Treatment of stroke with opiate antagonists — Effects of exogenous antagonists and dynorphin 1–13

Baskin, David S.; Kuroda, Hiroo; Hosobuchi, Yoshio; Lee, N. M.

doi:10.1016/0143-4179(85)90014-9

Cited by 34 publications

(10 citation statements)

References 9 publications

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Section: Methodsmentioning

confidence: 99%

“…The brains from gerbils that died or were killed were dissected, sectioned, and stained with 2,3,5-triphenyltetrazolium. 7 Coronal sections were made from the optic chiasm to the mamillary bodies. The infarct size was scored as 1, 2, or 3, with 1 indicating an infarct encompassing one quarter, 2 an infarct encompassing approximately one half, and 3 an infarct encompassing the entire area.…”

Section: Methodsmentioning

confidence: 99%

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Tetramethylpyrazine for treatment of experimentally induced stroke in Mongolian gerbils.

Wen

Lee

1989

Stroke

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Tetramethylpyrazine, a drug originally isolated from the rhizome of Ligustkum walliichi, has been used routinely in China for the treatment of stroke and angina pectoris. We evaluated this drug by testing its effectiveness in increasing the survival rate in a stroke model using Mongolian gerbils. Our results indicate that tetramethylpyrazine can increase survival rate only if it is administered before the induction of cerebral ischemia. Since we administered the drug intraperitoneally, it is possible that pretreatment was necessary to increase its effective concentration in the blood. Receptor binding studies indicated that tetramethylpyrazine was inactive against a variety of pharmacologically active receptors. (Stroke 1989;20:96-99) T he rhizome of Ligusticum walliichi has long been used by practitioners of traditional Chinese medicine in treating blood stasis and vital energy stagnation. In recent years, the active ingredient of this herb has been characterized and its chemical structure has been worked out (Figure 1). This compound, tetramethylpyrazine (TMP), has been reported to be effective for the treatment of angina pectoris 1 and cerebral thrombosis 2 in China. Experimentally, TMP has been shown to induce vasodilation, to increase coronary blood flow, and to inhibit ADP-induced platelet aggregation.3 These properties of TMP apparently account for its efficacy in the treatment of disorders associated with blood vessel occlusion.Although TMP has been used in a number of clinical trials for the treatment of cerebral thrombosis in China, 2 -4 its effectiveness in increasing survival rate has not been confirmed under stringent experimental conditions. As part of our overall effort to evaluate TMP, we tested it in a stroke model using Mongolian gerbils.3 -6 The following is a report of our findings. Materials and MethodsOne hundred seventy-nine male Mongolian gerbils weighing 70-80 g were maintained in our animal house with a day/night cycle of 12/12 hours. Food and water were given ad libitum. Gerbils were stabilized for at least 1 week before the initiation of the experiment. Gerbils were anesthetized with 0.25 mg/ kg pentobarbitol in 0.5 ml injection volume before unilateral cerebral infarction was induced by ligating one common carotid artery. A segment of the artery was tied doubly, and the artery was transected between the sutures. Gerbils were returned to their cages and observed approximately every 30 minutes for 3 hours. Gerbils dying within this period were excluded from the study; <2% of the gerbils died. At the end of the third hour, gerbils were injected intraperitoneally with either 2.5 mg TMP in 0.2 ml saline or 0.2 ml saline (vehicle). Signs of ischemia were then recorded by an independent observer.We used two experimental paradigms. In the first, gerbils were pretreated with either TMP or vehicle for 7 days before the induction of stroke; in the second, gerbils were not pretreated. In both paradigms, 2.5 mg TMP or vehicle was administered intraperitoneally once daily in the morning for 4 days...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Tetramethylpyrazine for treatment of experimentally induced stroke in Mongolian gerbils.

