Abstract WMP45: Targeted Inhibition of the Alternative Complement Pathway Enhances Rehabilitation-Induced Cognitive and Motor Recovery in a Murine Model of Chronic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Ali Alawieh ◽  
Meredith Andersen ◽  
DeAnna L Adkins ◽  
Stephen Tomlinson
Keyword(s):  
Cognitive Performance ◽  
Infarct Volume ◽  
Alternative Pathway ◽  
Artery Occlusion ◽  
Motor Recovery ◽  
Acute Injury ◽  
Neuroprotective Effects ◽  
Recovery Processes ◽  
Targeted Inhibition ◽  
A Site

Introduction: Activation of inflammatory cascades after stroke exacerbate acute injury and limit response to rehabilitation (rehab). The complement (C) system is a prominent component of inflammatory injury after stroke, but can also contribute to neuroprotective recovery processes. We investigated the neuroprotective effects of CR2fH, a site-targeted C inhibitor that specifically inhibits the alternative pathway and prevents amplification of the C cascade. We assessed how CR2fH affects chronic outcomes, and how acute C inhibition impacts the response to rehab therapy. Methods: Mice were subjected to 1hr middle cerebral artery occlusion and 15 days of reperfusion. Mice were treated with CR2fH or vehicle and then randomized to normal housing or an enriched environment (EE) to model cognitive and motor rehab. Animals were assessed for infarct volume using MRI at days 4 and 14 after injury, and for their performance on several motor and cognitive tasks. Expression of inflammatory markers in the brain was assessed using high throughput Nanostring analysis and immunostaining. Results: Compared to vehicle or EE only, treatment with CR2fH 90 mins after cerebral ischemia significantly reduced infarct volume and improved motor and cognitive performance up to 15 days, as assessed with mNSS scores, corner task, locomotor activity, pasta handling, and passive avoidance tasks (p’s<0.01). Less prominent, although still significant improvement was also achieved when CR2fH was administered 6 or 12 hrs. after ischemia (p’s<0.05). EE alone did not significantly reduce infarct volume or improve performance on motor tasks, but resulted in a significant improvement in cognitive performance compared to vehicle (p’s<0.05). A combination of EE and CR2fH therapy resulted in a significant potentiation of cognitive and motor recovery compared to either single intervention (p’s<0.05). CR2fH related behavioral improvements correlated with reduction in C deposition and inflammatory microglial activation during recovery. Conclusions: Since a humanized version of CR2fH, TT30, was shown to be safe, tolerated and nonimmunogenic in humans, targeted inhibition of alternative C pathway is a candidate therapy to promote recovery and potentiate response to rehab after stroke.

scholarly journals Angiopoietin-1 Mimetic Peptide Promotes Neuroprotection after Stroke in Type 1 Diabetic Rats

2018 ◽  
Vol 27 (12) ◽  
pp. 1744-1752 ◽  
Author(s):  
Poornima Venkat ◽  
Tao Yan ◽  
Michael Chopp ◽  
Alex Zacharek ◽  
Ruizhuo Ning ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Neuroprotective Effects ◽  
Ischemic Brain ◽  
Mimetic Peptide ◽  
Tnf Α ◽  
Bbb Permeability ◽  
Angiopoietin 1

Angiopoietin-1 (Ang1) mediates vascular maturation and immune response. Diabetes decreases Ang1 expression and disrupts Ang1/Tie2 signaling activity. Vasculotide is an Ang1 mimetic peptide, and has anti-inflammatory effects. In this study, we test the hypothesis that vasculotide treatment induces neuroprotection and decreases inflammation after stroke in type 1 diabetic (T1DM) rats. T1DM rats were subjected to embolic middle cerebral artery occlusion (MCAo) and treated with: 1) phosphate buffered saline (PBS); 2) vasculotide (3µg/kg, i.p. injection) administered half an hour prior to MCAo and at 8 and 24 hours after MCAo. Rats were sacrificed at 48 h after MCAo. Neurological function, infarct volume, hemorrhage, blood brain barrier (BBB) permeability and neuroinflammation were measured. Vasculotide treatment of T1DM-MCAo rats significantly improves functional outcome, decreases infarct volume and BBB permeability, but does not decrease brain hemorrhagic transformation compared with PBS-treated T1DM-MCAo rats. In the ischemic brain, Vasculotide treatment significantly decreases apoptosis, number of cleaved-caspase-3 positive cells, the expression of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF-α). Western blot analysis shows that vasculotide significantly decreases expression of receptor for advanced glycation end products (RAGE), MCP-1 and TNF-α in the ischemic brain compared with T1DM-MCAo rats. Vasculotide treatment in cultured primary cortical neurons (PCN) significantly decreases TLR4 expression compared with control. Decreased neuroinflammation and reduced BBB leakage may contribute, at least in part, to vasculotide-induced neuroprotective effects after stroke in T1DM rats.

