妥泰对沙土鼠脑缺血再灌注损伤保护作用的实验研究

目的 研究妥泰对沙土鼠脑缺血再灌注损伤的保护作用及作用机制。方法 采用沙土鼠双侧颈总动脉结扎制成的全脑缺血模型。56只沙土鼠随机分为假手术组、缺血组、治疗组和预防组。预防组的动物分别给予大、小剂量的妥泰(100 mg/kg、50mg/kg)灌胃观察3天而行手术,术后24小时处死动物;治疗组的动物术后立即分别给于大、小剂量的妥泰(100 mg/kg、50mg/kg)灌胃观察7天处死动物。测定各组沙土鼠血、脑组织中的MDA、SOD的含量。光镜和电镜下观察脑组织CA_1区的病理及超微结构改变。结果 与缺血组相比,妥泰治疗组和妥泰预防组脑组织中的MDA含量明显降低(P<0.01),而SOD含量明显增高(P<0.01)。光镜和电镜下观察发现,妥泰治疗组和妥泰预防组的脑CA_1区缺血改变较缺血组减轻,且大剂量组缺血改变明显减轻。结论 妥泰对沙土鼠脑缺血再灌注损伤具有良好的保护作用,且保护作用与妥泰的剂量大小有关。其脑保护作用机制之一为妥泰能有效抑制氧自由基的产生及毒性。     

Protection against ischemic brain damage using propentofylline in gerbils

We studied the xanthine derivative propentofylline (HWA 285) to determine its protection against ischemic brain damage when administered before and after ischemia. Transient forebrain ischemia was produced in 81 Mongolian gerbils by occluding both carotid arteries. The necessary surgery was performed under anesthesia with intraperitoneal pentobarbital/chloral hydrate 2 days before occlusion. We tested the parameters delayed selective hippocampal nerve cell damage, generation of seizures, and survival. Determination of the dose-response relation revealed the optimal dose of HWA 285 to be 10 mg/kg i.p. The effect of the drug on delayed selective nerve cell damage in the hippocampus was assessed by measuring the intensity of Nissl staining in the CA1 area by means of densitometry 4 days after a 10-minute occlusion. Gerbils treated with HWA 285 revealed significant protection of the CA1 neurons even when the drug was applied 1 hour after the end of the occlusion. In contrast to HWA 285, pentobarbital provided no detectable protection of the CA1 neurons in our experimental model when administered 1 hour after occlusion, suggesting different mechanisms of action. After a 15-minute occlusion, all six untreated gerbils developed convulsions and died within 2 days. Chronic (daily) treatment of nine gerbils with HWA 285 prevented the generation of convulsions in eight and allowed seven to survive for greater than 12 days.     

21-Aminosteroid lipid peroxidation inhibitor U74006F protects against cerebral ischemia in gerbils

U74006F (21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)-triene-3,20-dione, monomethane sulfonate) is a novel and potent inhibitor of central nervous system tissue lipid peroxidation that is devoid of classical steroid hormonal activities. Its possible efficacy in attenuating postischemic mortality and neuronal necrosis was examined in gerbils following 3-hour unilateral carotid artery occlusion. Male Mongolian gerbils received two intraperitoneal injections of either vehicle or U74006F (3 or 10 mg/kg), the first injection 10 minutes before and the second injection at the end of the 3-hour ischemic episode. In an initial series of experiments, vehicle-treated gerbils displayed 60.9% (14 of 23) survival 24 hours after ischemia, which decreased to 34.8% (8 of 23) at 48 hours. In contrast, the 10 mg/kg U74006F-treated group showed 86.7% (13 of 15) survival at 24 hours (p less than 0.15 vs. vehicle) and 80.0% (12 of 15) survival at 48 hours (p less than 0.02). In a second series, neurons in the hippocampal CA1 subfield and the medial and lateral cerebral cortex were counted in gerbils surviving 24 hours after unilateral carotid artery occlusion. Comparison of neuronal densities in the ischemic hemisphere with those in the contralateral nonischemic hemisphere revealed significant neuronal preservation in all three brain regions of 10 mg/kg i.p. x 2 U74006F-treated gerbils. Our results show that U74006F can improve survival and attenuate neuronal necrosis in a severe brain ischemia model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of a competitive NMDA antagonist (D-CPPene) in feline focal cerebral ischemia.

