Abstract 40: Xenon-Loaded Liposomes in Combination with IV tPA Extends the Time Window for Treatment of Thrombotic Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Tao Peng ◽  
Yifeng Miao ◽  
George L Britton ◽  
Melvin E Klegerman ◽  
Susan T Laing ◽  
...  
Keyword(s):  
Infarct Size ◽  
Continuous Wave ◽  
Time Window ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Neuronal Cell ◽  
Great Promise ◽  
Tunel Staining ◽  
Stroke Treatment ◽  
Iv Tpa

BACKGROUND: Xenon (Xe) provides great promise for stroke treatment due to its unique neuroprotective effect. Building on previous work for Xe-loaded liposomes (Xe-ELIP) to effectively deliver Xe into the brain, this study investigates the effect of Xe-ELIP in combination with intravenously (IV) administered tissue plasminogen activator (tPA) to extend the time window of treatment for embolic stroke. METHODS: Thrombotic strokes were induced in rats by injecting a standardized blood clot into the middle cerebral artery. In the treatment groups, Xe-ELIP (20mg/kg) and tPA (10mg/kg) were administrated IV at 2 and 4 hours, respectively, after the stroke onset. Continuous wave ultrasound (1 MHz, 50% duty cycle, 1 W/cm 2 ) was applied over the common carotid artery during Xe-ELIP administration to trigger Xe release. Behavioral tests were conducted three days after stroke. Following sacrifice, brain sections were evaluated with triphenyltetrazolium chloride (TTC) and Tunel staining. Infarct size was presented as normalized infarct volume (%). RESULTS: Thrombotic stroke without treatment exhibited the largest infarct size (18.98±2%); tPA treatment reduced the infarct size to 6.1±1% (p<0.001 vs. no treatment). Xe-ELIP in combination with tPA treatment further reduced the infarct size to 1.8±0.4% (p=0.032 vs. tPA treatment; Fig 1a) with lower hemorrhagic adverse effects, improved neurological function and reduced apoptosis (Fig 1b). CONCLUSIONS: This study demonstrates that Xe-ELIP in combination with IV tPA provides improved therapeutic efficacy with reduced neuronal cell death and tPA-associated hemorrhagic side effects. These results have important implications for extending the time window of treatment of thrombotic stroke.

Abstract 3097: Acute In-hospital Stroke: How Do We Do Compared To Strokes In The Emergency Department?

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Dolora Wisco ◽  
Christopher Newey ◽  
Pravin George ◽  
James Gebel
Keyword(s):  
Emergency Department ◽  
Time Window ◽  
Stroke Treatment ◽  
Intravenous Tissue Plasminogen Activator ◽  
Tertiary Center ◽  
Neuro Imaging ◽  
One Year ◽  
To Receive ◽  
Iv Tpa ◽  
Arterial Thrombolysis

Introduction: Intravenous tissue plasminogen activator (IV tPA) has been approved for treating strokes up to 3 hours after onset of symptoms and may be beneficial up to 4.5 hours in patients who qualify. Additionally, neuro-intervention, i.e., intra-arterial thrombolysis or thrombectomy, is also an approved treatment option. Population studies show that 6% receive IV tPA within 3 hours of stroke onset. However, in-hospital strokes present challenges to treating within an adequate time. We present here our experience with in-hospital strokes, treatments, and identifiable delays in treatments. Methods: Single, tertiary center retrospective study of 55 in-hospital strokes over a one-year period from January 2009 to January 2010, and strokes in the Emergency Department over 6 month period from January 2010 to June 2010. Results: Twenty-nine in-hospital strokes were evaluated within 3 hours of symptoms onset. Two (6.9%) received IV tPA, and four (13.8%) received neuro-intervention (either intra-arterial thrombolysis or thrombectomy). None of the patients who presented greater than 3 hours after symptom onset was treated with any treatment (n=28). When compared to patients who present to the ED within 3 hours, in-hospital strokes were less likely to get IV tPA (6.9% vs. 20.8%), and they were more likely to receive neuro-intervention (13.8% vs. 10.3%). Neuro-intervention was performed on 9.09% of all in-hospital strokes (1 of 5 presented beyond the 3 hour time window). For in-hospital strokes that receive any treatment within 3 hours, the average time to neurology evaluation, to CT, and to treatment are 35 min, 68 min, and 237 min, respectively. For strokes in the Ed, the average time to evaluation, to CT, and to treatment are 90 min, 28 min, and 66 min respectively. The delay for in-hospital strokes is in obtaining the CT and initiating the treatment. Discussion: In-hospital stroke patients wait longer than their ED counterparts to be taken to CT and to receive stroke treatment. They are also less likely to receive IV tPA, and more likely to receive neuro-intervention. The longer time to neuro-imaging and thrombolytic treatment may reflect the fact that patients suffering in-hospital strokes have more complex medical co-morbidities that must be taken account during the evaluation and administration of thrombolytic therapy.