scholarly journals Neuroprotective effect of Danshensu derivatives as anti-ischaemia agents on SH-SY5Y cells and rat brain

2013 ◽  
Vol 33 (4) ◽  
Author(s):  
Sunisa Seetapun ◽  
Jia Yaoling ◽  
Yang Wang ◽  
Yi Zhun Zhu
Keyword(s):  
Rat Brain ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
In Vitro Study ◽  
Artery Occlusion ◽  
Neuroprotective Effects ◽  
Inhibit Lipid Peroxidation ◽  
Cysteine Derivative

Novel Danshensu derivatives (3–8) were designed and synthesized to improve bioactivity based on the strategy of ‘medicinal chemical hybridization’. Our previous studies indicated that these compounds exhibited noticeable cardioprotective activities. Here, we investigate whether these novel Danshensu derivatives exert neuroprotective activities. An in vitro study revealed that these compounds could increase cell viability and reduce LDH (lactate dehydrogenase) leakage. Moreover, Danshensu-cysteine derivative compounds 6 and 8 could significantly inhibit lipid peroxidation of cell membrane and regulate the expression of apoptosis-related protein (Bcl-2, Bax and caspase 3). An in vivo study demonstrated that treatment with compound 6 at 30 mg/kg markedly decreased the infarct volume of MCAO (middle cerebral artery occlusion) insulted rat brain. Furthermore, treatment with compound 6 showed the antioxidant capacity by increasing the activity of SOD (superoxide dismutase) and GPx (glutathione peroxidase) and decreasing the level of MDA (malondialdehyde) and the ROS (reactive oxygen species) production significantly. These results suggested that these novel conjugates exert significant neuroprotective effects as anti-ischaemia agents and those with high potential merit further investigation.

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

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Joen-Rong Sheu ◽  
Zhih-Cherng Chen ◽  
Thanasekaran Jayakumar ◽  
Duen-Suey Chou ◽  
Ting-Lin Yen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ischemic Stroke ◽  
Infarct Volume ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Neuroprotective Effects ◽  
Occlusion Time ◽  
Oxide Synthase ◽  
Cerebral Artery Occlusion

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.

scholarly journals Rapid Tolerance to Focal Cerebral Ischemia in Rats is Attenuated by Adenosine A1 Receptor Antagonist

2002 ◽  
Vol 22 (2) ◽  
pp. 161-170 ◽  
Author(s):  
Michiko Nakamura ◽  
Kazuhiko Nakakimura ◽  
Mishiya Matsumoto ◽  
Takefumi Sakabe
Keyword(s):  
Receptor Antagonist ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Artery Occlusion ◽  
Ischemic Tolerance ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Induced Tolerance ◽  
Cerebral Artery Occlusion

Two types of ischemic tolerance in the brain, rapid and delayed, have been reported in terms of the interval between the conditioning and test insults. Although many reports showed that delayed-phase neuroprotection evoked by preconditioning is evident after 1 week or longer, there have been a few investigations about rapidly induced tolerance, and the reported neuroprotective effects become ambiguous 7 days after the insults. The authors examined whether this rapid ischemic tolerance exists after 7 days of reperfusion in a rat focal ischemic model, and investigated modulating effects of the adenosine A1 receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine). Preconditioning with 30 minutes of middle cerebral artery occlusion reduced infarct volume 7 days after 180 minutes of subsequent focal ischemia given after 1-hour reperfusion. The rapid preconditioning also improved neurologic outcome. These beneficial effects were attenuated by pretreatment of 0.1 mg/kg DPCPX, which did not influence the infarct volume after conditioning (30 minutes) or test (180 minutes) ischemia when given alone. The results show that preconditioning with a brief focal ischemia induces rapid tolerance to a subsequent severe ischemic insult, the effect of which is still present after 7 days of reperfusion, and that the rapid ischemic tolerance is possibly mediated through an adenosine A1 receptor–related mechanism.

