scholarly journals AMP-Dependent Hypothermia Affords Protection from Ischemic Brain Injury

2012 ◽  
Vol 33 (2) ◽  
pp. 171-174 ◽  
Author(s):  
Mirko Muzzi ◽  
Francesco Blasi ◽  
Alberto Chiarugi
Keyword(s):  
Brain Injury ◽  
Brain Ischemia ◽  
Adenosine Monophosphate ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Stroke Treatment ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Cerebral Artery Occlusion

In light of the relevance of therapeutic hypothermia to stroke treatment, we investigated whether 5′-adenosine monophosphate (AMP)-dependent cooling affords protection from ischemic brain injury. We show that hypothermia by AMP is because of adenosine A1 receptor (A1R) activation and is not invariantly associated with hypotension. Inhibition of ecto-5′-nucleotidase-dependent constitutive degradation of brain extracellular AMP by methylene-ADP (AMPCP) also suffices to prompt A1R-dependent hypothermia without hypotension. Both intraischemic and postischemic hypothermia by AMP or AMPCP reduce infarct volumes and mortality of mice subjected to transient middle cerebral artery occlusion. Data disclose that AMP-dependent hypothermia is of therapeutic relevance to treatment of brain ischemia.

scholarly journals Adenovirus-Mediated Gene Transfer of Glial Cell Line-Derived Neurotrophic Factor Prevents Ischemic Brain Injury after Transient Middle Cerebral Artery Occlusion in Rats

1999 ◽  
Vol 19 (12) ◽  
pp. 1336-1344 ◽  
Author(s):  
Hisashi Kitagawa ◽  
Chihoko Sasaki ◽  
Kenichi Sakai ◽  
Atsushi Mori ◽  
Yasuhide Mitsumoto ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Brain Injury ◽  
Gene Transfer ◽  
Neurotrophic Factor ◽  
Treated Group ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Gdnf Gene ◽  
Cerebral Artery Occlusion

To examine a possible protective effect of exogenous glial cell line-derived neurotrophic factor (GDNF) gene expression against ischemic brain injury, a replication-defective adenoviral vector containing GDNF gene (Ad-GDNF) was directly injected into the cerebral cortex at 1 day before 90 minutes of transient middle cerebral artery occlusion (MCAO) in rats. 2,3,5-Triphenyltetrazolium chloride staining showed that infarct volume of the Ad-GDNF-injected group at 24 hours after the transient MCAO was significantly smaller than that of vehicle- or Ad-LacZ-treated group. Enzyme-linked immunosorbent assay (ELISA) for immunoreactive GDNF demonstrated that GDNF gene products in the Ad-GDNF-injected group were higher than those of vehicle-treated group at 24 hours after transient MCAO. Immunoreactive GDNF staining was obviously detected in the cortex around the needle track just before or 24 hours after MCAO in the Ad-GDNF group, whereas no or slight GDNF staining was detected in the vehicle group. The numbers of TUNEL, immunoreactive caspase-3, and cytochrome c-positive neurons induced in the ipsilateral cerebral cortex at 24 hours after transient MCAO were markedly reduced by the Ad-GDNF group. These results suggest that the successful exogenous GDNF gene transfer ameliorates ischemic brain injury after transient MCAO in association with the reduction of apoptotic signals.

Abstract WP134: 3K3A-APC Protects Pericyte-deficient Mice From Ischemic Brain Injury

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Yaoming Wang ◽  
Mikko Huuskonen ◽  
Axel Montagne ◽  
Berislav Zlokovic
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Activated Protein C ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Neuroprotective Effects ◽  
Ischemic Brain ◽  
Functional Deficits ◽  
Favorable Safety ◽  
Cerebral Artery Occlusion