scholarly journals Neuroprotective Effect of DAHP via Antiapoptosis in Cerebral Ischemia

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yanhua Qin ◽  
Weiming Hu ◽  
Yang Yang ◽  
Zhiying Hu ◽  
Weiyun Li ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Caspase 3 ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Tunel Staining ◽  
Cox 2

Aberrant production of nitric oxide following inducible nitric oxide synthase (iNOS) expression has been implicated in cell death and contributes to ischemic brain injury. Tetrahydrobiopterin (BH4) is an essential cofactor of NOS activity. Herein, we evaluated antiapoptotic and anti-inflammatory effects of diamino-6-hydroxypyrimidine (DAHP), a guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) inhibitor on focal cerebral ischemia-reperfusion injury by middle cerebral artery occlusion and reperfusion (MCAO) and investigated the underlying mechanism. Sprague-Dawley rats were divided into five groups. Experimental groups were subjected to 1.5 h transient MCAO. T2-weighted imaging was performed to evaluate brain edema lesions in the stroke rats. Infarct volume was estimated by 2,3,5-triphenyltetrazolium chloride (TTC) staining after 24 h reperfusion. Western blotting and immunohistochemistry were performed to detect iNOS, caspase-3, Bcl-2, COX-2, and TNF-α protein expressions. Apoptosis was determined by TUNEL staining. T2 hyperintensity changes were observed in primary ischemic region. DAHP pretreatment significantly suppressed iNOS overexpression, caspase-3, and TNF-α. There was also attenuation of neuronal apoptosis with decrement in proteins Bcl-2 and COX-2 expressions. On the basis of our results, we hypothesize DAHP to have a neuroprotective function against focal cerebral ischemia and might attenuate brain injury by decreasing reactive oxygen species (ROS) production, subsequently inhibiting apoptosis.

scholarly journals Early Electroacupuncture Extends the rtPA Time Window to 6 h in a Male Rat Model of Embolic Stroke via the ERK1/2-MMP9 Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Xin-chang Zhang ◽  
Ya-hui Gu ◽  
Wen-tao Xu ◽  
Yang-yang Song ◽  
Ao Zhang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Edema ◽  
Time Window ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Hemorrhagic Transformation ◽  
Male Rat ◽  
Tight Junction Proteins ◽  
Therapeutic Time Window ◽  
Junction Proteins

Background. Recombinant tissue plasminogen activator (rtPA) is the only recommended pharmacological treatment for acute ischemic stroke, but it has a restricted therapeutic time window. When administered at time points greater than 4.5 h after stroke onset, rtPA disrupts the blood-brain barrier (BBB), which leads to serious brain edema and hemorrhagic transformation. Electroacupuncture (EA) exerts a neuroprotective effect on cerebral ischemia; however, researchers have not clearly determined whether EA increases the safety of thrombolysis and extends the therapeutic time window of rtPA administration following ischemic stroke. Objective. The present study was conducted to test the hypothesis that EA extends the therapeutic time window of rtPA for ischemic stroke in a male rat model of embolic stroke. Methods. SD rats were randomly divided into the sham operation group, model group, rtPA group, EA+rtPA group, and rtPA+MEK1/2 inhibitor group. An injection of rtPA was administered 6 h after ischemia. Rats were treated with EA at the Shuigou (GV26) and Neiguan (PC6) acupoints at 2 h after ischemia. Neurological function, infarct volume, BBB permeability, brain edema, and hemorrhagic transformation were assessed at 24 h after ischemia. Western blotting and immunofluorescence staining were performed to detect the levels of proteins involved in the ERK1/2 signaling pathway (MEK1/2 and ERK1/2), tight junction proteins (Claudin5 and ZO-1), and MMP9 in the ischemic penumbra at 24 h after stroke. Results. Delayed rtPA treatment aggravated hemorrhagic transformation and brain edema. However, treatment with EA plus rtPA significantly improved neurological function and reduced the infarct volume, hemorrhagic transformation, brain edema, and EB leakage in rats compared with rtPA alone. EA increased the levels of tight junction proteins, inhibited the activation of the ERK1/2 signaling pathway, and reduced MMP9 overexpression induced by delayed rtPA thrombolysis. Conclusions. EA potentially represents an effective adjunct method to increase the safety of thrombolytic therapy and extend the therapeutic time window of rtPA administration following ischemic stroke. This neuroprotective effect may be mediated by the inhibition of the ERK1/2-MMP9 pathway and alleviation of the destruction of the BBB.