The effects of a competitive, N-methyl-D-aspartate (NMDA) receptor antagonist, D(-)E-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylic acid (D-CPPene), on the volume of ischemic brain damage was assessed by quantitative histological study in 35 chloralose-anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery and the animals were killed by transcardiac perfusion fixation 6 hours later. Pretreatment with D-CPPene (1.5, 4.5, or 15 mg/kg, administered intravenously 15 minutes prior to occlusion, with subsequent drug infusions to maintain a plateau in the plasma drug concentrations) effected dose-dependent reductions in the volume of ischemic brain damage. At the highest dose studied (15 mg/kg, plus an infusion of 170 micrograms/kg/min), D-CPPene reduced the volume of ischemic damage in the cerebral cortex by more than 75% compared to vehicle-treated control animals. The plasma concentration of D-CPPene, which is associated with a half maximal reduction in the volume of ischemic damage, was estimated to be 24 micrograms/ml during the initial 120 minutes after the middle cerebral artery occlusion. Treatment with D-CPPene (15 mg/kg, plus an infusion of 170 micrograms/kg/min) initiated 1 hour after occlusion reduced the volume of ischemic brain damage in the cerebral cortex by 30%, but this response did not achieve statistical significance. Precise definition of dose dependency for the anti-ischemic effects of NMDA antagonists and the therapeutic time window are influenced greatly by brain pharmacokinetics of the agents.(ABSTRACT TRUNCATED AT 250 WORDS)     

NMDA receptor antagonism does not inhibit induction of ischemic tolerance in gerbil brainin vivo

Effects of high and moderate affinity uncompetitive NMDA receptor antagonists (+)MK-801 and memantine on ischemic tolerance were compared in relation to telemetrically controlled brain temperature. The tolerance to an injurious 3 min test of global forebrain ischemia in Mongolian gerbils was induced 48 h earlier by 2 min preconditioning ischemia. Normothermic preconditioning was virtually harmless, and greatly reduced neurodegeneration evoked by test ischemia. In hyperthermic animals it was injurious and failed to induce tolerance. Memantine (5 mg/kg) and (+)MK-801 (3 mg/kg) injected i.p. 1 h before preconditioning did not inhibit ischemic tolerance in the normothermic gerbils, while in hyperthermic animals treated with (+)MK-801 ischemic tolerance was partially restored. Subchronic 3 day infusion of memantine (30 mg/kg/day) significantly decreased neurodegeneration, and preconditioning in the normothermic gerbils further reduced neuronal damage. Hyperthermia exacerbated preconditioning ischemia and in this way reduced expression of tolerance, while (+)MK-801 partially reversed this effect. Our results do not confirm previous reports on the role of NMDA receptors in the induction of ischemic tolerance in gerbils.     

The highly selective cyclooxygenase-2 inhibitor DFU is neuroprotective when given several hours after transient cerebral ischemia in gerbils

Several studies suggest that cyclooxygenase-2 contributes to the delayed progression of ischemic brain damage. In this study we examined whether the highly selective cyclooxygenase-2 inhibitor DFU reduces neuronal damage when administered several hours after 5 min of transient forebrain ischemia in gerbils. The extent of ischemic injury was assessed behaviorally by measuring the increases in locomotor activity and by histopathological evaluation of the extent of CA1 hippocampal pyramidal cell injury 7 days after ischemia. DFU treatment (10 mg/kg, p.o.) significantly reduced hippocampal neuronal damage even if the treatment is delayed until 12 h after ischemia. These results suggest that selective cyclooxygenase-2 inhibitors may be a valuable therapeutic strategy for ischemic brain injury.     

Effect of indomethacin on edema following single and repetitive cerebral ischemia in the gerbil

BACKGROUND AND PURPOSE: Repetitive periods of cerebral ischemia result in more severe injury than a single period of ischemia of similar total duration. We investigated the possibility of prostaglandin mediation of this increased injury by attempting to modify brain edema formation with indomethacin pretreatment. METHODS: Under halothane/N2O anesthesia, groups of gerbils underwent bilateral carotid occlusion to induce forebrain ischemia. Group I underwent a single 15-minute period of carotid occlusion. Group II underwent three 5-minute periods of occlusion at hourly intervals. Groups III and IV were similar to groups I and II, respectively, but received 0.2 mg/kg indomethacin before carotid occlusion. Cortical and cerebellar water and sodium contents were determined in control animals (n = 6) at time zero and in experimental animals 24, 48, and 72 hours after ischemia (n = 6-10 gerbils/group at each time point). RESULTS: Cortical water and sodium contents in group II peaked 48 hours after insult (82.15 +/- 0.31% and 420 +/- 14 meq/kg dry wt, respectively) and were significantly higher than control and group I values at both 24 and 48 hours. Cortical water did not change from control in group I animals. Indomethacin pretreatment significantly attenuated increases in water and sodium content seen at 48 hours in gerbils undergoing repetitive ischemia (peak 80.02 +/- 0.45% and 300 +/- 39 meq/kg dry wt), but did not affect mortality. CONCLUSIONS: Indomethacin lessens edema after repetitive cerebral ischemia, suggesting that elevations of cyclooxygenase products are responsible, at least in part, for severe brain edema following repetitive ischemia.     

