Model Of Complete Cerebral Ischemia Research Articles

Glutamate metabolism in cerebral mitochondria after ischemia and post-ischemic recovery during aging: relationships with brain energy metabolism.

Glutamate is involved in cerebral ischemic injury, but its role has not been completely clarified and studies are required to understand how to minimize its detrimental effects, contemporarily boosting the positive ones. In fact, glutamate is not only a neurotransmitter, but primarily a key metabolite for brain bioenergetics. Thus, we investigated the relationships between glutamate and brain energy metabolism in an invivo model of complete cerebral ischemia of 15min and during post-ischemic recovery after 1, 24, 48, 72, and 96h in 1-year-old adult and 2-year-old aged rats. The maximum rates (Vmax ) of glutamate dehydrogenase (GlDH), glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase were assayed in somatic mitochondria (FM) and in intra-synaptic 'Light' mitochondria and intra-synaptic 'Heavy' mitochondria ones purified from cerebral cortex, distinguishing post- and pre-synaptic compartments. During ischemia, none of the enzymes were modified in adult animals. In aged ones, glutamate-oxaloacetate transaminase was increased in FM and GlDH in intra-synaptic 'Heavy' mitochondria, stimulating glutamate catabolism. During post-ischemic recovery, FM did not show modifications at both ages while, in intra-synaptic mitochondria of adult animals, glutamate catabolism was increased after 1h of recirculation and decreased after 48 and 72h, whereas it remained decreased up to 96h in aged rats. These results, with those previously published about Krebs' cycle and Electron Transport Chain (Villa etal., [2013] Neurochem. Int. 63, 765-781), demonstrate that: (i) Vmax of energy-linked enzymes are different in the various cerebral mitochondria, which (ii) respond differently to ischemia and post-ischemic recovery, also (iii) with respect to aging.

Temperature changes of > or = 1 degree C alter functional neurologic outcome and histopathology in a canine model of complete cerebral ischemia.

Changes in basal temperature of > or = 1 degree C (e.g., fever-induced hyperthermia or anesthesia-related hypothermia) are a common occurrence in neurologically impaired patients. The current study tested the hypothesis that temperature changes as small as 1 degree C or 2 degrees C would significantly alter post-ischemic functional neurologic outcome and cerebral histopathology. The hypothesis was tested in a canine model of transient, complete cerebral ischemia. After institutional approval, 21 dogs were randomly assigned to one of three temperature-specific groups: (1) a reference group maintained at 37.0 +/- 0.3 degree C (target temperature +/- range); (2) a 38.0 +/- 0.3 degree C group; or (3) a 39.0 +/- 0.3 degree C group (n = 7 per group). Complete cerebral ischemia 12.5 min in duration was produced using an established model of arterial hypotension plus intracranial hypertension. Right atrial and cranial (beneath the temporalis muscles) temperatures were maintained at the target value, beginning 20 min before ischemia and ceasing 1 h postischemia. Thereafter, temperatures were returned to 37.0 +/- 0.3 degree C in all dogs. After discharge from the intensive care environment, all dogs were placed in a temperature-controlled recovery area. Neurologic assessment was performed by a blinded observer at 24, 48, and 72 h postischemia using a 100-point scoring scale. After the 72 h examination (with the dogs anesthetized) or at the time of ischemia-related death, the brains were excised and preserved. The brains subsequently were histologically scored by a neuropathologist who was unaware of the treatment groups. All 21 dogs were included in the analysis of neurologic function; however, only dogs that survived for > or = 24 h postischemia were included in the histopathology analysis. Dogs were well matched for systemic physiologic variables throughout the study, with the exception of temperature. During the 72 h postischemic examination, dogs maintained at 37 degrees C were either normal or near normal. In contrast, dogs maintained at 39 degrees C were either comatose or died from ischemia-related causes. Dogs maintained at 38 degrees C were intermediate between 37 degrees C and 39 degrees C dogs. When compared with the reference group, both 38 degrees C and 39 degrees C dogs had significantly worse neurologic function scores (P < 0.01 and < 0.001, respectively) and histopathology scores (P < 0.01 for both). There also was a significant correlation between neurologic function and histopathology rank scores (rs = 0.96; P < 0.001). Small, clinically relevant changes in temperature (1 degree C or 2 degrees C) resulted in significant alterations in both postischemic neurologic function and cerebral histopathology. Assuming that our results are transferable to humans, the results suggest that, in patients at imminent risk for ischemic neurologic injury, body temperature should be closely monitored. Further, the clinician should aggressively treat all episodes of hyperthermia until the patient is no longer at risk for ischemic neurologic injury.