scholarly journals Neuroprotective Effects of a Novel Nitrone, NXY-059, after Transient Focal Cerebral Ischemia in the Rat

1999 ◽  
Vol 19 (7) ◽  
pp. 778-787 ◽  
Author(s):  
Satoshi Kuroda ◽  
Ryoichi Tsuchidate ◽  
Maj-Lis Smith ◽  
Kirk R. Maples ◽  
Bo K. Siesjö
Keyword(s):  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Recovery Period ◽  
Artery Occlusion ◽  
Transfer Constant ◽  
Neuroprotective Effects ◽  
Transient Focal Cerebral Ischemia ◽  
Therapeutic Opportunity ◽  
Cerebral Artery Occlusion ◽  
Antiischemic Effect

Recent results have demonstrated that the spin trapping agent α-phenyl- N- tert-butyl nitrone (PBN) reduces infarct volume in rats subjected to 2 hours of middle cerebral artery occlusion, even when given 1 to 3 hours after the start of recirculation. In the current study, the authors assessed the effect of NXY-059, a novel nitrone that is more soluble than PBN. Loading doses were given of 0.30, 3.0, or 30 mg · kg−1 followed by 0.30, 3.0, or 30 mg · kg−1 · h−1 for 24 or 48 hours. Dose–response studies showed that when treatment was begun 1 hour after recirculation, 0.30 mg · kg−1 had a small and 30 mg · kg-i a marked effect on infarct volume. At equimolar doses (3.0 mg · kg−1 for NXY-059 and 1.4 mg · kg−1 for PBN), NXY-059 was more efficacious than PBN. Similar results were obtained when a recovery period of 7 days was allowed. The window of therapeutic opportunity for NXY-059 was 3 to 6 hours after the start of recirculation. Studies of the transfer constant of [14C]NXY-059 showed that, in contrast to PBN, this more soluble nitrone penetrates the blood-brain barrier less extensively. This fact, and the pronounced antiischemic effect of NXY-059, suggest that the delayed events leading to infarction may be influenced by reactions occurring at the blood–endothelial interface.

scholarly journals Gingko biloba Extract (EGb 761) Prevents Ischemic Brain Injury by Activation of the Akt Signaling Pathway

2009 ◽  
Vol 37 (03) ◽  
pp. 547-555 ◽  
Author(s):  
Jae-Hyeon Cho ◽  
Jin-Hee Sung ◽  
Eun-Hae Cho ◽  
Chung-Kil Won ◽  
Hyo-Jong Lee ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Male Rats ◽  
Ischemic Brain Injury ◽  
Protective Effects ◽  
Egb 761 ◽  
Neuroprotective Effects ◽  
Ischemic Brain ◽  
Gingko Biloba

EGb 761 is a standardized extract of Gingko biloba that exerts protective effects against ischemic brain injury. This study investigated whether EGb 761 modulates the neuroprotective effects through Akt and its downstream targets, Bad and FKHR. Adult male rats were treated with EGb 761 (100 mg/kg) or vehicle prior to middle cerebral artery occlusion (MCAO). Brains were collected 24 hours after MCAO and infarct volumes were analyzed. EGb 761 significantly reduced infarct volume. Potential activation was mearsured by phosphorylation of Akt at Ser473, Bad at Ser136, and FKHR at Ser256 using Western blot analysis. EGb 761 prevented the injury-induced decrease of pAkt and its down stream targets, pBad and pFKHR. Furthermore, EGb 761 prevented the injury-induced increase of cleaved caspase-3 levels. In conclusion, this study suggests that EGb 761 prevents cell death due to brain injury and that EGb 761 protection is affected by preventing the injury-induce decrease of Akt phosphorylation.