Pericytes play a key role in maintaining the blood-brain barrier (BBB) integrity. BBB disruption occurs during early stages after ischemic stroke. However, the role of pericytes in the pathogenesis of ischemic stroke remains still understudied. 3K3A-APC, a recombinant variant of activated protein C, has shown benefits in preclinical models of ischemic stroke and has favorable safety profile and reduces hemorrhage in Phase 2 study in ischemic stroke patients (RHAPSODY). In the present study, we used PDGFRβ heterozygous knockout (PDGFRβ+/-) mice to investigate the effects of pericyte deficiency on ischemic brain injury using transient proximal middle cerebral artery occlusion (tMCAO). Additionally, we investigated the effects of 3K3A-APC therapy (0.2mg/kg i.v. 4h after stroke) in this model. Compared to controls, pericyte deficiency in PDGFRβ+/- mice resulted in ~35% increase in the infarct and edema volumes, reduction in pericyte coverage from 58% to 25%, and increased IgG and fibrin deposition suggesting accelerated BBB breakdown 24h after stroke. Additionally, PDGFRβ+/- mice showed by 36% more degenerating Fluoro-Jade+ neurons and exhibited accelerated neurobehavioral abnormalities. 3K3A-APC improved neuropathological changes and functional deficits. Our results suggest that pericyte deficiency worsens brain damage and functional outcome after ischemic stroke in mice suggesting that pericytes may play an important role in protecting brain from post-ischemic. We also suggests that 3K3A-APC protects pericyte function in stroked mice which could contribute to its overall neuroprotective effects.

scholarly journals Progesterone Administration during Reperfusion, but not Preischemia Alone, Reduces Injury in Ovariectomized Rats

2002 ◽  
Vol 22 (10) ◽  
pp. 1181-1188 ◽  
Author(s):  
Stephanie J. Murphy ◽  
Marguerite T. Littleton-Kearney ◽  
Patricia D. Hurn
Keyword(s):  
Brain Injury ◽  
Artery Occlusion ◽  
Ovariectomized Rats ◽  
Ischemic Brain Injury ◽  
Regional Cerebral Blood ◽  
Triphenyltetrazolium Chloride ◽  
Caudate Putamen ◽  
Early Reperfusion ◽  
Ischemic Brain ◽  
Cerebral Artery Occlusion

Although progesterone is neuroprotective in traumatic brain injury, its efficacy in stroke is unclear. The authors determined whether there are infarction differences after middle cerebral artery occlusion (MCAO) in ovariectomized rats treated acutely with progesterone before MCAO or both pre- and postischemia. Rats received vehicle, 5 (P5), 10 (P10), or 20 (P20) mg/kg progesterone intraperitoneally 30 minutes before MCAO. In another cohort, animals received vehicle or 5 (P5R) mg/kg progesterone intraperitoneally 30 minutes before MCAO, at reperfusion initiation, and at 6-hour reperfusion. Animals underwent 2-hour MCAO by the intraluminal filament technique, followed by 22-hour reperfusion. Cortical (CTX) and caudate-putamen (CP) infarctions were determined by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis. End-ischemic and early reperfusion regional cerebral blood flow (CBF) was measured by [14C]-iodoantipyrine quantitative autoradiography in vehicle- or progesterone (5 mg/kg)-treated rats. Cortical infarction (% contralateral CTX) was 31 ± 30% (vehicle), 39 ± 23% (P5), 41 ± 14% (P10), and 28 ± 20% (P20). Caudate-putamen infarction (% contralateral CP) was 45 ± 37% (vehicle), 62 ± 34% (P5), 75 ± 17% (P10), and 52 ± 30% (P20). In vehicle and P5R groups, CTX infarction was 37 ± 20% and *20 ± 17%, respectively (* P < 0.05 from vehicle). In vehicle and P5R groups, CP infarction was 63 ± 26% and 43 ± 29%, respectively. End-ischemic regional CBF and CBF recovery during initial reperfusion was unaffected by progesterone treatment. These data suggest that progesterone administration both before MCAO and during reperfusion decreases ischemic brain injury.

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