The effect of a platelet activating factor antagonist (BN 52021) on neurologic outcome and histopathology in a canine model of complete cerebral ischemia.

Research has demonstrated that platelet activating factor may modulate, in part, the severity of postischemic neurologic injury. The proposed mechanism involves a platelet activating factor-mediated release of cerebral cellular lipids and free fatty acids, resulting in increased cerebral edema and cell injury. The present study tested the hypothesis that a specific platelet activating factor antagonist, BN 52021, would improve neurologic outcome after 12 min of complete global cerebral ischemia in a canine model. Using an established canine model of complete cerebral ischemia, dogs were assigned randomly to receive, in a blinded fashion, either 20 mg/kg BN 52021 intravenously (N = 8) or placebo (N = 7) 5 min before cerebral ischemia. After cerebral ischemia and recovery, neurologic assessment was performed by a blinded observer for 72 h. Immediately thereafter, the brains were harvested and later were evaluated histologically by a neuropathologist blinded to the treatment groups. Dogs were well matched for systemic physiologic variables during all portions of the study. One placebo-treated dog and one BN 52021-treated dog were not included in the statistical analysis because of failure to meet preestablished protocol criteria. BN 52021, when compared to placebo, affected neither neurologic functional recovery nor overall histopathology scores. Regional histopathology was improved in BN 52021-treated dogs in only 1 of 18 brain regions studied (i.e., the parietal cortex). When both treatment groups were combined, there was a significant correlation between neurologic function rank and histopathology rank. The present data demonstrate that the platelet activating factor antagonist BN 52021, at a dose of 20 mg/kg intravenously given 5 min before cerebral ischemia, did not protect the brain from injury in this canine model of complete global ischemia.

Pretreatment with U74006F improves neurologic outcome following complete cerebral ischemia in dogs.

We examined the 21-aminosteroid U74006F, a potent inhibitor of lipid peroxidation, for potential neuroprotective effects in a canine model of complete cerebral ischemia. Two 1.5-mg/kg boluses were administered to six dogs, the first bolus 15 minutes prior to a 12-minute episode of complete cerebral ischemia and the second bolus after 11 minutes of ischemia, 1 minute prior to reperfusion. Using this dosage regimen, plasma U74006F levels of greater than 0.3 microgram/ml were maintained for up to an hour postischemia. An additional six animals received equal volumes of the citrate vehicle solution. At 24 and 48 hours postischemia, the dogs were neurologically evaluated by an observer blinded as to treatment selection. All six U74006F-treated animals had a normal neurologic outcome at 48 hours postischemia, while the citrate vehicle-treated animals all suffered moderate to severe neurologic deficits. The difference in outcome was significant at both 24 and 48 hours (p less than 0.005). Although U74006F is a 21-aminosteroid, it is not reported to possess glucocorticoid activity. This is supported by the present finding that no changes in plasma glucose concentration were observed following administration of the drug. The systemic vitamin E levels of citrate vehicle-treated animals decreased significantly (from 4.10 +/- 0.46 micrograms/ml to 2.95 +/- 0.38 micrograms/ml, p less than 0.05), whereas the vitamin E levels in U74006F-treated animals did not decrease significantly. These results suggest that U74006F may be of benefit in improving neurologic outcome when administered prior to an episode of complete cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of nimodipine to improve neurologic outcome after eighteen minutes of cardiac arrest in the cat.

The calcium entry blocker nimodipine was administered to cats following resuscitation from 18 min of cardiac arrest to evaluate its effect on neurologic and neuropathologic outcome in a clinically relevant model of complete cerebral ischemia. Cardiac arrest (ventricular fibrillation) was maintained for 18 min and resuscitation was performed by a standardized protocol in 40 cats. Beginning at 5 min post-resuscitation, nimodipine, 10 micrograms/kg over 2 min followed by 1 microgram/kg per min for 10 h, or the same volume of placebo was administered in a randomized, blinded fashion. Neurologic deficits were scored at 2, 4, and 7 days post-resuscitation by observers blinded to the treatment group. Thirty cats were evaluated neurologically at 7 days post-resuscitation and were entered into data analysis (n = 15 per group). Neither neurologic deficit scores nor neuropathologic scores were significantly different between groups. The authors conclude that nimodipine administration in the manner and doses stated does not improve neurologic outcome in cats following resuscitation from cardiac arrest.