Protective effects of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane) on acutely induced cerebral ischemia in Mongolian gerbils and spontaneously hypertensive rats (SHR)

Effects of new antihypoxic agent (bifemelane) on survival and brain metabolism were studied in acute cerebral ischemia induced by bilateral carotid artery ligation in mongolian gerbils and SHR. Either 10 mg/kg or 30 mg/kg body weight of bifemelane solved in distilled water was intraperitoneally administered 1 hr in gerbils and 1.5 hrs in SHR prior to carotid ligation, and same amount of vehicle was also given in similar manner for control animals. Brain tissue metabolites such as lactate, pyruvate and ATP were determined by using the enzymatic technique in the ischemic brain frozen in situ 1 hr after carotid ligations in SHR. Mean survival times following carotid ligations were 186 +/- 255 min (+/- SD) in control gerbils, 429 +/- 455 min in those with 10 mg/kg of bifemelane, and 310 +/- 429 min in those with 30 mg/kg respectively, its difference between control and 10 mg/kg group being significant (P less than 0.05). Supratentorial lactate concentrations in the ischemic brains of SHR were substantially the same among the groups, whereas ATP levels were 0.62 +/- 0.24 mM/kg in control animals, 1.10 +/- 0.67 mM/kg in rats with 10 mg/kg of the drug, and 1.13 +/- 0.42 mM/kg in those with 30 mg/kg, respectively. In animals with a high dose pretreatment, the reduction of ATP was significantly smaller than that in control (P less than 0.02), indicating that this agent prevents a decline of high energy phosphate in the ischemic brain although anaerobic metabolites increase similarly in animals of all experiment groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of the 21-aminosteroid U74006F in improving neurological recovery after spinal cord injury in rats.

The efficacy of three different regimens of the 21-aminosteroid U74006F in counteracting the neurological damage after spinal cord compression causing paraparesis in rats was investigated. Three groups of ten animals each were given totally 6 mg/kg of U74006F in different regimens beginning one hour after injury (A: bolus doses of 1.5 mg/kg at 1, 4, 7 and 10 hours; B: bolus of 1.5 mg/kg at 1 hour and 4.5 mg/kg as an infusion over the next 9 hours; and C: infusion alone, 6 mg/kg, given between 1 and 10 hours after trauma). Two groups of ten animals each received vehicle alone in administration modes comparable to those of the U74006F treated animals. The motor function was assessed daily on the inclined plane. On day one, the capacity angle had decreased from about 62 degrees preoperatively to 28-30 degrees in the two vehicle-treated groups and in group C. In these groups there was a similar improvement in neurological function and on day 9 the capacity angles were 49-55 degrees. In groups A and B, both of which received a bolus dose of U74006F at 1 hour, the neurological outcome improved on day one with capacity angles of 38-40 degrees. The difference in neurological function between the animals given U74006F as bolus doses and those given vehicle alone persisted over the entire observation span until day 9. The data suggest that early treatment with a bolus dose seems to be required in order to obtain an effect of U74006F on neurological recovery.     

