A novel indication of platonin, a therapeutic immunomodulating medicine, on neuroprotection against ischemic stroke in mice

Abstract Thrombosis and stroke are major causes of disability and death worldwide. However, the regular antithrombotic drugs may have unsatisfactory results and side effects. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers and some acute inflammation. Here, we explored the neuroprotective effects of platonin against middle cerebral artery occlusion (MCAO)-induced ischemic stroke in mice. Platonin(200 μg/kg) substantially reduced cerebral infarct volume, brain edema, neuronal cell death and neurological deficit scores, and improved the MCAO-reduced locomotor activity and rotarod performance. Platonin(5–10 μM) potently inhibited platelet aggregation and c-Jun NH2-terminal kinase (JNK) phosphorylation in collagen-activated platelets. The antiaggregation effect did not affect bleeding time but increased occlusion time in platonin(100 and 200 μg/kg)-treated mice. Platonin(2–10 μM) was potent in diminishing collagen- and Fenton reaction-induced ∙OH formation. Platonin(5–10 μM) also suppressed the expression of nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1β, and JNK phosphorylation in lipopolysaccharide-stimulated macrophages. MCAO-induced expression of 3-nitrotyrosine and Iba1 was apparently attenuated in platonin(200 μg/kg)-treated mice. In conclusion, platonin exhibited remarkable neuroprotective properties against MCAO-induced ischemia in a mouse model through its antiaggregation, antiinflammatory and antiradical properties. The observed therapeutic efficacy of platonin may consider being a novel medcine against ischemic stroke.

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Abstract 114: Neuroprotective Role of Brain Pericytes through PDGFRβ-Akt Signaling in Ischemic Stroke

Stroke ◽

10.1161/str.43.suppl_1.a114 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Koichi Arimura ◽

Tetsuro Ago ◽

Masahiro Kamouchi ◽

Hiroshi Sugimori ◽

Junya Kuroda ◽

...

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

Infarct Volume ◽

Neurovascular Unit ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Akt Signaling ◽

Artery Occlusion ◽

Brain Functions ◽

Brain Pericytes

Brain pericytes are a constituent of the neurovascular unit and play various important roles in brain functions, such as regulation of capillary blood flow, maintenance of blood-brain barrier and angiogenesis. Previous reports have elucidated that PDGF-B prevents neuronal cell death during ischemic insults in adult rodent models; however, the detailed mechanisms by which PDGF-B signaling protects neurons from ischemic damage are not fully understood. In the present study, we investigated whether brain pericytes play neuroprotective roles in brain ischemia, using a permanent middle cerebral artery occlusion stroke model (MCAO) and cultured human brain pericytes. Immunohistochemistry revealed that the expression of PDGF receptorβ(PDGFRβ) was induced predominantly in pericytes in peri-infarct areas. PDGF-B induced marked phosphorylation of Akt in cultured pericytes. Consistently, Akt was markedly phosphorylated in the PDGFRβ-expressing pericytes in peri-infarct areas. PDGF-B upregulated the expression of neurotrophins, such as neuronal growth factor (NGF) and neurotrophin-3 (NT-3), through Akt activation in the cultured pericytes. We subjected PDGFRβheterozygous knockout (PDGFRβ+/-) mice to MCAO. Infarct volume, as assessed by MAP2 immunostaining, was significantly greater in PDGFRβ+/- than wild-type mice ( 48% increase at day 7, p < 0.01 , n=5). The number of TUNEL positive apoptotic cells was significantly greater in PDGFRβ+/- mice (54 % increase at day 4, p < 0.001 , n=6). Production of NGF and NT-3 at mRNA and protein levels in infarct areas was significantly decreased in PDGFRβ+/- mice (NGF: 28% decrease, p<0.05, NT-3: 22% decrease, p<0.05). Since it has been established that neurotrophin receptors are induced in peri-infarct areas, the decreases in neurotrophin production may increase apoptotic neuronal cell death in the PDGFRβ+/- mice. In conclusion, brain pericytes may have a direct neuroprotective role through secreting neurotrophins via PDGFRβ-Akt signaling, thereby decreasing infarct volume in ischemic stroke.

