Experimental CNS ischemia

Background and Purpose Activated leukocytes appear to potentiate central nervous system reperfusion injury, and agents that block leukocyte adhesion have shown neuroprotective efficacy in experimental models. Doxycycline, a tetracycline antibiotic, inhibits leukocyte function in vitro, presumably through divalent cation binding. We used a model of focal central nervous system reperfusion injury to determine the efficacy of doxycycline treatment in preserving neurological function.Methods Rabbits randomly received 10 mg/kg IV doxycycline 30 minutes before ischemia (pretreatment group) or 45 minutes after ischemia (posttreatment group) or received phosphate-buffered saline vehicle (control group) followed by 10 mg/kg q 8 hours times two. The average length of reversible spinal cord ischemia required to produce paraplegia (P M ) at 18 hours was calculated for each group.

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Reduction of central nervous system reperfusion injury in rabbits using doxycycline treatment.

Clark

Calcagno

Gabler

et al. 1994

“…The derivation of this type of analysis has been described in detail, 21 and its utility as a pharmacologic screen has been demonstrated. 22 ' 23 For the spinal cord ischemia model, at each point on the abscissa, the percentage of paraplegic animals in the group is calculated and plotted as the ordinate. The total increases from 0% at the shortest duration of occlusion to 100% at the longest duration.…”

Section: Methodsmentioning

confidence: 99%

Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment.

Clark

Madden

Rothlein

et al. 1991

183

Activated leukocytes appear to be directly involved in ischemic central nervous system injury. A surface glycoprotein (CD18) on the leukocyte is required for endothelial adherence and subsequent function and can be blocked with leukocyte adhesion antibody treatment. We used two animal models to determine the efficacy of anti-CD18 antibody treatment in preserving neurologic function after central nervous system ischemia. We gave a dose of 1 mg/kg anti-CD18 to treatment rabbits 30 minutes before inducing irreversible ischemia in the brain with intraarterial microspheres or in the spinal cord using reversible aortic occlusion. Treatment with anti-CD18 produced a significant reduction in neurologic deficits in the reversible spinal cord model, but not in the irreversible microsphere model. This protective effect supports the active role of leukocytes in central nervous system reperfusion ischemic injury and offers potential for future therapy. {Stroke 1991;22:877-883) T he appearance of leukocytes in injured ischemic tissue traditionally has been believed to represent a pathophysiologic response to existing injury. Recent evidence indicates they also may be important in the pathogenesis and extension of ischemic injury. "4 Two proposed mechanisms of leukocyte potentiation of ischemia are 1) microvascular occlusion from direct mechanical obstruction and cytotoxic effects on the endothelium, and 2) central nervous system (CNS) tissue infiltration and neuronal cytotoxic injury. "7 The leukocyte-mediated tissue damage may be irreversible even if blood flow is restored. Leukocyte adhesion is an early step in both of these mechanisms.Recent studies have identified a specific leukocyte membrane glycoprotein complex (CD 18) that is critically important for adherence. Monoclonal antibodies (anti-CD 18) to these glycoproteins have been Received October 1, 1990; accepted March 27, 1991. shown to inhibit adherence-dependent leukocyte functions in vitro. 89 In vivo studies using anti-CD18 have shown a reduction of ischemic injury and decreased leukocyte tissue infiltration in heart, lung, intestinal, and systemic shock models.10 -14 These data indicate that leukocyte endothelial adhesion is probably a critical early event in the process leading to neutrophil-mediated tissue reperfusion injury. To date, there have been no published studies using anti-CD 18 to reduce CNS ischemic injury. It is not known how the blood-brain barrier influences leukocyte adhesion and migration or if it would alter anti-CD 18 effects. Because neutrophil infiltratiori is present early in CNS ischemic injury, 15 -17 it is anticipated that leukocytes also will have a critical role in CNS ischemic injury. To test this hypothesis, we evaluated the therapeutic efficacy of anti-CD18 in two models of selective CNS ischemia in rabbits. These models were chosen to compare the treatment efficacy of anti-CD 18 in a reperfusion model versus an irreversible microemboli model. Materials and MethodsWe used male New Zealand White rabbits weighing 2-3 kg. We select...

“…1 Several serotonin (5HT) inhibitors including cyproheptadine and brom-lysergic acid diethylamide (BOL) have been shown to reduce neurologic deficits in a rabbit spinal cord ischemia model. 2 ' 3 To further explore how these 5HT inhibitors provided protection, we conducted a series of observations on the biochemical, physiological and morphological effects of these drugs during CNS ischemia.…”

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confidence: 99%

Studies of the influence of biogenic amines on central nervous system ischemia.

Zivin¹,

DeGirolami²

1986

Several serotonin inhibitors have been shown to reduce neurologic deficits in experimental CNS ischemia. Using biochemical and histological methods we tested the effects of the serotonin inhibitors cyproheptadine and brom-LSD in a highly reproducible rabbit spinal cord ischemia model. Detailed mapping of regional spinal cord blood flow was used to guide sampling for the biochemical studies. We found that it is possible to study biochemical and morphological aspects of spinal cord ischemia in great detail using a combination of quite precise techniques. However, at this level of resolution there were no substantial changes in biogenic amine concentrations in severely ischemic or marginally perfused tissue after the durations of ischemia that cause the onset of irreversible tissue damage. Treatment with doses of serotonin inhibitors that produce preservation of neurological function did not cause significant alterations of tissue concentrations of biogenic amines or tissue morphology in treated versus untreated animals.