Correlation between lactate and neuronal cell damage in the rat brain after focal ischemia: An in vivo 1H magnetic resonance spectroscopic (1H-MRS) study

2010 ◽  
Vol 51 (3) ◽  
pp. 344-350 ◽  
Author(s):  
Chul-Woong Woo ◽  
Byong Sop Lee ◽  
Sang Tae Kim ◽  
Ki-Soo Kim
Keyword(s):  
Magnetic Resonance ◽  
Rat Brain ◽  
Neuronal Damage ◽  
Cell Damage ◽  
Infarct Volume ◽  
Neuronal Cell ◽  
Focal Ischemia ◽  
Tunel Staining ◽  
Resonance Spectroscopy ◽  
Lipid Levels

Background: Increased levels of lactate are observed by 1H magnetic resonance spectroscopy (1H-MRS) in rat brains after stroke. However, it is not known whether the changes in lactate levels are predictive of the degree of neuronal damage. Purpose: To investigate the correlation between changes in lactate and lipid levels measured by 1H-MRS and neuronal cell damage in the rat brain. Material and Methods: A middle cerebral artery occlusion (MCAO) model was used to evaluate focal ischemia in rats (n=36). After MCAO for 90 min T2-weighted images (T2WIs), diffusion-weighted images (DWIs), and 1H-MRS data were obtained from brains immediately, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours, 3 days, and 7 days after reperfusion. Infarct volumes were measured in T2WIs obtained 4 weeks after reperfusion. The degree of neuronal damage was measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining in three rats from each group at the same time as brain images were collected. Results: Creatine (Cr)-normalized lactate + lipid levels ([Lac+Lip]/Cr) were negatively correlated with Cr-normalized N-acetyl-L-aspartate levels (NAA/Cr) and positively correlated with TUNEL-positive cell numbers up to 24 hours after reperfusion. (Lac+Lip)/Cr at 6 hours and 9 hours was significantly correlated with NAA/Cr at 7 days, but there was no significant correlation between (Lac+Lip)/Cr during the first 24 hours and infarct volume at 4 weeks. Conclusion: Up to 24 hours after reperfusion, (Lac+Lip)/Cr was strongly negatively correlated with NAA/Cr, and was a good predictor of neuronal damage at 7 days; however, it was not predictive of final infarct volume at 4 weeks.

High Prestroke Physical Activity Is Associated with Reduced Infarct Growth in Acute Ischemic Stroke Patients Treated with Intravenous tPA and Randomized to Remote Ischemic Perconditioning

2017 ◽  
Vol 44 (1-2) ◽  
pp. 88-95 ◽  
Author(s):  
Rolf A. Blauenfeldt ◽  
Kristina D. Hougaard ◽  
Kim Mouridsen ◽  
Grethe Andersen
Keyword(s):  
Physical Activity ◽  
Ischemic Stroke ◽  
Infarct Size ◽  
Acute Ischemic Stroke ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Intravenous Thrombolysis ◽  
Stroke Patients ◽  
Remote Ischemic Perconditioning ◽  
Final Infarct Size