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L-Arginine Levels in Blood as a Marker of Nitric Oxide–Mediated Brain Damage in Acute Stroke: A Clinical and Experimental Study

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000080651.64357.c6 ◽

2003 ◽

Vol 23 (8) ◽

pp. 978-984 ◽

Cited By ~ 26

Author(s):

Arola Armengou ◽

Olivia Hurtado ◽

Rogelio Leira ◽

María Obón ◽

Carlos Pascual ◽

...

Keyword(s):

Nitric Oxide ◽

Experimental Study ◽

Ischemic Stroke ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Brain Damage ◽

Cerebral Artery ◽

Infarct Volume ◽

Artery Occlusion ◽

Cerebral Artery Occlusion

There are no useful markers in blood of nitric oxide (NO)-mediated brain damage. Because l-arginine (l-arg) is the only known substrate for NO generation, the authors investigated the plasma profile of l-arg after cerebral ischemia, and the relationship of L-arg concentrations in blood with stroke outcome and infarct volume in a clinical and experimental study. l-Arg levels were determined with high-performance liquid chromatography in blood and CSF samples obtained on admission, and in blood 48 hours after inclusion, in 268 patients admitted with a hemispheric ischemic stroke lasting 8.2 ± 5.9 hours. Infarct volume was measured by days 4 to 7 using computed tomography. Plasma l-arg profiles were analyzed in a separate group of 29 patients seen within 8 hours of onset (median, 4.5 hours) and in 24 male Fischer rats treated with subcutaneous vehicle or 20-mg/kg 1400W (a specific inducible NO synthase inhibitor) every 8 hours for 3 days after performing sham or permanent middle cerebral artery occlusion. Plasma l-arg concentrations decreased after the ischemic event, both in patients and rats, and peaked between 6 and 24 hours. In patients, there was a highly correlation between l-arg levels in CSF and plasma at 48 hours ( r = 0.85, P< 0.001). CSF and plasma l-arg concentrations negatively correlated with infarct volume ( r = −0.40 and r = −0.35, respectively, P <0.001), and were significantly lower in patients with early neurologic deterioration and in those with poor outcome (Barthel index <85) at 90 days ( P <0.001). In rats, the administration of 1400W resulted in a 55% significant reduction of infarct volume measured 72 hours after permanent middle cerebral artery occlusion, an effect that correlated with the inhibition caused by 1400W on the ischemia-induced decrease of plasma l-arg concentrations at 6 to 24 hours after the onset of the ischemia. Taken together, these data indicate that determination of l-arg levels in blood might be useful to evaluate the neurotoxic effects of NO generation. These findings might be helpful to guide future neuroprotective strategies in patients with ischemic stroke.

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ARL 17477, a Potent and Selective Neuronal NOS Inhibitor Decreases Infarct Volume after Transient Middle Cerebral Artery Occlusion in Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199607000-00009 ◽

1996 ◽

Vol 16 (4) ◽

pp. 599-604 ◽

Cited By ~ 120

Author(s):

Zheng G. Zhang ◽

David Reif ◽

James Macdonald ◽

Wen Xue Tang ◽

Dietgard K. Kamp ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Cerebral Artery ◽

Cell Damage ◽

Infarct Volume ◽

Artery Occlusion ◽

Arterial Blood ◽

Mca Occlusion ◽

Nos Inhibitor ◽

Oxide Synthase ◽

Cerebral Artery Occlusion

We tested the effects of administration of a selective neuronal nitric oxide synthase (nNOS) inhibitor, ARL 17477, on ischemic cell damage and regional cerebral blood flow (rCBF), in rats subjected to transient (2 h) middle cerebral artery (MCA) occlusion and 166 h of reperfusion (n = 48) and in rats without MCA occlusion (n = 25), respectively. Animals were administered ARL 17477 (i.v.): 10 mg/kg; 3 mg/kg; 1 mg/kg; N-nitro-L-arginine (L-NA) 10 mg/kg L-NA 1 mg/kg; and Vehicle. Administration of ARL 17477 1 mg/kg, 3 mg/kg and 10 mg/kg reduced ischemic infarct volume by 53 (p < 0.05), 23, and 6.5%, respectively. L-NA 1 mg/kg and 10 mg/kg increased infarct volume by 2 and 15%, respectively (p > 0.05). Administration of ARL 17477 (10 mg/kg) significantly (p < 0.05) decreased rCBF by 27 ± 5.3 and 24 ± 14.08% and cortical NOS activity by 86 ± 14.9 and 91 ± 8.9% at 10 min or 3 h, respectively, and did not alter mean arterial blood pressure (MABP). L-NA (10 mg/kg) significantly reduced rCBF by 23 ± 9.8% and NOS activity by 81 ± 7% and significantly (p < 0.05) increased MABP. Treatment with 3 mg/kg and 1 mg/kg ARL 17477 reduced rCBF by only 2.4 ± 4.5 and 0%, respectively, even when NOS activity was reduced by 63 ± 13.4 and 45 ± 15.7% at 3 h, respectively, (p < 0.05). The data demonstrate that ARL 17477 inhibits nNOS in the rat brain and causes a dose-dependent reduction in infarct volume after transient MCA occlusion.

