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Sustained Neurological Recovery After Stroke in Aged Rats Treated With a Novel Prostacyclin Analog.

ABSTRACT: BACKGROUND AND PURPOSE:Targeting the prostaglandin I2 prostanoid (IP) receptor to reduce stroke injury has been hindered by the lack of selective drugs. MRE-269 is the active metabolite of selexipag showing a high selectivity toward the IP receptor. Selexipag has been recently approved for clinical use in pulmonary hypertension. We hypothesized that postischemic treatment with MRE-269 provides long-lasting neuroprotection with improved neurological outcomes in a clinically relevant rat stroke model. METHODS:Aged male Sprague-Dawley rats underwent transient middle cerebral artery occlusion and were randomly selected to receive either vehicle or MRE-269 (0.25 mg/kg) intravenously starting at 4.5 hours post ischemia. Accelerating rotarod and adhesive removal tests were conducted before and at 3, 7, 14, and 21 days after stroke. Infarct volume was quantified by magnetic resonance imaging at 48 hours and 21 days post middle cerebral artery occlusion. In parallel experiments, cerebral cortex samples from stroke and nonstroke sides from vehicle- and MRE-269-treated groups were collected at 18 hours post middle cerebral artery occlusion for molecular biology analyses. RESULTS:Quantitative magnetic resonance imaging data showed that postischemic MRE-269 treatment significantly reduced infarct volume compared with vehicle-treated rats at both 48 hours and 3 weeks after stroke. MRE-269 treatment resulted in a significant long-term recovery in both locomotor and somatosensory functions after middle cerebral artery occlusion, which was associated with a reduced weight loss in animals receiving the IP receptor agonist. Postischemic MRE-269 treatment reduced proinflammatory cytokines/chemokines and oxidative stress. Damage to the blood-brain barrier, as assessed by extravasation of immunoglobulin G to the ischemic brain, was significantly reduced by MRE-269, which was associated with a reduction in matrix metalloproteinase-9 activity in the brain of stroked aged rats given the IP agonist at 4.5 hours after ischemia onset. CONCLUSIONS:Our data suggest that targeting the IP receptor with MRE-269 is a novel strategy to reduce cerebral ischemia injury and promote long-term neurological recovery in ischemic stroke.

SUBMITTER: Yang C

PROVIDER: S-EPMC5508605 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Sustained Neurological Recovery After Stroke in Aged Rats Treated With a Novel Prostacyclin Analog.

Yang Changjun C DeMars Kelly M KM Alexander Jon C JC Febo Marcelo M Candelario-Jalil Eduardo E

Stroke 20170606 7

<h4>Background and purpose</h4>Targeting the prostaglandin I<sub>2</sub> prostanoid (IP) receptor to reduce stroke injury has been hindered by the lack of selective drugs. MRE-269 is the active metabolite of selexipag showing a high selectivity toward the IP receptor. Selexipag has been recently approved for clinical use in pulmonary hypertension. We hypothesized that postischemic treatment with MRE-269 provides long-lasting neuroprotection with improved neurological outcomes in a clinically rel ...[more]

PMID: 28588054

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Project description:AimVasculotide (VT), an angiopoietin-1 mimetic peptide, exerts neuroprotective effects in type one diabetic (T1DM) rats subjected to ischemic stroke. In this study, we investigated whether delayed VT treatment improves long-term neurological outcome after stroke in T1DM rats.MethodsMale Wistar rats were induced with T1DM, subjected to middle cerebral artery occlusion (MCAo) model of stroke, and treated with PBS (control), 2 µg/kg VT, 3 µg/kg VT, or 5.5 µg/kg VT. VT treatment was initiated at 24 h after stroke and administered daily (i.p) for 14 days. We evaluated neurological function, lesion volume, vascular and white matter remodeling, and inflammation in the ischemic brain. In vitro, we evaluated the effects of VT on endothelial cell capillary tube formation and inflammatory responses of primary cortical neurons (PCN) and macrophages.ResultsTreatment of T1DM-stroke with 3 µg/kg VT but not 2 µg/kg or 5.5 µg/kg significantly improves neurological function and decreases infarct volume and cell death compared to control T1DM-stroke rats. Thus, 3 µg/kg VT dose was employed in all subsequent in vivo analysis. VT treatment significantly increases axon and myelin density, decreases demyelination, decreases white matter injury, increases number of oligodendrocytes, and increases vascular density in the ischemic border zone of T1DM stroke rats. VT treatment significantly decreases MMP9 expression and decreases the number of M1 macrophages in the ischemic brain of T1DM-stroke rats. In vitro, VT treatment significantly decreases endothelial cell death and decreases MCP-1, endothelin-1, and VEGF expression under high glucose (HG) and ischemic conditions and significantly increases capillary tube formation under HG conditions when compared to non-treated control group. VT treatment significantly decreases inflammatory factor expression such as MMP9 and MCP-1 in macrophages subjected to LPS activation and significantly decreases IL-1? and MMP9 expression in PCN subjected to ischemia under HG conditions.ConclusionDelayed VT treatment (24 h after stroke) significantly improves neurological function, promotes vascular and white matter remodeling, and decreases inflammation in the ischemic brain after stroke in T1DM rats.