MK-801, an excitatory amino acid antagonist, does not improve neurologic outcome following cardiac arrest in cats.

The excitatory amino antagonist MK-801 was administered to cats following resuscitation from cardiac arrest to evaluate its effect on neurologic and neuropathologic outcome in a clinically relevant model of complete cerebral ischemia. In 29 cats studied, cardiac arrest (ventricular fibrillation) was maintained for 18 min and resuscitation was successfully performed in 21 cats. Four animals underwent a sham arrest. MK-801 or placebo was administered in a blinded, randomized manner. Beginning at 5 min post resuscitation (PR), MK-801 330 micrograms/kg over 2 min followed by 73 micrograms/kg/h for 10 h or the same volume of placebo was administered. Resuscitated animals remained paralyzed and sedated in an intensive care setting for 24-30 h PR. Neurologic examinations were performed at 2, 4, and 7 days PR by observers blinded to the treatment groups. Seventeen cats were entered into data analysis (nine MK-801-treated and eight placebo-treated). MK-801-treated animals had a significantly greater neurologic deficit score (NDS) rank (0 = normal, 100 = brain death) 2 days PR (mean rank 12.1 vs. 5.6; p = 0.008). This difference is most likely due to ongoing sedative actions of MK-801. There were no significant differences in NDS rank at 4 (10.3, MK-801 vs. 7.5, placebo) and 7 (9.6, MK-801 vs. 8.3, placebo) days PR. There were no significant differences in frontal cortex, hippocampus, occipital cortex, or cerebellar neuropathology between groups. Sham-arrested cats had normal neurologic and neuropathologic evaluations. In the circumstance of complete cerebral ischemia as employed in the current study, MK-801 had no beneficial effect upon neurologic or neuropathologic outcome.

Failure of deferoxamine, an iron chelator, to improve neurologic outcome following complete cerebral ischemia in dogs.

Eleven minutes of complete cerebral ischemia was produced in 17 dogs by temporary ligation of the venae cavae and aorta. Immediately prior to the ischemic episode, 7 dogs received deferoxamine, an iron chelator, 50 mg/kg i.v., and 10 dogs received an equivalent volume of saline placebo i.v. Five dogs failed to meet preestablished protocol criteria and were excluded from data analysis. Neurologic recovery was evaluated by an observer blind to the treatment groups in the remaining 12 dogs at 48 hours postischemia. The neurologic effects of complete cerebral ischemia were compared between dogs treated with deferoxamine and those receiving placebo treatment. One of 6 deferoxamine-treated dogs was normal and 5 were moderately to severely damaged. Similarly, 1 of 6 placebo-treated dogs was normal and 5 were moderately to severely damaged. The authors conclude that deferoxamine does not provide cerebral protection in this model of complete cerebral ischemia.

Nicardipine increases cerebral blood flow but does not improve neurologic recovery in a canine model of complete cerebral ischemia.

The effects of the calcium entry blocker nicardipine on CBF, CMRO2, and neurologic outcome following 10 min of complete cerebral ischemia were examined in dogs. In CBF and CMRO2 studies, the CBF in the untreated group (seven dogs) and the nicardipine group (seven dogs; 20 micrograms kg-1 at 30 min postischemia and a subsequent infusion of 2 micrograms kg-1 min-1 for 90 min) initially increased to 300-400% and then returned to preischemic values at 30 min postischemia. Thereafter the CBF in the untreated group significantly decreased to 50% of preischemic values for the following 90-min period (hypoperfusion), while the CBF in the nicardipine group did not differ from preischemic values. The CMRO2 in both groups decreased to approximately 50-80% of preischemic values after 15 min postischemia and did not differ between the groups throughout the study. In neurologic outcome studies, 18 dogs were divided into three groups (of six dogs each): untreated; saline infusion only, posttreated; nicardipine as in CBF and CMRO2 studies, pretreated; nicardipine 20 micrograms kg-1 at 2 min preischemia and a subsequent infusion of 2 micrograms kg-1 min-1 from immediately postischemia to 120 min postischemia. Nicardipine treatment initiated either before or after ischemia failed to improve neurologic outcome at 48 h postischemia. Thus, the increase of postischemic global CBF by nicardipine is not accompanied by neurologic recovery in a canine model of complete cerebral ischemia.