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Blocking A1 astrocyte conversion with semaglutide attenuates blood-brain barrier disruption in mice after middle cerebral artery occlusion

10.21203/rs.3.rs-434590/v1 ◽

2021 ◽

Author(s):

Qi Zhang ◽

Chang Liu ◽

Rubing Shi ◽

Huimin Shan ◽

Lidong Deng ◽

...

Keyword(s):

Ischemic Stroke ◽

Middle Cerebral Artery ◽

Signaling Pathways ◽

Middle Cerebral Artery Occlusion ◽

Blood Brain Barrier ◽

Infarct Volume ◽

Artery Occlusion ◽

Rna Seq ◽

Neurobehavioral Outcomes ◽

Cerebral Artery Occlusion

Abstract Background Astrocytes play an essential role in the modulation of blood-brain barrier function. Neurological diseases induce astrocytes to transform into a neurotoxic A1 phenotype, thus exacerbating brain injury. However, the effect of A1 astrocyte on the function of BBB after stroke is unknown. Method: Adult male ICR mice (n = 78) were subjected to 90-minute transient middle cerebral artery occlusion. Immunohistochemical staining of A1 (C3d) and A2 (S100A10) was performed to characterize phenotypic changes of astrocytes overtime after stroke. Glucagon-like peptide-1 receptor agonist semaglutide was intraperitoneally injected into the mice to inhibit A1 astrocyte. Infarct volume, atrophy volume, neurobehavioral outcomes, and BBB permeability were examined. RNA-seq was adopted to explore the potential targets and signaling pathways of A1 astrocytes induced BBB dysfunction. Results Astrocytes assumed the A2 phenotype at the early stage of ischemic stroke but gradually transformed to the A1 phenotype. Semaglutide treatment reduced M1 microglia polarization and A1 astrocytes conversion after ischemic stroke (p < 0.05). Ischemia induced brain infarct volume, atrophy volume and neuroinflammation were reduced in the semaglutide treated mice. Neurobehavioral outcomes were improved compared to the control mice (p < 0.05). Further study demonstrated that semaglutide treatment reduced the gap formation of tight junction proteins ZO-1, claudin-5 and occludin, as well as IgG leakage following three days of ischemic stroke (p < 0.05). In vitro experiments revealed that A1 astrocyte-conditioned medium disrupted BBB integrity. RNA-seq further showed that A1 astrocytes were enriched in inflammatory factors and chemokines, as well as significantly modulating TNF and chemokine signaling pathways, which are closely related to barrier damage. Conclusion We concluded that astrocytes undergo a conversion from A2 phenotype to A1 phenotype overtime after ischemic stroke. A1 astrocytes aggravated BBB disruption, suggesting that block of A1 astrocytes conversion provides a novel strategy for the treatment of ischemic stroke.

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Heme–Hemopexin Complex Attenuates Neuronal Cell Death and Stroke Damage

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.19 ◽

2009 ◽

Vol 29 (5) ◽

pp. 953-964 ◽

Cited By ~ 62

Author(s):

Rung-chi Li ◽

Sofiyan Saleem ◽

Gehua Zhen ◽

Wangsen Cao ◽

Hean Zhuang ◽

...

