Effects of ifenprodil, a polyamine site NMDA receptor antagonist, on reperfusion injury after transient focal cerebral ischemia

1997 ◽  
Vol 87 (6) ◽  
pp. 921-926 ◽  
Author(s):  
Aclan Doğgan ◽  
A. Muralikrishna Rao ◽  
Mustafa K. Başkaya ◽  
V. L. Raghavendra Rao ◽  
Jane Rastl ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Reperfusion Injury ◽  
Brain Edema ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Male Rats ◽  
Temporal Muscle ◽  
Transient Focal Cerebral Ischemia

✓ Polyamines and N-methyl-d-aspartate (NMDA) receptors are both thought to play an important role in secondary neuronal injury after cerebral ischemia. Ifenprodil, known as a noncompetitive inhibitor of polyamine sites at the NMDA receptor, was studied after transient focal cerebral ischemia occurred. Spontaneously hypertensive male rats, each weighing between 250 and 350 g, underwent 3 hours of tandem middle cerebral artery (MCA) and common carotid artery occlusion followed by reperfusion for a period of 3 hours or 21 hours. Intravenous ifenprodil (10 µg/kg/minute) or saline infusion was started immediately after the onset of MCA occlusion and continued throughout the ischemic period. Physiological parameters including blood pressure, blood gas levels, blood glucose, hemoglobin, and rectal and temporal muscle temperatures were monitored. Six rats from each group were evaluated at 6 hours postocclusion for brain water content, an indicator of brain edema, and Evans blue dye extravasation for blood-brain barrier breakdown. Infarct volume was also measured in six rats from each group at 6 and 24 hours postocclusion. Ifenprodil treatment significantly reduced brain edema (82.5 ± 0.4% vs. 83.5 ± 0.4%, p < 0.05) and infarct volume (132 ± 14 mm3 vs. 168 ± 25 mm3, p < 0.05) compared with saline treatment, with no alterations in temporal muscle (brain) or rectal (body) temperature (35.9 ± 0.4°C vs. 36.2 ± 0.2°C; 37.7 ± 0.4°C vs. 37.6 ± 0.6°C; not significant). These results demonstrate that ifenprodil has neuroprotective properties after ischemia/reperfusion injury in the absence of hypothermia. This indicates that antagonists selective for the polyamine site of the NMDA receptors may be a viable treatment option and helps to explain some of the pathophysiological mechanisms involved in secondary injury after transient focal cerebral ischemia has occurred.

scholarly journals Short Therapeutic Window for MK-801 in Transient Focal Cerebral Ischemia in Normotensive Rats

1996 ◽  
Vol 16 (1) ◽  
pp. 107-113 ◽  
Author(s):  
I. Margaill ◽  
S. Parmentier ◽  
J. Callebert ◽  
M. Allix ◽  
R. G. Boulu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nmda Receptors ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Activity ◽  
Therapeutic Window ◽  
Left Middle Cerebral Artery ◽  
Mk 801 ◽  
Transient Focal Cerebral Ischemia

The present study investigates the role of N-methyl-D-aspartate (NMDA) receptors in a model of transient focal cerebral ischemia in normotensive rats. The left middle cerebral artery and both common carotid arteries were occluded for 60 min. Preliminary studies indicated that this gave reproducible infarctions of the cortex and striatum. These infarctions were the result of severe ischemia followed by complete reperfusion after clamp removal, as showed by striatal tissue Po2 monitoring. Microdialysis indicated that glutamate concentration increased immediately after occlusion and returned to the baseline value 40 min after clamp removal. MK-801 (1 mg kg−1 i.v.), an antagonist of the NMDA glutamatergic receptor, reduced the cortical infarct volume by 29% (p < 0.001) and the striatal infarct volume by 14% (p < 0.05) when given just prior to ischemia, but had no neuroprotective activity when given 30 min after the onset of ischemia. This short therapeutic window for MK-801 suggests that NMDA receptors play only a transient role in reversible focal ischemia in rats.

Abstract WP295: Remote Limb Ischemic Conditioning in Murine Focal Cerebral Ischemia

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Kazuo Kitagawa ◽  
Moeko Saitoh ◽  
Kentaro Ishizuka
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Limb Ischemia ◽  
Brain Protection ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Transient Focal Cerebral Ischemia ◽  
Cortical Cerebral Blood Flow ◽  
Doppler Flowmeter

Background & Aims: Remote ischemic conditioning (RIC) could induce brain protection in cerebral ischemia. The conditioning can be divided into pre-, per- and post-conditioning. The aim of this study is to clarify which RIC is the most effective in murine focal ischemia. Methods: Adult male C57BL/6 mice were used in this study. Transient focal cerebral ischemia was produced with nylon-suture model by occluding middle cerebral artery (MCAO) for 45 minutes. Cortical cerebral blood flow (rCBF) was continuously measured during ischemia with laser Doppler flowmeter. Twenty-four hours after MCAO, the animals were sacrificed and their brains were removed. After cutting coronal 1-mm brain sections, infarct volume was measured after TTC staining. Fifty mice were divided into five groups (each n=10); sham RIC group, delayed preRIC group (RIC 24 hours before MCAO), early preRIC group (RIC 5 minutes before MCAO), perRIC group (RIC during MCAO), and postRIC group (RIC 5 minutes after MCAO). Hind limb ischemia was induced by making the snare as tight as possible using a hemostatic forceps for 5 minutes followed by loosening it for 5 minutes. Four cycles were performed as RIC. Results: Infarct volume were 58.8±10.1 mm 3 in sham RIC, 54.8±19.4 mm 3 in delayed preRIC, 69.3±10.8 mm 3 in early preRIC, 38.0±22.1 mm 3 in perRIC, and 64.5±13.5 mm 3 in postRIC groups. Infarct volume in perRIC was significantly smaller than that in sham RIC and other groups (P<0.01). However, infarct volume of other RIC groups was not different with sham RIC group. After MCAO, rCBF reduced to 15.6% of baseline level in sham RIC, 11.2% in delayed preRIC, 11.9% in early preRIC, 13.4% in perRIC, and 10.8% in postRIC group. No difference was found in residual rCBF among all groups. At the end of MCAO, rCBF compared to rCBF immediate after occlusion was 102±21% in sham RIC, 112±25% in delayed preRIC, 98±22% in early preRIC, 131±33% in perRIC and 105±19% postRIC groups. Relative rCBF change at the end of MCAO in perRIC was significantly more than that in sham RIC group (P<0.05). Conclusions: Among four RIC procedures, only perRIC showed clear brain protection against transient MCAO. Change during rCBF may suggest that enhancement of collateral circulation play a role in part on brain protective effect of perRIC.