Background: A high prestroke physical activity (PA) level is associated with reduced stroke rate, stroke mortality, better functional outcome, and possible neuroprotective abilities. The aim of the present study was to examine the possible neuroprotective effect of prestroke PA on 24-h cerebral infarct growth in a cohort of acute ischemic stroke patients treated with intravenous tPA and randomized to remote ischemic perconditioning. Methods: In this predefined subanalysis, data from a randomized clinical trial investigating the effect of remote ischemic perconditioning (RIPerC) on AIS was used. Prestroke (7 days before admission) PA was quantified using the PA Scale for the Elderly (PASE) questionnaire at baseline. Infarct growth was evaluated using MRI (acute, 24-h, and 1-month). Results: PASE scores were obtained from 102 of 153 (67%) patients with a median (interquartile range) age of 66 (58-73) years. A high prestroke PA level correlated significantly with reduced acute infarct growth (24 h) in the linear regression model (4th quartile prestroke PA level compared with the 1st quartile), β4th quartile = -0.82 (95% CI -1.54 to -0.10). However, the effect of prestroke PA was present mainly in patients randomized to RIPerC, β4th quartile = -1.14 (95% CI -2.04 to -0.25). In patients randomized to RIPerC, prestroke PA was a predictor of final infarct size (1-month infarct volume), β4th quartile = -1.78 (95% CI -3.15 to -0.41). Conclusion: In AIS patients treated with RIPerC, as add-on to intravenous thrombolysis, the level of PA the week before the stroke was associated with decreased 24-h infarct growth and final infarct size. These results are highly encouraging and stress the need for further exploration of the potentially protective effects of both PA and remote ischemic conditioning.

scholarly journals VEGF Protects Brain against Focal Ischemia without Increasing Blood–Brain Permeability When Administered Intracerebroventricularly

2005 ◽  
Vol 25 (9) ◽  
pp. 1111-1118 ◽  
Author(s):  
Dilaver Kaya ◽  
Yasemin Gürsoy-Özdemir ◽  
Muge Yemisci ◽  
Neşe Tuncer ◽  
Sevinç Aktan ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Time Window ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Hemorrhagic Transformation ◽  
Vascular Endothelial ◽  
Blood Brain ◽  
Endothelial Growth Factor

Delayed administration of vascular endothelial growth factor (VEGF) promotes functional recovery after focal cerebral ischemia. However, early intravenous injection of VEGF increases blood–brain barrier (BBB) leakage, hemorrhagic transformation and infarct volume whereas its application to cortical surface is neuroprotective. We have investigated whether or not early intracerebroventricular administration of VEGF could replicate the neuroprotective effect observed with topical application and the mechanism of action of this protection. Mice were subjected to 90 mins middle cerebral artery (MCA) occlusion and 24 h of reperfusion. Vascular endothelial growth factor (8 ng, intracerebroventricular) was administered 1 or 3 h after reperfusion. Compared with the vehicle-treated (intracerebroventricular) group, VEGF decreased the infarct volume along with BBB leakage in both treatment groups. Neurologic disability scores improved in parallel to the changes in infarct volume. Independently of the decrease in infarct size, VEGF also reduced the number of TUNEL-positive apoptotic neurons. Phospo-Akt levels were significantly higher in ischemic hemispheres of the VEGF-treated mice. Contrary to intracerebroventricular route, intravenous administration of VEGF (15 μg/kg) enhanced the infarct volume as previously reported for the rat. In conclusion, single intracerebroventricular injection of VEGF protects brain against ischemia without adversely affecting BBB permeability, and has a relatively long therapeutic time window. This early neuroprotective action, observed well before recovery-promoting actions such as angiogenesis, possibly involves activation of the PI-3-Akt pathway.

scholarly journals Evaluation of the Effectiveness of Post-Stroke Metformin Treatment Using Permanent Middle Cerebral Artery Occlusion in Rats

2021 ◽  
Vol 14 (4) ◽  
pp. 312
Author(s):  
Gintare Zemgulyte ◽  
Shigeru Tanaka ◽  
Izumi Hide ◽  
Norio Sakai ◽  
Katryna Pampuscenko ◽  
...  
Keyword(s):  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Neuroprotective Effect ◽  
Artery Occlusion ◽  
Metformin Treatment ◽  
Stroke Treatment ◽  
Post Stroke ◽  
Anti Inflammatory ◽  
Cerebral Artery Occlusion