Wen

Lee

1989

Stroke

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“…In the mouse middle cerebral artery occlusion model, the K-agonist, GR89696, was efficacious when the start of dosing was delayed for 6 h after occlusion. Interestingly, the NMDA receptor antagonist SL820715 is only effective at time points up to 3 h post-occlusion in the mouse middle cerebral artery occlusion model (Baskin et al, 1985), although in this latter study an effect on infarct size was not observed. Assessments of neurological function were not made in the present study.…”

Section: Discussionmentioning

confidence: 52%

Neuroprotective actions of GR89696, a highly potent and selective κ‐opioid receptor agonist

Birch

Rogers

Hayes

et al. 1991

British J Pharmacology

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1 The effect of a novel, highly potent and selective K-opioid receptor agonist, GR89696, has been evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in the Mongolian gerbil and permanent, unilateral middle cerebral artery occlusion in the mouse.2 In the Mongolian gerbil model, administration of GR89696 (3 to 30pgkg-1, s.c.), immediately before and at 4h after insult, produced a dose-dependent reduction in the hippocampal CA1 neuronal cell loss resulting from a 7-min bilateral carotid occlusion. Similar effects were obtained with two other K-agonists, GR86014 (1mgkg-', s.c.) and GR91272 (1mgkg-', s.c.). The neuroprotective effect of GR89696 was completely blocked by prior administration of the opioid receptor antagonist, naltrexone, at 10mgkg 1, s.c. Repeated post-treatment with GR89696 (lOOpgkg-1, s.c.) or GR44821 (lOmgkg-1, s.c.) was also effective in protecting completely the hippocampal CA1 neurones from ischaemia-induced neurodegeneration. 3 In the permanent, unilateral middle cerebral artery occlusion model in the mouse, repeated administration of GR89696 at 300pugkg-1, s.c. produced a 50% reduction in cerebrocortical infarct volume. In these experiments GR89696 was dosed 5min, 4, 8, 12, 16, 20 and 24 h after occlusion on the first day and then three times daily for the next three days. GR89696 (300.ugkg-1) also produced a significant 35% reduction in infarct volume in this model when the initiation of dosing was delayed for 6 h after the insult. 4 The results indicate that the potent K-opioid receptor agonist, GR89696, is neuroprotective in both global and focal cerebral ischaemia models and suggest that, with this class of compound, there may be a considerable time window for pharmacological intervention.

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“…Opiate receptor antagonists have exhibited cytoprotective activity in preclinical focal and global models of ischemia. [73][74][75] Several small trials of naloxone have failed to conclusively show efficacy in acute ischemic stroke. 76 -80 The equivocal results are likely due to under-powering of these small studies to detect small but significant treatment effects.…”

Section: Other Neurotransmitter Modulatorsmentioning

confidence: 99%

Clinical trials for cytoprotection in stroke

Labiche

Grotta

2004

Neurotherapeutics

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Summary:To date, many cytoprotective drugs have reached the stage of pivotal phase 3 efficacy trials in acute stroke patients. (Table 1) Unfortunately, throughout the neuroprotective literature, the phrase "failure to demonstrate efficacy" prevails as a common thread among the many neutral or negative trials, despite the largely encouraging results encountered in preclinical studies. The reasons for this discrepancy are multiple, and have been discussed by Dr. Zivin in his review. Many of the recent trials have addressed deficiencies of the previous ones with more rigorous trial design, including more specific patient selection criteria (ensure homogeneity of stroke location and severity), stratified randomization algorithms (time-totreat), narrowed therapeutic time-window and pharmacokinetic monitoring. Current trials have also incorporated biologic surrogate markers of toxicity and outcome such as drug levels and neuroimaging. Lastly, multi-modal therapies and coupled cytoprotection/reperfusion strategies are being investigated to optimize tissue salvage. This review will focus on individual therapeutic strategies and we will emphasize what we have learned from these trials both in terms of trial design and the biologic effect (or lack thereof) of these agents.

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Treatment of stroke with opiate antagonists — Effects of exogenous antagonists and dynorphin 1–13

Cited by 34 publications

References 9 publications

Tetramethylpyrazine for treatment of experimentally induced stroke in Mongolian gerbils.

Tetramethylpyrazine for treatment of experimentally induced stroke in Mongolian gerbils.

Neuroprotective actions of GR89696, a highly potent and selective κ‐opioid receptor agonist

Clinical trials for cytoprotection in stroke

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