Abstract TP97: Experimental Stroke During Aging: Docosahexaenoic Acid Therapy Provides Robust Neuroprotection

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Ludmila Belayev ◽  
Larissa Khoutorova ◽  
Andre Obenaus ◽  
Nicolas G Bazan
Keyword(s):  
Cerebral Ischemia ◽  
Docosahexaenoic Acid ◽  
Focal Cerebral Ischemia ◽  
Brain Temperature ◽  
Brain Infarction ◽  
Splitting Method ◽  
Experimental Stroke ◽  
Aged Rats ◽  
Acid Therapy ◽  
Postural Reflex

Introduction: Recently we have shown that docosahexaenoic acid (DHA) is neuroprotective after experimental stroke in young rats. The purpose of this study was to determine whether treatment with DHA would be protective in aged rats after focal cerebral ischemia. Methods: Isoflurane/nitrous oxide-anesthetized normothermic (brain temperature 36-36.5 o C) male Sprague-Dawley aged rats (16-months old) received 2h middle cerebral artery occlusion (MCAo) by poly-L-lysine-coated intraluminal suture. The behavioral function was evaluated during occlusion (60 min), and on days 1, 3 and 7 after MCAo; a grading scale of 0-12 was employed (0=normal and 12=maximal deficit). The agent (DHA, 5 mg/kg; n=6) or vehicle (saline; n=7) was administered i.v. at 3h after MCAo onset. The composite neuroscore comprises two different neurological tests, the postural reflex test and the forelimb placing test, to measure visual, tactile and proprioceptive stimuli, which were evaluated on days 1, 2, 3 and 7. High resolution ex vivo MRI using an 11.7T Bruker was performed on day 7. The core and penumbra were automatically identified using the Hierarchical Region Splitting method for penumbra identification. Histopathology and immunostaining were conducted after completion of MRI on day 7. Results: DHA treatment improved neurological scores on days 1 (by 18%), 2 (by 25%), 3 (by 22%) and 7 (by 36%). Total, cortical and subcortical lesion volumes computed from T2WI were significantly reduced by DHA treatment (by 62-75%). DHA treatment also reduced cortical, subcortical and total brain infarction (by 65- 80%). In addition, DHA therapy decreased ED-1 positive microglia/microphages (by 62%), GFAP-positive astrocytes (by 21%), and NeuN-positive neurons (by34%), and it increased SMI-71-positive vessels (by 46%) in the ischemic penumbra. Conclusion: DHA therapy is highly neuroprotective in aged rats following focal cerebral ischemia and has potential for the effective treatment of ischemic stroke in aged individuals.

Docosahexaenoic acid reduces cellular inflammatory response following permanent focal cerebral ischemia in rats

2013 ◽  
Vol 24 (12) ◽  
pp. 2127-2137 ◽  
Author(s):  
Cheng-Yi Chang ◽  
Yu-Hsiang Kuan ◽  
Jian-Ri Li ◽  
Wen-Ying Chen ◽  
Yen-Chuan Ou ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Docosahexaenoic Acid ◽  
Inflammatory Response ◽  
Focal Cerebral Ischemia ◽  
Cellular Inflammatory Response

scholarly journals Neuroprotection by Brazilian Green Propolis againstIn vitroandIn vivoIschemic Neuronal Damage

2005 ◽  
Vol 2 (2) ◽  
pp. 201-207 ◽  
Author(s):  
Masamitsu Shimazawa ◽  
Satomi Chikamatsu ◽  
Nobutaka Morimoto ◽  
Satoshi Mishima ◽  
Hiroichi Nagai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Brain Infarction ◽  
Folk Medicine ◽  
Neuroprotective Function ◽  
Brazilian Green Propolis

We examined whether Brazilian green propolis, a widely used folk medicine, has a neuroprotective functionin vitroand/orin vivo.In vitro, propolis significantly inhibited neurotoxicity induced in neuronally differentiated PC12 cell cultures by either 24 h hydrogen peroxide (H2O2) exposure or 48 h serum deprivation. Regarding the possible underlying mechanism, propolis protected against oxidative stress (lipid peroxidation) in mouse forebrain homogenates and scavenged free radicals [induced by diphenyl-p-picrylhydrazyl (DPPH). In micein vivo, propolis [30 or 100 mg/kg; intraperitoneally administered four times (at 2 days, 1 day and 60 min before, and at 4 h after induction of focal cerebral ischemia by permanent middle cerebral artery occlusion)] reduced brain infarction at 24 h after the occlusion. Thus, a propolis-induced inhibition of oxidative stress may be partly responsible for its neuroprotective function againstin vitrocell death andin vivofocal cerebral ischemia.