Electroconvulsive shock and postsynaptic catecholamine effects: Increased psychomotor stimulant action of apomorphine and clonidine in reserpine pretreated mice by repeated ECS

Male mice were administered electric convulsive shocks (ECS) once daily for one (ECS X I), three (ECS X III) or seven days (ECS X VII). One (day 1), three (day 3) or six days (day 6) later they received reserpine 10 mg/kg, followed 2 hours later by clonidine, 1.5 mg/kg, and/or apomorphine, 1.5 mg/kg. Control animals received the same drug treatments but no ECS. The motor activity was recorded for 1 hour, starting immediately after the last drug injection. The behavioral depression induced by reserpine was equally pronounced in ECS-pretreated animals as in the control animals. The psychomotor stimulant effects of clonidine and/or apomorphine, given after reserpine was, however, enhanced by pretreatment with ECS X VII, DAY 1. Pretreatment wit- ECS X VII increased the motor activity also in animals given reserpine, apomorphine and clonidine at day 3 or day 6. ECS X III was also effective in this respect at day 1, whereas ECS X I, day 1, was ineffective. Mice given ECS X VII but no drug treatment showed at day 1 an increased motor activity during the initial 10 min and a decreased activity during the last 10 of the 1 hour recording period. At day 3 and day 6 after ECS X VII the motor activity was increased in comparison to that in untreated control animals during the whole 1 hour period. Animals given repeated ECS furthermore showed increased irritability and reduced body weight. The results indicate that repeated ECS increase the sensitivity of postsynaptic catecholamine receptors in the brain or alter neuronal structures which are connected to these receptors.     

5-Aminoimidazole-4-carboxamide riboside (AICAr) administration reduces cerebral ischemic damage in the Mongolian gerbil

Cerebral ischemic damage in gerbils was assessed by locomotor activity studies and histopathological examination of the hippocampal CA1 pyramidal cell layer. Pretreatment with AICAr (50 and 500 mg/kg) 30 min prior to a 5-min ischemic episode in unanesthetized gerbils, significantly attenuated the degree of ischemic neuronal damage as measured by either technique with the 500 mg/kg dose; the 50 mg/kg dose, although showing a trend, was not significant. A potential mechanism for AICAr-induced cerebroprotection may be that it is metabolized to uric acid, a free radical scavenger.     

Nicardipine reduces ischemic brain injury. Magnetic resonance imaging/spectroscopy study in cats

We investigated whether the calcium channel entry blocker nicardipine would reduce ischemic brain damage in barbiturate-anesthetized cats subjected to permanent unilateral occlusion of the middle cerebral artery. The evolution of cerebral injury was assessed in vivo in 24 cats by a combination of proton magnetic resonance imaging and phosphorus-31 magnetic resonance spectroscopy for 5 hours following occlusion. Immediately thereafter, the volume of histochemically ischemic brain tissue was determined planimetrically in triphenyl tetrazolium chloride-stained serial coronal sections. Nicardipine was initially administered as an intravenous bolus injection of 10 mg/kg/hr 15 minutes before or 15 minutes after occlusion, followed by continuous infusion at 8 mg/kg/hr for the 5 hours of the experiment. Compared with untreated controls, cats that received nicardipine before or after occlusion showed a significant reduction in the extent of edema in the ipsilateral cerebral cortex, internal capsule, and basal ganglia. The results of phosphorus-31 magnetic resonance spectroscopy studies suggest that nicardipine may protect against cerebral ischemic damage by an action on cellular metabolic processes that preserve high-energy phosphates during the ischemic period.     

Effects of clomethiazole on radial-arm maze performance following global forebrain ischemia in gerbils

The functional and neuroanatomical protective effects of clomethiazole (CMZ) were examined in an animal model of global forebrain ischemia. Gerbils underwent sham-surgery or were rendered ischemic by the application of aneurysm clips to both carotid arteries for 6 min. Three treatment groups received CMZ (50 mg/kg, 100 mg/kg, or 150 mg/kg) 30 min before ischemia, and one group was given 150 mg/kg of CMZ 30 min after ischemia. Following recovery, the gerbils were tested in a radial-arm maze to assess memory functions. Histological evaluation was assessed blindly using a percentile scoring system. The results indicate that pre-ischemic treatment with 100 mg/kg and 150 mg/kgof CMZ reduced brain damage and working memory errors significantly. Treatment dosage of150 mg/kg of CMZ was the most effective in preventing neuronal damage in the hippocampus and eliminating the working memory deficit typically induced by ischemia.     

Experimental cerebral ischemia produces platelet aggregates

Human studies indicate that transient platelet abnormalities accompany acute cerebral ischemia. Although these abnormalities may precipitate the ischemi process, ischemia could also alter platelet function. Platelets were therefore studied in gerbils subjected to 1 hour of unilateral carotid artery occlusion. Venous blood from five clinically affected gerbils contained more aggregated platelets (37.8% +/- 6.4) than did blood from eight unaffected animals (11.1% +/- 3.0; p less than 0.01). Platelets labeled with 3H-serotonin were increased in ischemic brain; the ratio of radioactivity in the ipsilateral versus contralateral hemisphere was greater in eight affected (1.09 +/- 0.03) than in 19 unaffected (1.00 +/- 0.01; p less than 0.02) animals. The radioactive serotonin was located predominantly within blood vessels. Cerebral ischemia thus stimulated the formation of platelet aggregates, a response which could contribute to the ischemic process.     

