7nAChR in the hippocampus was detected by immunohistochemistry. The contents of acetylcholine (ACh), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), activities of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and catalase (CAT) were evaluated by enzyme linked immunosorbent assay. The neural apoptosis and autophagy were determined by TUNEL staining and LC3 staining, respectively. ECH significantly lessened the brain infarct volume and ameliorated neurological deficit in infarct volume and water content (both P<0.01). Compared with MCAO rats, administration of ECH revealed shorter escape latency and long retention time at 7, 14 and 28 days (all P<0.01), increased the α7nAChR protein expression, ACh content, and ChAT activity, and decreased AChE activity in MCAO rats (all P<0.01). ECH significantly decreased MDA content and increased the GSH content, SOD, and CAT activities compared with MCAO rats (all P<0.05). ECH suppressed neuronal apoptosis by reducing TUNEL-positive cells and also enhanced autophagy in MCAO rats (all P<0.01). ECH treatment helped improve cognitive impairment by attenuating neurological damage and enhancing autophagy in MCAO rats.

Optogenetics stimulates nerve reorganization in the contralesional anterolateral primary motor cortex in a mouse model of ischemic stroke.

The anterolateral motor cortex of rodents is an important motor auxiliary area, and its function is similar to that of the premotor area in humans. Activation and inhibition of the contralesional anterolateral motor cortex (cALM) have been shown to have direct effects on motor behavior. However, the significance of cALM activation and inhibition in the treatment of stroke remains unclear. This study investigated the role of optogenetic cALM stimulation in a mouse model of cerebral stroke. The results showed that 21-day optogenetic cALM inhibition, but not activation, improved neurological function. In addition, optogenetic cALM stimulation substantially altered dendritic structural reorganization and dendritic spine plasticity, as optogenetic cALM inhibition resulted in increased dendritic length, number of dendritic spines, and number of perforated synapses, whereas optogenetic activation led to an increase in the number of multiple synapse boutons and the number of dendritic intersections. Furthermore, RNA-seq analysis showed that multiple biological processes regulated by the cALM were upregulated immediately after optogenetic cALM inhibition, and that several immediate-early genes (including cFOS, Erg1, and Sema3f) were expressed at higher levels after optogenetic inhibition than after optogenetic activation. These results were confirmed by quantitative reverse transcription-polymerase chain reaction. Finally, immunofluorescence analysis showed that the c-FOS signal in layer V of the primary motor cortex in the ischemic hemisphere was higher after optogenetic cALM activation than it was after optogenetic cALM inhibition. Taken together, these findings suggest that optogenetic cALM stimulation promotes neural reorganization in the primary motor cortex of the ischemic hemisphere, and that optogenetic cALM inhibition and activation have different effects on neural plasticity. The study was approved by the Experimental Animal Ethics Committee of Fudan University (approval No. 201802173S) on March 3, 2018.

The protective effects of apigenin on OLN-93 cellular model of cerebral stroke

The protective effects of apigenin on OLN-93 cellular model of cerebral stroke

DSIP-Like KND Peptide Reduces Brain Infarction in C57Bl/6 and Reduces Myocardial Infarction in SD Rats When Administered during Reperfusion.

A structural analogue of the DSIP, peptide KND, previously showed higher detoxification efficacy upon administration of the cytotoxic drug cisplatin, compared to DSIP. DSIP and KND were investigated using the model of acute myocardial infarction in male SD rats and the model of acute focal stroke in C57Bl/6 mice. A significant decrease in the myocardial infarction area was registered in KND-treated animals relative to saline-treated control animals (19.1 ± 7.3% versus 42.1 ± 9.2%). The brain infarction volume was significantly lower in animals intranasally treated with KND compared to the control saline-treated animals (7.4 ± 3.5% versus 12.2 ± 5.6%). Injection of KND in the first minute of reperfusion in the models of myocardial infarction and cerebral stroke reduced infarction of these organs, indicating a pronounced cardioprotective and neuroprotective effect of KND and potentiality for the treatment of ischemia-reperfusion injuries after transient ischemic attacks on the heart and brain, when administered during the reperfusion period. A preliminary pilot study using the model of myocardial infarction with the administration of DSIP during occlusion, and the model of cerebral stroke with the administration of KND during occlusion, resulted in 100% mortality in animals. Thus, in the case of ischemia-reperfusion injuries of the myocardium and the brain, use of these peptides is only possible during reperfusion.

Effects of Magnetic Nanoparticle Drug Delivery Systems on Thrombosis and Neuroprotection in Brain Stroke Model.