scholarly journals Nuclear Translocation of Apoptosis-Inducing Factor after Focal Cerebral Ischemia

2004 ◽  
Vol 24 (4) ◽  
pp. 458-466 ◽  
Author(s):  
Nikolaus Plesnila ◽  
Changlian Zhu ◽  
Carsten Culmsee ◽  
Moritz Gröger ◽  
Michael A. Moskowitz ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Cytochrome C ◽  
Nuclear Translocation ◽  
Focal Cerebral Ischemia ◽  
Mitochondrial Protein ◽  
Neuronal Cell ◽  
Experimental Stroke ◽  
Cytochrome C Release ◽  
Apoptosis Inducing Factor

Signaling cascades associated with apoptosis contribute to cell death after focal cerebral ischemia. Cytochrome c release from mitochondria and the subsequent activation of caspases 9 and 3 are critical steps. Recently, a novel mitochondrial protein, apoptosis-inducing factor (AIF), has been implicated in caspase-independent programmed cell death following its translocation to the nucleus. We, therefore, addressed the question whether AIF also plays a role in cell death after focal cerebral ischemia. We detected AIF relocation from mitochondria to nucleus in primary cultured rat neurons 4 and 8 hours after 4 hours of oxygen/glucose deprivation. In ischemic mouse brain, AIF was detected within the nucleus 1 hour after reperfusion after 45 minutes occlusion of the middle cerebral artery. AIF translocation preceded cell death, occurred before or at the time when cytochrome c was released from mitochondria, and was evident within cells showing apoptosis-related DNA fragmentation. From these findings, we infer that AIF may be involved in neuronal cell death after focal cerebral ischemia and that caspase-independent signaling pathways downstream of mitochondria may play a role in apoptotic-like cell death after experimental stroke.

3-Aminobenzamide reduces brain infarction and neutrophil infiltration after transient focal cerebral ischemia in mice

2003 ◽  
Vol 184 (2) ◽  
pp. 973-980 ◽  
Author(s):  
Jérôme Y Couturier ◽  
Li Ding-Zhou ◽  
Nicole Croci ◽  
Michel Plotkine ◽  
Isabelle Margaill
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Brain Infarction ◽  
Neutrophil Infiltration ◽  
Transient Focal Cerebral Ischemia

Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke

2004 ◽  
Vol 76 (4) ◽  
pp. 519-527 ◽  
Author(s):  
Mushfiquddin Khan ◽  
Bipanjeet Sekhon ◽  
Manu Jatana ◽  
Shailendra Giri ◽  
Anne G. Gilg ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Rat Model ◽  
Focal Cerebral Ischemia ◽  
Experimental Stroke

scholarly journals Blocking TLR2 in vivo Protects against Accumulation of Inflammatory Cells and Neuronal Injury in Experimental Stroke

2010 ◽  
Vol 31 (2) ◽  
pp. 757-766 ◽  
Author(s):  
Gina Ziegler ◽  
Dorette Freyer ◽  
Denise Harhausen ◽  
Uldus Khojasteh ◽  
Wilfried Nietfeld ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Focal Cerebral Ischemia ◽  
Neuronal Survival ◽  
Inflammatory Cells ◽  
Experimental Stroke ◽  
Wild Type ◽  
Antibody Treatment ◽  
Cell Counts