Keyword(s):

Cortical Neurons ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Artery Occlusion ◽

Neuronal Cultures ◽

Tert Butyl Hydroperoxide ◽

Primary Mouse ◽

Free Heme ◽

Cerebral Artery Occlusion ◽

The Brain

Hemoproteins undergo degradation during hypoxic/ischemic conditions, but the prooxidant free heme that is released cannot be recycled and must be degraded. The extracellular heme associates with its high-affinity binding protein, hemopexin (HPX). Hemopexin is shown here to be expressed by cortical neurons and it is present in mouse cerebellum, cortex, hippocampus, and striatum. Using the transient ischemia model (90-min middle cerebral artery occlusion followed by 96-h survival), we provide evidence that HPX is protective in the brain, as neurologic deficits and infarct volumes were significantly greater in HPX−/− than in wild-type mice. Addressing the potential protective HPX cellular pathway, we observed that exogenous free heme decreased cell survival in primary mouse cortical neuron cultures, whereas the heme bound to HPX was not toxic. Heme-HPX complexes induce HO1 and, consequently, protect primary neurons against the toxicity of both heme and prooxidant tert-butyl hydroperoxide; such protection was decreased in HO1−/− neuronal cultures. Taken together, these data show that HPX protects against heme-induced toxicity and oxidative stress and that HO1 is required. We propose that the heme-HPX system protects against stroke-related damage by maintaining a tight balance between free and bound heme. Thus, regulating extracellular free heme levels, such as with HPX, could be neuroprotective.

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Treatment Effects of Ischemic Stroke by Berberine, Baicalin, and Jasminoidin from Huang-Lian-Jie-Du-Decoction (HLJDD) Explored by an Integrated Metabolomics Approach

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/9848594 ◽

2017 ◽

Vol 2017 ◽

pp. 1-20 ◽

Cited By ~ 14

Author(s):

Qian Zhang ◽

Xiaowei Fu ◽

Junsong Wang ◽

Minghua Yang ◽

Lingyi Kong

Keyword(s):

Ischemic Stroke ◽

Treatment Effects ◽

Infarct Volume ◽

Artery Occlusion ◽

H Nmr ◽

Abnormal Metabolism ◽

Cerebral Artery Occlusion ◽

First Time ◽

Integrated Metabolomics

Berberine, baicalin, and jasminoidin were major active ingredients of Huang-Lian-Jie-Du-Decoction (HLJDD), a famous prescription of traditional Chinese medicine (TCM), which has been used for the treatment of ischemic stroke. The aim of the present study was to classify their roles in the treatment effects of ischemic stroke. A rat model of middle cerebral artery occlusion (MCAO) was constructed to mimic ischemic stroke and treatment effects of berberine, baicalin, and jasminoidin, and HLJDD was assessed by neurologic deficit scoring, infarct volume, histopathology, immunohistochemistry, biochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. In addition, the 1H NMR metabolomics approach was used to assess the metabolic profiles, which combined with correlation network analysis successfully revealed metabolic disorders in ischemic stroke concerning the treatment of the three principal compounds from HLJDD for the first time. The combined results suggested that berberine, baicalin, and jasminoidin are responsible for the effectiveness of HLJDD on the treatment of ischemic stroke by amelioration of abnormal metabolism and regulation of oxidative stress, neuron autophagy, and inflammatory response. This integrated metabolomics approach showed its potential in understanding the function of complex formulae and clarifying the role of its components in the overall treatment effects.

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PSD-93 mediates the crosstalk between neuron and microglia and facilitates acute ischemic stroke injury by binding to CX3CL1

10.21203/rs.2.20106/v2 ◽

2020 ◽

Author(s):

qingxiu zhang ◽

Lei He ◽

Mo Chen ◽

Hui Yang ◽

Xiaowei Cao ◽

...

Keyword(s):

Ischemic Stroke ◽

Amino Acid ◽

Amino Acid Sequence ◽

Acute Ischemic Stroke ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Artery Occlusion ◽