scholarly journals Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

2014 ◽  
Vol 306 (2) ◽  
pp. R149-R156 ◽  
Author(s):  
Zhijuan Cao ◽  
Adithya Balasubramanian ◽  
Sean P. Marrelli
Keyword(s):  
Cerebral Perfusion ◽  
Transient Receptor Potential ◽  
Mild Hypothermia ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Receptor Potential ◽  
Artery Occlusion ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channel ◽  
Neuroprotective Effects

Traditional methods of therapeutic hypothermia show promise for neuroprotection against cerebral ischemia-reperfusion (I/R), however, with limitations. We examined effectiveness and specificity of pharmacological hypothermia (PH) by transient receptor potential vanilloid 1 (TRPV1) channel agonism in the treatment of focal cerebral I/R. Core temperature (Tcore) was measured after subcutaneous infusion of TRPV1 agonist dihydrocapsaicin (DHC) in conscious C57BL/6 WT and TRPV1 knockout (KO) mice. Acute measurements of heart rate (HR), mean arterial pressure (MAP), and cerebral perfusion were measured before and after DHC treatment. Focal cerebral I/R (1 h ischemia + 24 h reperfusion) was induced by distal middle cerebral artery occlusion. Hypothermia (>8 h) was initiated 90 min after start of reperfusion by DHC infusion (osmotic pump). Neurofunction (behavioral testing) and infarct volume (TTC staining) were measured at 24 h. DHC (1.25 mg/kg) produced a stable drop in Tcore (33°C) in naive and I/R mouse models but not in TRPV1 KO mice. DHC (1.25 mg/kg) had no measurable effect on HR and cerebral perfusion but produced a slight transient drop in MAP (<6 mmHg). In stroke mice, DHC infusion produced hypothermia, decreased infarct volume by 87%, and improved neurofunctional score. The hypothermic and neuroprotective effects of DHC were absent in TRPV1 KO mice or mice maintained normothermic with heat support. PH via TRPV1 agonist appears to be a well-tolerated and effective method for promoting mild hypothermia in the conscious mouse. Furthermore, TRPV1 agonism produces effective hypothermia in I/R mice and significantly improves outcome when initiated 90 min after start of reperfusion.

scholarly journals Attenuating of NF-Κb/VCAM-1 Expression in Middle Cerebral Artery Occlusion (MCAO) Model by Viola Odorata: Protection Against Injury Ischemia- Reperfusion Injury in Rats

2021 ◽  
Author(s):  
Kiana Karimifar ◽  
◽  
Hiva Alipanah ◽  
Ava Soltani Hekmat ◽  
Mohammad Reza Bigdeli ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Treated Group ◽  
Artery Occlusion ◽  
Control Group ◽  
Neuroprotective Effects ◽  
Inflammatory Processes ◽  
Group 5 ◽  
Group 2

Background: The death of neurons and cerebral edema are the main consequences of stroke. However, inflammatory processes play a key role in aggravating cerebral damage following stroke. The aim of this study was to investigate the effects of Viola odorant extract (VOE) on infarct volume (IV), neurologic deficits (ND), and expression of NF-κB and VCAM-1 in the MCAO model. Method: The animals were randomly separated into 5 groups: (1) control group, (2) vehicle-treated group, (3) MCAO group, (4) VOE25 group, (5) VOE50 group, (6) VOE75 group (n=12). VOE (25, 50, and 75 mg/kg) or distilled water were administered daily for 30 days. Two hours after the last gavage, rats were exposed to 60 minutes of MCAO. Twenty-four hours later, the IV, ND, and NF-κB/VCAM-1 expression were evaluated. Results: V. odorata extract (VOE) exhibited excellent neuroprotective effects by reducing infarct volume (mainly in the core and sub-cortex areas), and induced down-regulation of NF-kB and VCAM-1 expression. Conclusion: This finding suggests that V. odorata could also activate intracellular pathways, which ultimately reduces the expression of NF-κB and VCAM-1 and be useful for developing a novel medical herbs for treating cerebral ischemia.

scholarly journals Neuroprotective Effects of Insulin-Like Growth Factor-Binding Protein Ligand Inhibitors in Vitro and in Vivo