Reduced infarct volume in TLR2-knockout mice compared with C57Bl/6 wild-type mice has recently been shown in experimental stroke and confirmed in this study. We now also show a significant decrease of CD11b-positive cell counts and decreased neuronal death in the ischemic hemispheres of TLR2-deficient mice compared with C57Bl/6wt mice 2 days after transient focal cerebral ischemia. To examine the potential benefit of intravascular TLR2 inhibition, C57Bl/6wt mice were treated intraarterially with TLR2-blocking anti-TLR2 antibody (clone T2.5) after 45 minutes of cerebral ischemia and compared with control antibody (isotype) treated wild-type mice. Whereas T2.5-treated mice had no reduction in infarct volumes at 48 hours after reperfusion, they did have decreased numbers of CD11b-positive inflammatory cells and decreased neuronal death compared with isotype-treated control mice. Comparison of the isotype antibody treatment to control (saline) treatment showed no effects on infarct volumes or neuronal survival. However, mice treated with the control isotype antibody had increased numbers of CD11b-positive inflammatory cells compared with saline-treated animals. Thus, antibody treatment itself (i.e., control isotype antibody, but potentially of any antibody) may have adverse effects and limit therapeutic benefit of anti-TLR2-antibody therapy. We conclude that TLR2 mediates leukocyte and microglial infiltration and neuronal death, which can be attenuated by TLR2 inhibition. The TLR2 inhibition in vivo improves neuronal survival and may represent a future stroke therapy.

Delayed treatment with magnesium: reduction of brain infarction and improvement of electrophysiological recovery following transient focal cerebral ischemia in rats

2005 ◽  
Vol 102 (6) ◽  
pp. 1085-1093 ◽  
Author(s):  
E-Jian Lee ◽  
Ming-Yang Lee ◽  
Guan-Liang Chang ◽  
Li-Hsuan Chen ◽  
Yu-Ling Hu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Brain Infarction ◽  
Artery Occlusion ◽  
Sprague Dawley ◽  
Content Type ◽  
Delayed Treatment ◽  
Cerebral Ischemia Reperfusion ◽  
Fine Print

Object. The authors examined whether delayed treatment with Mg++ would reduce brain infarction and improve electrophysiological and neurobehavioral recovery following cerebral ischemia—reperfusion. Methods. Male Sprague—Dawley rats were subjected to right middle cerebral artery occlusion for 90 minutes followed by 72 hours of reperfusion. Magnesium sulfate (750 µmol/kg) or vehicle was given via intracarotid infusion at the beginning of reperfusion. Neurobehavioral outcome and somatosensory evoked potentials (SSEPs) were examined before and 72 hours after ischemia—reperfusion. Brain infarction was assessed after the rats had died. Before ischemia—reperfusion, stable SSEP waveforms were recorded after individual fore- and hindpaw stimulations. At 72 hours of perfusion the SSEPs recorded from ischemic fore- and hindpaw cortical fields were depressed in vehicle-injected animals and the amplitudes decreased to 19 and 27% of baseline, respectively (p < 0.001). Relative to controls, the amplitudes of SSEPs recorded from both ischemic fore- and hindpaw cortical field in the Mg++-treated animals were significantly improved by 23% (p < 0.005) and 39% (p < 0.001) of baselines, respectively. In addition, Mg++ improved sensory and motor neurobehavioral outcomes by 34% (p < 0.01) and 24% (p < 0.05), respectively, and reduced cortical (p < 0.05) and striatal (p < 0.05) infarct sizes by 42 and 36%, respectively. Conclusions. Administration of Mg++ at the commencement of reperfusion enhances electrophysiological and neurobehavioral recovery and reduces brain infarction after cerebral ischemia—reperfusion. Because Mg++ has already been used clinically, it may be worthwhile to investigate it further to see if it holds potential benefits for patients with ischemic stroke and for those who will undergo carotid endarterectomy.

scholarly journals α2-Adrenoceptors do not Mediate Neuroprotection in Acute Ischemic Stroke in Mice

2011 ◽  
Vol 31 (10) ◽  
pp. e1-e7 ◽  
Author(s):  
Marc Brede ◽  
Stefan Braeuninger ◽  
Friederike Langhauser ◽  
Lutz Hein ◽  
Norbert Roewer ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Blood Pressure Lowering Effect ◽  
Α2 Adrenoceptors ◽  
Arterial Blood ◽  
Neuroprotective Function