Amino Acid Sequences ◽

Glutamate Excitotoxicity ◽

Underlying Mechanisms

Abstract Background: Postsynaptic density 93 (PSD-93) mediates glutamate excitotoxicity induced by ischemic brain injury, which then induces microglial inflammatory response. However, the underlying mechanisms of how PSD-93 mediates the crosstalk between neurons and microglia in the postsynaptic dense region remain elusive. CX3 chemokine ligand 1 (CX3CL1) is a chemokine specifically expressed in neurons while its receptor CX3CR1 is highly expressed in microglia. In this study, we aimed to investigate the role of PSD-93 and CX3CL1 interaction in the crosstalk between neuron and microglia in acute ischemic stroke.Methods: Male C57BL/6 mice were used to establish middle cerebral artery occlusion model and co-immunoprecipitation and immunoblotting were used to detect the binding of PSD-93 and CX3CL1 at different time points following cerebral ischemic/reperfusion (I/R). ELISA was used to detect soluble CX3CL1. Yeast two-hybrid and co-immunoprecipitation were used to identify special amino acid sequences responsible for the interaction between PSD-93 and CX3CL1. Finally, a fusion small peptide Tat-CX3CL1 was designed to inhibit PSD-93 and CX3CL1 interaction.Results: The binding of PSD-93 and CX3CL1 peaked at 6 h after I/R. The binding sites were located in the 420-535 amino acid sequence of PSD-93 and 357-395 amino acid sequence of CX3CL1. Tat-CX3CL1 (357-395aa) could inhibit the interaction of PSD-93 and CX3CL1 and inhibited the pro-inflammatory cytokine IL-1β and TNF-α expression and provided neuroprotection following reperfusion.Conclusions: PSD-93 binds CX3CL1 to activate microglia and initiate neuroinflammation. Specific blockade of PSD-93-CX3CL1 interaction reduces I/R induced neuronal cell death, and provides a new therapeutic target for ischemic stroke.

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Protection against Neurological Symptoms by Consuming Corn Silk Water Extract in Artery-Occluded Gerbils with Reducing Oxidative Stress, Inflammation, and Post-Stroke Hyperglycemia through the Gut-Brain Axis

Antioxidants ◽

10.3390/antiox11010168 ◽

2022 ◽

Vol 11 (1) ◽

pp. 168

Author(s):

Jin Ah Ryuk ◽

Byoung Seob Ko ◽

Na Rang Moon ◽

Sunmin Park

Keyword(s):

Ischemic Stroke ◽

Neuronal Cell Death ◽

Cell Mass ◽

Water Extract ◽

Neuronal Cell ◽

Artery Occlusion ◽

Sham Control ◽

Β Cell ◽

Post Stroke ◽

Corn Silk

Corn silk (Stigma maydis), rich in flavonoids, is traditionally used to treat edema, depression, and hyperglycemia and may alleviate ischemic stroke symptoms in Chinese medicine. This study examined whether corn silk water extract (CSW) could alleviate ischemic stroke symptoms and post-stroke hyperglycemia in Mongolian gerbils with transient cerebral ischemia and reperfusion (I/R). After being given 0.05% (I/R-LCSW) and 0.2% (I/R-HCSW), 0.02% aspirin (I/R-aspirin), and cellulose (I/R-control) in their 40 energy% fat diets for three weeks, the gerbils underwent an artery occlusion for eight minutes and reperfusion. They took the assigned diet for an additional three weeks. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. CSW intake reduced neuronal cell death in gerbils with I/R and dose-dependently improved the neurological symptoms, including drooped eyes, crouched posture, flexor reflex, and walking patterns. CSW intake also alleviated the short-term memory and spontaneous alteration and grip strength compared to the I/R-control group. The protection against ischemic stroke symptoms was associated with the reduced tumor necrosis factor-α, interleukin-1β, superoxide, and lipid peroxide levels, promoting superoxide dismutase activity in the hippocampus in the CSW groups, compared to the I/R-control. The blood flow measured by Doppler was improved with CSW compared to the I/R-control. Furthermore, CSW intake prevented the post-stroke hyperglycemia related to decreasing pancreatic β-cell mass as much as the Sham-control, and it was related to protection against β-cell apoptosis, restoring the β-cell mass similar to the Sham-control. CSW intake elevated the relative abundance of Lactobacillus, Bifidobacterium, Allobaculum, and Akkermansia compared to the I/R-control. Picrust2 analysis showed that CSW increased the propionate and butyrate metabolism and the starch and glucose metabolism but reduced lipopolysaccharide biosynthesis compared to the I/R-control. In conclusion, CSW intake protects against neuronal cell death and post-hyperglycemia by reducing oxidative stress and inflammation and increasing blood flow and the β-cell mass. The alleviation was associated with promoting the gut-brain axis by changing the gut microbiome community.