scholarly journals Lack of Neuroprotection of Inhibitory Peptides Targeting Jun/JNK after Transient Focal Cerebral Ischemia in Spontaneously Hypertensive Rats

2011 ◽  
Vol 31 (12) ◽  
pp. e1-e8 ◽  
Author(s):  
William R Gow ◽  
Kym Campbell ◽  
Amanda J Meade ◽  
Paul M Watt ◽  
Nadia Milech ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Receptor Activation ◽  
Glutamate Excitotoxicity ◽  
Functional Score ◽  
Adhesive Tape ◽  
Tat Peptide ◽  
Spontaneously Hypertensive ◽  
Transient Focal Cerebral Ischemia

In this study, we have assessed the ability of two TAT-fused peptides PYC36d-TAT and JNKI-1d-TAT (JNKI-1 or XG-102), which respectively inhibit jun proto-oncogene (c-Jun) and c-Jun N-terminal kinase (JNK) activation, to reduce infarct volume and improve functional outcome (adhesive tape removal) after transient focal cerebral ischemia in Spontaneously Hypertensive (SH) rats. PYC36d-TAT and JNKI-1d-TAT peptide batches used for experiments were tested in vitro and protected cortical neurons against glutamate excitotoxicity. Rats were treated intravenously with three different doses of PYC36d-TAT (7.7, 76, or 255 nmol/kg), JNKI-1d-TAT (255 nmol/kg), d-TAT peptide (255 nmol/kg), or saline (vehicle control), 10 minutes after reperfusion after 90 minutes of middle cerebral artery occlusion (MCAO). Contrary to other stroke models, no treatment significantly reduced infarct volume or improved functional score measurements compared with vehicle-treated animals when assessed 48 hours after MCAO. Additionally, assessment of the JNKI-1d-TAT peptide, when administered 1 or 2 hours after reperfusion after 90 minutes of MCAO, also did not improve histological or functional outcomes at 48 hours after occlusion. This study is the first to evaluate the efficacy of PYC36d-TAT and JNKI-1d-TAT using the SH rat, which has recently been shown to be more sensitive to AMPA receptor activation rather than to NMDA receptor activation after cerebral ischemia, and which may have contributed to the negative findings.

Role of Arginine Vasopressin V1 and V2 Receptors for Brain Damage After Transient Focal Cerebral Ischemia

2005 ◽  
Vol 25 (8) ◽  
pp. 1012-1019 ◽  
Author(s):  
Abedin Vakili ◽  
Hiroharu Kataoka ◽  
Nikolaus Plesnila
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Brain Edema ◽  
Brain Damage ◽  
Arginine Vasopressin ◽  
Focal Cerebral Ischemia ◽  
Edema Formation ◽  
Transient Focal Cerebral Ischemia ◽  
Brain Edema Formation

Brain edema formation is one of the most important mechanisms responsible for brain damage after ischemic stroke. Despite considerable efforts, no specific therapy is available yet. Arginine vasopressin (AVP) regulates cerebral water homeostasis and has been involved in brain edema formation. In the current study, we investigated the role of AVP V1 and V2 receptors on brain damage, brain edema formation, and functional outcome after transient focal cerebral ischemia, a condition comparable with that of stroke patients undergoing thrombolysis. C57/BL6 mice were subjected to 60-min middle cerebral artery occlusion (MCAO) followed by 23 h of reperfusion. Five minutes after MCAO, 100 or 500 ng of [deamino-Pen(1), O-Me-Tyr(2), Arg(8)]-vasopressin (AVP V1 receptor antagonist) or [adamantaneacetyl(1), O-Et-d-Tyr(2), Val(4), Abu(6), Arg(8,9)]-vasopressin (AVP V2 receptor antagonist) were injected into the left ventricle. Inhibition of AVP V1 receptors reduced infarct volume in a dose-dependent manner by 54% and 70% (to 29±13 and 19±10 mm3 versus 63±17 mm3 in controls; P<0.001), brain edema formation by 67% (to 80.4%±1.0% versus 82.7%±1.2% in controls; P<0.001), blood-brain barrier disruption by 75% ( P<0.001), and functional deficits 24 h after ischemia, while V2 receptor inhibition had no effect. The current findings indicate that AVP V1 but not V2 receptors are involved in the pathophysiology of secondary brain damage after focal cerebral ischemia. Although further studies are needed to clarify the mechanisms of neuroprotection, AVP V1 receptors seem to be promising targets for the treatment of ischemic stroke.

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