We assessed the neuroprotective potential of α2-adrenoceptors in ischemic stroke using mice with targeted deletions of individual α2-adrenoceptor subtypes (α 2A−/−, α 2B−/−, α 2C−/−, α 2A/C−/−). The effects of the α2-adrenoceptor agonist clonidine were studied in parallel. Focal cerebral ischemia was induced with or without clonidine pretreatment by transient middle cerebral artery occlusion. Neurologic outcome and infarct volumes were evaluated on day 1. Cerebral blood flow (CBF) and mean arterial pressure were determined. α2- Adrenoceptor null mice did not display larger infarct volumes compared with wild-type (WT) mice under basal conditions ( P>0.05). In line with this finding, pretreatment with clonidine did not protect from ischemic brain damage in WT mice or α 2A−/−, α 2B−/−, and α 2C−/− mice. Clonidine induced smaller infarct volumes only in α 2A/C−/− mice ( P < 0.05), but this did not translate into improved neurologic function ( P > 0.05). Importantly, while clonidine caused a significant decrease in arterial blood pressure in all groups, it had no blood pressure lowering effect in α 2A/C−/− mice, and this correlated with higher CBF and smaller infarct volumes in this group. In summary, we could not demonstrate a neuroprotective function of α2-adrenoceptors in focal cerebral ischemia. Careful controlling of physiological parameters relevant for stroke outcome is recommended in experimental stroke studies.

scholarly journals Evaluation of the PBR/TSPO Radioligand [18F]DPA-714 in a Rat Model of Focal Cerebral Ischemia

2009 ◽  
Vol 30 (1) ◽  
pp. 230-241 ◽  
Author(s):  
Abraham Martín ◽  
Raphaël Boisgard ◽  
Benoit Thézé ◽  
Nadja Van Camp ◽  
Bertrand Kuhnast ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Pet Imaging ◽  
Time Course ◽  
Focal Cerebral Ischemia ◽  
Quantitative Information ◽  
Translocator Protein ◽  
Experimental Stroke ◽  
Tspo Expression

Focal cerebral ischemia leads to an inflammatory reaction involving an overexpression of the peripheral benzodiazepine receptor (PBR)/18-kDa translocator protein (TSPO) in the cerebral monocytic lineage (microglia and monocyte) and in astrocytes. Imaging of PBR/TSPO by positron emission tomography (PET) using radiolabeled ligands can document inflammatory processes induced by cerebral ischemia. We performed in vivo PET imaging with [18F]DPA-714 to determine the time course of PBR/TSPO expression over several days after induction of cerebral ischemia in rats. In vivo PET imaging showed significant increase in DPA ( N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) uptake on the injured side compared with that in the contralateral area on days 7, 11, 15, and 21 after ischemia; the maximal binding value was reached 11 days after ischemia. In vitro autoradiography confirmed these in vivo results. In vivo and in vitro [18F]DPA-714 binding was displaced from the lesion by PK11195 and DPA-714. Immunohistochemistry showed increased PBR/TSPO expression, peaking at day 11 in cells expressing microglia/macrophage antigens in the ischemic area. At later times, a centripetal migration of astrocytes toward the lesion was observed, promoting the formation of an astrocytic scar. These results show that [18F]DPA-714 provides accurate quantitative information of the time course of PBR/TSPO expression in experimental stroke.

scholarly journals Brain-to-cervical lymph node signaling after stroke

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Elga Esposito ◽  
Bum Ju Ahn ◽  
Jingfei Shi ◽  
Yoshihiko Nakamura ◽  
Ji Hyun Park ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymph Node ◽  
Cerebral Ischemia ◽  
Systemic Inflammation ◽  
Cervical Lymph Node ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
Brain Infarction ◽  
Surgical Removal ◽  
Lymphatic Endothelial Cells

AbstractAfter stroke, peripheral immune cells are activated and these systemic responses may amplify brain damage, but how the injured brain sends out signals to trigger systemic inflammation remains unclear. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. In rats subjected to focal cerebral ischemia, lymphatic endothelial cells proliferate and macrophages are rapidly activated in CLNs within 24 h, in part via VEGF-C/VEGFR3 signalling. Microarray analyses of isolated lymphatic endothelium from CLNs of ischemic mice confirm the activation of transmembrane tyrosine kinase pathways. Blockade of VEGFR3 reduces lymphatic endothelial activation, decreases pro-inflammatory macrophages, and reduces brain infarction. In vitro, VEGF-C/VEGFR3 signalling in lymphatic endothelial cells enhances inflammatory responses in co-cultured macrophages. Lastly, surgical removal of CLNs in mice significantly reduces infarction after focal cerebral ischemia. These findings suggest that modulating the brain-to-CLN pathway may offer therapeutic opportunities to ameliorate systemic inflammation and brain injury after stroke.

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