Stroke is the second leading cause of death worldwide. Treatment options for ischemic stroke are limited, and the development of new therapeutic agents or combined therapies is imperative. Growing evidence suggests that metformin treatment, due to its anti-inflammatory action, exerts a neuroprotective effect against ischemia/reperfusion-induced brain damage. Experimental assessment has typically been performed in models of cerebral transient ischemia followed by long-term reperfusion. The aim of this study was to evaluate the neuroprotective effect of metformin treatment after permanent middle cerebral artery occlusion (pMCAO) without reperfusion in rats. Neurological deficits were assessed using the Longa scale, which offers a graded scale on body movement following pMCAO. Both infarct size and brain oedema area were measured by staining with 2,3,5-triphenyltetrazolium chloride. The number of neurons and total and activated microglia, as well as interleukin 10 (IL-10) production, in brain sections were evaluated by immunohistochemical staining. Our results show that metformin treatment improves the neurological state and reduces infarct size after 120 h of pMCAO. Metformin also prevents neuronal loss in the ischemic cortex but not in the striatum after 48 h of pMCAO. Moreover, post-stroke treatment with metformin significantly decreases the number of total and activated microglia at 48 h. The anti-inflammatory effect of metformin is associated with increased IL-10 production at 48 h after pMCAO. The results of the present study suggest that post-stroke treatment with metformin exerts anti-inflammatory and neuroprotective effects in a pMCAO model.

Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia

1996 ◽  
Vol 85 (1) ◽  
pp. 117-124 ◽  
Author(s):  
Marin B. Marinov ◽  
Kimberly S. Harbaugh ◽  
P. Jack Hoopes ◽  
Harold J. Pikus ◽  
Robert E. Harbaugh
Keyword(s):  
Infarct Size ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Artery Occlusion ◽  
Suture Technique ◽  
Neuroprotective Effects ◽  
Tetrazolium Chloride ◽  
Content Type ◽  
Fine Print

✓ The known cytoprotective properties of MgSO4 led the authors to study its effects on infarct size in rats when administered intraarterially before reversible focal ischemia. Following an intracarotid infusion of MgSO4 in the amount of 30 mg/kg (24 animals), 90 mg/kg (18 animals), or an equal volume of vehicle (23 animals), middle cerebral artery occlusion was produced in rats by means of an intraluminal suture technique. Reperfusion occurred after 1.5 (42 animals) or 2 hours (23 animals) of ischemia. Automated, volumetric measurements of 2′,3′,5′-triphenyl-2H-tetrazolium chloride—stained coronal brain sections demonstrated a statistically significant decrease in infarct size for MgSO4 treatment groups compared to controls. Cytoprotection was greater in animals subjected to 1.5 hours of ischemia (28.4% reduction in infarct volume, p ≤ 0.001, Student's t-test), than in those having 2 hours of ischemia (19.3% reduction, p < 0.05). Animals given 90 mg/kg MgSO4 prior to 1.5 hours of ischemia (12 animals) showed a 59.8% reduction in infarct volume compared to controls (11 animals, p < 0.001) and a 43.1% reduction compared to the 30 mg/kg group (11 animals, p < 0.001). Analysis of variance demonstrated the statistically significant effects of MgSO4 doses on infarct volume across all groups (F = 22.95, p < 0.0001). The neuroprotective effect of intraarterial MgSO4 in this model is robust, dose dependent, and related to the duration of ischemia. The compound may be valuable for limiting infarction if given intraarterially before induction of reversible ischemia during cerebrovascular surgery.

scholarly journals DJ-1 Protects against Neurodegeneration Caused by Focal Cerebral Ischemia and Reperfusion in Rats

2007 ◽  
Vol 28 (3) ◽  
pp. 563-578 ◽  
Author(s):  
Daijiro Yanagisawa ◽  
Yoshihisa Kitamura ◽  
Masatoshi Inden ◽  
Kazuyuki Takata ◽  
Takashi Taniguchi ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Focal Cerebral Ischemia ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Neuronal Cell ◽  
Ischemia And Reperfusion ◽  
Triphenyltetrazolium Chloride ◽  
Cerebral Ischemia And Reperfusion