Project description:BackgroundStroke is the leading cause of disability worldwide, resulting in severe damage to the central nervous system and disrupting neurological functions. There is no effective therapy for promoting neurological recovery. Growing evidence suggests that the composition of exosomes from different microenvironments may benefit stroke. Therefore, it is reasonable to assume that exosomes secreted in response to infarction microenvironment could have further therapeutic effects.MethodsIn our study, cerebral infarct tissue extracts were used to pretreat umbilical cord mesenchymal stem cells (UCMSC). Infarct-preconditioned exosomes were injected into rats via tail vein after middle cerebral artery occlusion (MCAO). The effect of infarct-preconditioned exosomes on the neurological recovery of rats was examined using Tunel assay, 2,3,5-triphenyltetrazolium chloride (TTC) assay, magnetic resonance imaging (MRI) analyses, modified Neurological Severity Score (mNSS), Morris water maze (MWM), and vascular remodeling analysis. Mi-RNA sequencing and functional enrichment analysis were used to validate the signal pathway involved in the effect of infarct-preconditioned exosomes. Human umbilical vein endothelial cells (HUVECs) were co-cultured with the isolated exosomes. Cell Counting Kit-8 (CCK-8) assay, scratch healing, and Western blot analysis were used to detect the biological behavior of HUVECs.ResultsThe results showed that compared with normal exosomes, infarct-preconditioned exosomes further promoted vascular remodeling and recovery of neurological function after stroke. The function of upregulated miRNAs and their target genes which is beneficial to vascular smooth muscle cells verified the importance of vascular remodeling in improving stroke. Better resistance to oxygen-glucose deprivation/reoxygenation (OGD/R), reduced apoptosis, and enhanced migration were observed in infarct-preconditioned exosomes-treated umbilical vein endothelial cells.ConclusionsOur results demonstrated that infarct-preconditioned exosomes promoted neurological recovery after stroke by enhancing vascular endothelial remodeling, suggested that infarct-preconditioned exosomes could be a novel way to alleviate brain damage following a stroke.

Project description:BackgroundResolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A4 (LXA 4) is an anti-inflammatory, pro-resolution lipid mediator that reduces neuroinflammation in stroke. Since LXA 4 is rapidly inactivated, potent analogs have been synthesized, including BML-111. We hypothesized that post-ischemic, intravenous treatment with BML-111 for 1 week would provide neuroprotection and reduce neurobehavioral deficits at 4 weeks after ischemic stroke in rats. Additionally, we investigated the potential protective mechanisms of BML-111 on the post-stroke molecular and cellular profile.MethodsA total of 133 male Sprague-Dawley rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) and BML-111 administration was started at the time of reperfusion. Two methods of week-long BML-111 intravenous administration were tested: continuous infusion via ALZET ® osmotic pumps (1.25 and 3.75 μg μl-1 hr-1), or freshly prepared daily single injections (0.3, 1, and 3 mg/kg). We report for the first time on the stability of BML-111 and characterized an optimal dose and a dosing schedule for the administration of BML-111.ResultsOne week of BML-111 intravenous injections did not reduce infarct size or improve behavioral deficits 4 weeks after ischemic stroke. However, post-ischemic treatment with BML-111 did elicit early protective effects as demonstrated by a significant reduction in infarct volume and improved sensorimotor function at 1 week after stroke. This protection was associated with reduced pro-inflammatory cytokine and chemokine levels, decreased M1 CD40+ macrophages, and increased alternatively activated, anti-inflammatory M2 microglia/macrophage cell populations in the post-ischemic brain.ConclusionThese data suggest that targeting the endogenous LXA 4 pathway could be a promising therapeutic strategy for the treatment of ischemic stroke. More work is necessary to determine whether a different dosing regimen or more stable LXA 4 analogs could confer long-term protection.

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Sustained Neurological Recovery After Stroke in Aged Rats Treated With a Novel Prostacyclin Analog.

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Sustained Neurological Recovery After Stroke in Aged Rats Treated With a Novel Prostacyclin Analog.

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