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Phosphodiesterase 10A is a critical target for neuroprotection in a mouse model of ischemic stroke

10.21203/rs.3.rs-469225/v3 ◽

2021 ◽

Author(s):

Mustafa Caglar Beker ◽

Ahmet B. Caglayan ◽

Serdar Altunay ◽

Elif Ozbay ◽

Nilay Ates ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Volume ◽

Artery Occlusion ◽

Cyclic Monophosphate ◽

Tnf Α ◽

Liquid Chromatography Tandem Mass ◽

Inflammatory Processes ◽

Phosphodiesterase 10A ◽

Cerebral Artery Occlusion ◽

Blood Brain Barrier Integrity

Abstract Phosphodiesterase 10A (PDE10A) hydrolyzes adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP). It is highly expressed in the striatum. Recent evidence implied that PDE10A may be involved in the inflammatory processes following injury, such as ischemic stroke. Its role in ischemic injury was unknown. Herein, we exposed mice to 90 or 30 min middle cerebral artery occlusion, followed by the delivery of the highly selective PDE10A inhibitor TAK-063 (0.3 mg/kg or 3 mg/kg) immediately after reperfusion. Animals were sacrificed after 24 or 72 hours, respectively. Both TAK-063 doses enhanced neurological function, reduced infarct volume, increased neuronal survival, reduced brain edema, and increased blood-brain barrier integrity, alongside cerebral microcirculation improvements. Post-ischemic neuroprotection was associated with increased phosphorylation (i.e., activation) of pro-survival Akt, Erk-1/2 and GSK-3α/β, decreased phosphorylation (i.e., activation) of pro-survival mTOR, increased HIF-1α, MMP-9 and anti-apoptotic Bcl-xL abundance, and reduced pro-apoptotic Bax abundance. Interestingly, PDE10A inhibition reduced inflammatory cytokines/chemokines, including IFN-γ and TNF-α, analyzed by planar surface immunoassay. In addition, liquid chromatography-tandem mass spectrometry revealed 40 proteins were significantly altered by TAK-063. Our study established PDE10A as a target for ischemic stroke therapy.

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Influence of simultaneous pressor and vasodilatory agents on the evolution of infarct growth in experimental acute middle cerebral artery occlusion

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2020-016539 ◽

2020 ◽

pp. neurintsurg-2020-016539

Author(s):

Niloufar Saadat ◽

Gregory A Christoforidis ◽

Yong Ik Jeong ◽

Mira Liu ◽

Alexey Dimov ◽

...

Keyword(s):

Ischemic Stroke ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Infarct Volume ◽

Volume Growth ◽

Artery Occlusion ◽

Blood Pressure Elevation ◽

And Control ◽

Cerebral Artery Occlusion

BackgroundThis study sought to test the hypothesis that simultaneous central blood pressure elevation and potent vasodilation can mitigate pial collateral-dependent infarct growth in acute ischemic stroke.MethodsTwenty mongrel canines (20–30 kg) underwent permanent middle cerebral artery occlusion (MCAO). Eight subjects received continuous infusion of norepinephrine (0.1–1.5200 µg/kg/min; titrated to a median of 34 mmHg above baseline mean arterial pressure) and hydralazine (20 mg) starting 30 min following MCAO. Pial collateral recruitment was scored prior to treatment and used to predict infarct volume based on a previously reported parameterization. Serial diffusion magnetic resonance imaging (MRI) acquisitions tracked infarct volumes over a 4-hour time frame. Infarct volumes and infarct volume growth between treatment and control groups were compared with each other and to predicted values. Fluid-attenuated inversion recovery (FLAIR) MRI, susceptibility weighted imaging (SWI), and necropsy findings were included in the evaluation.ResultsDifferences between treatment and control group varied by pial collateral recruitment based on indicator-variable regression effects analysis with interaction confirmed by regression model fit. Benefit in treatment group was only in subjects with poor collaterals which had 35.7% less infarct volume growth (P=0.0008; ANOVA) relative to controls. Measured infarct growth was significantly lower than predicted by the model (linear regression partial F-test, slope P<0.001, intercept=0.003). There was no evidence for cerebral hemorrhage or posterior reversible encephalopathy syndrome.ConclusionOur results indicate that a combination of norepinephrine and hydralazine administered in the acute phase of ischemic stroke mitigates infarct evolution in subjects with poor but not good collateral recruitment.

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