Reactive oxygen species (ROS) is massively produced in the brain after cerebral ischemia and reperfusion. It reacts strongly with cellular components, which has detrimental effects and leads to neuronal cell death. DJ-1, which was found to be the causative gene of familial Parkinson's disease PARK7, is a multifunction protein, which plays a key role in transcriptional regulation, and a molecular chaperone. In this study, we investigated the neuroprotective effect of DJ-1 against neurodegeneration caused by ischemia/reperfusion injury. Cerebral ischemia was induced in rats by 120 mins of middle cerebral artery occlusion (MCAO) using an intraluminal introduction method. The intrastriatal injection of recombinant glutathione S-transferase-tagged human DJ-1 (GST-DJ-1) markedly reduced infarct size in 2,3,5-triphenyltetrazolium chloride staining at 3 days after MCAO. In addition, we performed a noninvasive evaluation of ischemic size using magnetic resonance imaging and found a significant reduction of infarct size with the administration of GST-DJ-1. In GST-DJ-1-treated rats, behavioral dysfunction and nitrotyrosine formation were significantly inhibited. Furthermore, GST-DJ-1 markedly inhibited H2O2-mediated ROS production in SH-SY5Y cells. These results indicate that GST-DJ-1 exerts a neuroprotective effect by reducing ROS-mediated neuronal injury, suggesting that DJ-1 may be a useful therapeutic target for ischemic neurodegeneration.

Abstract 41: Targeting the Neurovascular Bed by Co-delivery of Therapeutics for Synergic Stroke Treatments

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Tao Peng ◽  
Yi-Feng Miao ◽  
George L Britton ◽  
Hyunggun Kim ◽  
David D McPherson ◽  
...  
Keyword(s):  
Infarct Size ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Free Radical Scavenger ◽  
Tunel Staining ◽  
Radical Scavenger ◽  
Therapeutic Effects ◽  
Triphenyltetrazolium Chloride ◽  
Infarct Size Reduction ◽  
Neurovascular Damage

BACKGROUND: Due to the multifaceted pathology of neurovascular damage in stroke, providing combined therapies aimed at underline different mechanisms may be a promising strategy. We have demonstrated that echogenic liposomes (ELIP) can effectively deliver xenon (Xe), a N -methyl-D-aspartate receptor antagonist, into brain tissue for dose-dependent neuroprotection. This study evaluates the synergic therapeutic effects of ELIP delivering Xe with an anti-inflammatory gas, hydrogen sulfide (H 2 S), or a free radical scavenger, hydrogen (H 2 ), in a rat stroke model. METHODS: A gas mixture of 1% H 2 S with 99% Xe or 30% H 2 with 70% Xe was loaded into ELIP by a pressurization-freeze method. Rats (n=25) undergoing 2-hour middle cerebral artery occlusion were then treated with low-dose Xe-ELIP, H 2 S/Xe-ELIP, or H 2 /Xe-ELIP, respectively, at 3 hours after stroke onset. One MHz low-amplitude (0.18 MPa) ultrasound was directed over the internal carotid artery to trigger gas release. Behavioral tests were conducted for three days following surgery. After sacrifice, brain sections were evaluated for infarction and apoptotic neuronal death using triphenyltetrazolium chloride (TTC) and TUNEL staining. Infarct size was evaluated as normalized infarct volume (%). RESULTS: Strokes without treatment had an infarct size of 27± 6%. Strokes with Xe-ELIP treatment exhibited an infarct size of 20±4% (p=0.232 vs. no treatment). Strokes with H 2 S/Xe-ELIP and H 2 /Xe-ELIP treatments demonstrated a further infarct size reduction to 7.1±1.6% (p=0.017 vs. no treatment) and 8.8±1.9% (p=0.032 vs. no treatment), respectively. Neurologic behavior tests reflected infarct size. CONCLUSIONS: In this study, using echogenic immunoliposomes as a vehicle, co-delivery of therapeutics targeting different mechanisms of neurovascular damage results in a synergic therapeutic effect. This methodology provides an avenue for evaluation of other synergic agents for use in acute stroke.

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