2003 ◽  
Vol 23 (10) ◽  
pp. 1160-1167 ◽  
Author(s):  
Kenneth B Mackay ◽  
Sarah A Loddick ◽  
Gregory S Naeve ◽  
Alicia M Vana ◽  
Gail M Verge ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
Igf I

The role of brain insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in neuroprotection was further investigated using in vitro and in vivo models of cerebral ischemia by assessing the effects of IGF-I, IGF-II, and high affinity IGFBP ligand inhibitors (the peptide [Leu24, 59, 60, Ala31]hIGF-I (IGFBP-LI) and the small molecule NBI-31772 (1-(3,4-dihydroxybenzoyl)-3-hydroxycarbonyl-6, 7-dihydroxyisoquinoline), which pharmacologically displace and elevate endogenous, bioactive IGFs from IGFBPs. Treatment with IGF-I, IGF-II, or IGFBP-LI (2 μg/mL) significantly ( P < 0.05) reduced CA1 damage in organotypic hippocampal cultures resulting from 35 minutes of oxygen and glucose deprivation by 71%, 60%, and 40%, respectively. In the subtemporal middle cerebral artery occlusion (MCAO) model of focal ischemia, intracerebroventricular (icv) administration of IGF-I and IGF-II at the time of artery occlusion reduced ischemic brain damage in a dose-dependent manner, with maximum reductions in total infarct size of 37% ( P < 0.01) and 38% ( P < 0.01), respectively. In this model of MCAO, icv administration of NBI-31772 at the time of ischemia onset also dose-dependently reduced infarct size, and the highest dose (100 μg) significantly reduced both total (by 40%, P < 0.01) and cortical (by 43%, P < 0.05) infarct volume. In the intraluminal suture MCAO model, administration of NBI-31772 (50 μg icv) at the time of artery occlusion reduced both cortical infarct volume (by 40%, P < 0.01) and brain swelling (by 24%, P < 0.05), and it was still effective when treatment was delayed up to 3 hours after the induction of ischemia. These results further define the neuroprotective properties of IGFs and IGFBP ligand inhibitors in experimental models of cerebral ischemia.

Abstract 2244: Synergistic Benefit Of Combined Amlodipine Plus Atorvastatin On Neuronal Damage After Stroke In Zucker Metabolic Rat

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Hriromi Kawai ◽  
Shoko Deguchi ◽  
Kentaro Deguchi ◽  
Toru Yamashita ◽  
Yasuyuki Ohta ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Neuronal Damage ◽  
Infarct Volume ◽  
Neurovascular Unit ◽  
Treated Group ◽  
Artery Occlusion ◽  
Single Treatment ◽  
Neuroprotective Effects ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1

Stroke is a major neurologic disorder and a leading cause of death in the world. We compared neuroprotective effects of single or combination therapy of amlodipine (AM) and atorvastatin (AT) in such a metabolic syndrome model Zucker rat after 90min of transient middle cerebral artery occlusion (tMCAO). The animals were pretreated with vehicle, AM, AT, or the combination of AM plus AT for 28 days, and at 24 h of tMCAO, infarct volume and immunohistochemical analyses were performed. The combination of AM plus AT treatment decreased the infarct volume stronger than each single treatment withAMor AT. The numbers of positive cells of oxidative stress markers such as 8-hydroxy-2′-deoxyguanosin (8-OHdG), 4-hydroxy-2-nonenal (4-HNE), and advanced end glycation products (AGE) and inflammation markers such as tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) decreased dramatically in the combination-treated group compared with single AM or AT-treated group. The present study showed that single AM or AT treatment showed neuroprotective effects both with antioxidative and anti-inflammatory mechanisms, but combination therapy of AM plus AT presented a further synergistic benefit in acute ischemic neural damages. Moreover, the single treatment with AM or AT itself exerted neuroprotective effects with reducing inductions of MMP-9 and AT2R, as well as with preserving collagen IV, and the combination therapy of AM plus AT showed a further synergistic benefit against acute ischemic neural damages. Single AT was more protective on these 3 molecules than single AM at this time point of 24 h after tMCAO. Thus, the combination therapy with AM plus AT extended the neuroprotectives effect of single treatment with AM or AT on a part of neurovascular unit and a hypertension related receptor.

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