Nanomaterials refer to solid materials that are composed of ultrafine particles on the order of nanometers. Nanomaterials show broad application prospects in the fields of chemistry, metallurgy, electronics, aerospace, biology and medicine. The incidence of stroke in China ranks first in the world and the mortality rate is much higher than that in European and American countries. Drugs that are sensitive to the internal environment of the living body can be combined in the nuclear department to prevent them from reacting with the biological environment before reaching the target site, thereby reducing the efficacy or causing toxic side effects on other cells, tissues and organs. This project uses transgenic mice as experimental materials to establish an animal model of cerebral stroke. The light-embedded stroke model is used to simulate the pathological state of acute ischemic stroke. In vivo imaging and immunohistochemical techniques are used to analyze the administration of magnetic nanoparticles. Effects of the system on thrombolysis and neurological function protection in cerebral stroke models.

Circular RNA circPHKA2 Relieves OGD-Induced Human Brain Microvascular Endothelial Cell Injuries through Competitively Binding miR-574-5p to Modulate SOD2.

Background Circular RNA phosphorylase kinase regulatory subunit alpha 2 (circPHKA2; hsa_circ_0090002) has a significantly, specifically different expression in acute ischemic stroke (AIS) patients' blood. Here, we intended to investigate the role and mechanism of circPHKA2 in oxygen-glucose deprivation- (OGD-) induced stoke model in human brain microvascular endothelial cells (HBMEC). Methods Expression of circPHKA2, microRNA- (miR-) 574-5p, and superoxide dismutase-2 (SOD2) was detected by quantitative PCR and western blotting. Cell injury was measured by detecting cell proliferation (EdU assay and CCK-8 assay), migration (transwell assay), neovascularization (tube formation assay), apoptosis (flow cytometry and western blotting), endoplasmic reticulum stress (western blotting), and oxidative stress (assay kits). Direct intermolecular interaction was determined by bioinformatics algorithms, dual-luciferase reporter assay, biotin-labelled miRNA capture, and argonaute 2 RNA immunoprecipitation. Results circPHKA2 was downregulated in AIS patients' blood in SOD2-correlated manner. Reexpressing circPHKA2 rescued EdU incorporation, cell viability and migration, tube formation, B cell lymphoma-2 (Bcl-2) expression, and SOD activity of OGD-induced HBMEC and alleviate apoptotic rate and levels of Bcl-2-associated protein (Bax), glucose-regulated protein 78 kD (GRP78), C/EBP-homologous protein (CHOP), caspase-12, reactive oxygen species (ROS), and malondialdehyde (MDA). Additionally, blocking SOD2 partially attenuated these roles of circPHKA2 overexpression. Molecularly, circPHKA2 upregulated SOD2 expression via interacting with miR-574-5p, and miR-574-5p could target SOD2. Similarly, allied to neurovascular protection of circPHKA2 was the downregulation of miR-574-5p. Conclusion circPHKA2 could protect HBMEC against OGD-induced cerebral stroke model via the miR-574-5p/SOD2 axis, suggesting circPHKA2 as a novel and promising candidate in ischemic brain injury.

Oleuropein Improved Post Cerebral Stroke Cognitive Function by Promoting Histone Acetylation and Phosphorylation of cAMP Response Element-Binding Protein in MCAO Rats.

Background:Post-stroke cognitive impairment (PSCI) is commonest clinical disorder in which peripheral cholinergic activity is important. Oleuropein (OLP) is polyphenol is present in olive oil. Here we evaluated the effect of OLP in cognitive dysfunction rats in post cerebral stroke model.Methods:The post cerebral stroke cognitive dysfunction PSD rat model was created by occlusion of transient middle cerebral artery. The rats were divided into 6 groups named, Sham + Vehicle, Sham + OLP (50 mg/kg), PSD rats + Vehicle, PSD rats + OLP (20, 50 or 100 mg/kg). The spatial learning was assessed by Morris water maze (MWM). The expression of choline acetyltransferase (ChAT), acetylcholine (ACH), extent of histone acetylation and phosphorylation of cAMP response element-binding protein (CREB) were evaluated by Western blot assay and immunofluorescence staining.Results:Treatment of OLP at various doses showed higher number of spontaneous and rewarded alterations and lesser percentage bias compared to vehicle treated PSD rats. OLP resulted in decreased levels of ChAT and ACH, whereas the degree of histone acetylation and phosphorylation of CREB improved in dose dependent pattern.Conclusion:treatment of OLP improved PSCI via increasing the phosphorylation of CREB and histone acetylation, thus attenuating cholinergic activity.

Chrysophanol protects PC12 cells against oxygen glucose deprivation-evoked injury by up-regulating miR-216a

ABSTRACT Background Cerebral stroke refers to an acute onset of neurological deficit syndrome. In this research, we attempted to probe into the underlying mechanisms by which chrysophanol (CP) performed its regulatory roles in cerebral stroke. Methods OGD inducement was conducted in PC12 cells to construct a cerebral stroke model. Subsequently, CCK-8 assay, western blot, flow cytometry were utilized to determine cell viability, proliferation, and apoptosis, respectively. qRT-PCR was employed for detecting miR-216a expression level. Afterward, cell transfection was performed to alter miR-216a expression. Further, experiments were conducted to determine the expression of crucial factors participated in PI3 K/AKT and JAK2/STAT3 pathways for exploring the underlying mechanisms. Results OGD inducement suppressed cell viability, while promoted cell apoptosis. Besides, it enhanced the expression of proliferation-associated p53, p21, and apoptosis-associated Bax, and Cleaved-caspase-3, while suppressed the expression of Bcl-2. Furthermore, CHR exposure ameliorated the effects that OGD-evoked, and elevated the expression of miR-216a, as well as the expression of crucial factors participated in PI3 K/AKT and JAK2/STAT3 pathways. However, miR-216a silencing markedly reversed the effects triggered by CHR exposure. Conclusion CHR exposure relieved OGD-evoked PC12 cell damage by elevating miR-216a expression and thereby activating of PI3 K/AKT and JAK2/STAT3 pathways.

Investigation and comparison of the protective activities of three functional proteins—lactoferrin, α-lactalbumin, and β-lactoglobulin—in cerebral ischemia reperfusion injury

The objective of this study was to evaluate the protection conferred by lactoferrin, α-lactalbumin, and β-lactoglobulin in cerebral ischemia reperfusion (I/R) injury. Rat pheochromocytoma (PC12) cells were used to construct an oxygen and glucose deprivation model in vitro, and ICR mice underwent carotid artery "ligation-relaxation" to construct a cerebral I/R injury model in vivo. The levels of toll-like receptor 4 (TLR4) and downstream factors including nuclear factor-κB, tumor necrosis factor-α, and IL-1β were measured. Metabonomics detection and data mining were conducted to identify the specific metabolic sponsor of the 3 proteins. The results showed that lactoferrin, α-lactalbumin, and β-lactoglobulin protected neurons from cerebral I/R injury by increasing the level of bopindolol and subsequently inhibiting the TLR4-related pathway to different degrees; β-lactoglobulin had the strongest activity of the 3 proteins. In summary, this study is the first to investigate and compare the protective effects of lactoferrin, α-lactalbumin, and β-lactoglobulin in a cerebral stroke model. The results implicate TLR4 as a novel target of the 3 bioactive proteins to prevent cerebral I/R injury.

ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress.

The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an invivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.

Development of a three-channel automatic climbing training system for rat rehabilitation after ischemic stroke.

This paper reports the development of a three-channel automatic speed-matching climbing training system that could train three rats at the same time for rehabilitation after an ischemic stroke. An infrared (IR) remote sensor was installed at the end of each channel to monitor the real-time position of a climbing rat. This research was carried out in five stages: i) system design; ii) hardware circuit; iii) running speed control; iv) functional testing; and v) verification using an animal model of cerebral stroke. The rehabilitated group significantly outperformed the middle cerebral artery occlusion (MCAo) sedentary group in the rota-rod and inclined plate tests 21 days after a stroke. The rehabilitated group also had a cerebral infarction volume of 28.34±19.4%, far below 56.81±18.12% of the MCAo group 28 days after the stroke, validating the effectiveness of this training platform for stroke rehabilitation. The running speed of the climbing rehabilitation training platform was designed to adapt to the physical conditions of subjects, and overtraining injuries can be completely prevented accordingly.

Transtail Artery Access in Rats: A New Technique for Repeatable Selective Angiography

Transtail artery approach successfully enables selective arterial catheterization and angiography in the rat. This technique is effective and repeatable. In addition to its utility in imaging, it may also have a wide range of applications in transcatheter therapy and experimental cerebral stroke models.

Cyclic angiotensin-(1-7) contributes to rehabilitation of animal performance in a rat model of cerebral stroke

Peptidase-resistant, lanthionine-stabilized angiotensin-(1-7), termed cAng-(1-7), has shown therapeutic efficacy in animal models of cardiovascular, metabolic, kidney and pulmonary disease. Goal of the present study was testing the capacity of subcutaneously administered cAng-(1-7) to induce rehabilitation of animal performance in the transient middle cerebral artery occlusion rat model of cerebral stroke. 24 h after ischemic stroke induction, cAng-(1-7) was administered for 28 days at a dose of 500 μg/kg/day, either daily via subcutaneous injection or continuously via an alzet pump. Both ways of administration of cAng-(1-7) were equally effective. Measurements were continued until day 50. Compared to vehicle, cAng-(1-7) clearly demonstrated significantly increased capillary density (p < 0.01) in the affected hemisphere and improved motor and somatosensory functioning. The modified neurological severity score (p < 0.001 at days 15 and 50), stepping test (p < 0.001 at days 36–50), forelimb placement test (p < 0.001 at day 50), body swing test (p < 0.001 at days 43 and 50) all demonstrated that cAng-(1-7) caused significantly improved animal performance. Taken together the data convincingly indicate rehabilitating capacity of subcutaneously injected cAng-(1-7) in cerebral ischemic stroke.