Free radical scavenger protects against inner hair cell loss after cochlear ischemia

We investigated the protective effects of edaravone, a free radical scavenger, against ischemic damage of inner hair cells (IHCs) in gerbils. Cochlear ischemia was induced in the animals by occluding the vertebral arteries bilaterally for 15 min. Edaravone (1 mg/kg, i.v.) or saline was administered 1 h after ischemia. Hearing was assessed by auditory brain response (ABR). In animals treated with saline, the ABR threshold shift was 24.1 dB and there was a 26.5% decrease in the number of IHCs. By contrast, in animals treated with edaravone, the threshold shift was 7.5 dB and only 8.8% of IHCs was lost. These results suggest that edaravone protects against damage to the inner ear following transient ischemia.     

Interleukin-1 receptor antagonist attenuates regional neuronal cell death and cognitive dysfunction after experimental brain injury.

The effect of systemic administration of human recombinant interleukin-1 receptor antagonist (rhIL-1ra) on behavioral outcome and histopathologic damage after lateral fluid-percussion brain injury of moderate severity was evaluated. In study 1, brain-injured Sprague Dawley rats received timed subcutaneous injections beginning 15 minutes after injury of either 100 mg/kg rhIL-1ra (high dose, total dose = 1900 mg/kg), 10 mg/kg rhIL-1ra (low dose, total dose = 190 mg/kg), or vehicle over 7 days. No effect of low-dose rhIL-1ra was observed in study 1. High-dose rhIL-1ra significantly attenuated posttraumatic neuronal loss in the injured hippocampal CA3 region (P < 0.05), dentate hilus (P < 0.05), and cortex (P < 0.05) but impaired recovery of motor function at 7 days after trauma (P < 0.05). In study 2, rats were pretrained to learn a visuospatial task in a Morris water maze, subjected to fluid-percussion brain injury or sham treatment, and randomly assigned to receive multiple subcutaneous injections at timed intervals of 100 mg/kg rhIL-1ra (total dose = 900 mg/kg) or vehicle over 42 hours, followed by continuous infusion of a lower concentration of rhIL-1ra (20 mg/kg/day, total dose = 100 mg/kg), or vehicle for 5 days using subcutaneously implanted osmotic minipumps. Postinjury administration of rhIL-1ra significantly attenuated cognitive deficits compared with vehicle-treated animals at 42 hours (P < 0.05) but did not affect motor function at 48 hours, 1 week, and 2 weeks. These results suggest that inhibitors of cytokine pathways may be therapeutically useful for the treatment of brain trauma.     

Prediction of cerebral ischemia by ophthalmoscopy after carotid occlusion in gerbils.

BACKGROUND AND PURPOSE: The Mongolian gerbil provides a unique model of unilateral focal cerebral ischemia because of the lack of posterior communicating arteries in all gerbils as well as an absence of an anterior communicating artery in approximately 20% of the gerbil population. It is unclear how to identify unequivocably the subpopulation of animals that would suffer a severe focal cerebral ischemia after unilateral carotid occlusion. METHODS: Ninety-three male gerbils were exposed to unilateral occlusion of the right common carotid artery. The severity of neuronal loss was evaluated histologically in gerbils selected as having significant focal ischemia based on either behavioral criteria (i.e., the demonstration of stereotypical behavior within 1 hour after occlusion) or ophthalmoscopic criteria (i.e., interruption of the retinal arterial perfusion within 10 minutes of carotid ligation as assessed with an ophthalmoscope). After 3 hours of unilateral carotid occlusion, cerebral blood flow was reinstated for 24 hours before fixation for histological analysis. The viability of the CA1 region of the hippocampus, lateral cortex, and medial cortex was scored on a scale of 0-4 based on the percentage of apparent neuronal loss (e.g., 0, no damage; 4, > 75% damage (the Viability Index). RESULTS: Twenty-eight percent of the gerbils met the behavioral selection criteria, and 17% met the ophthalmoscopic criteria. In the specimens selected by behavioral criteria (n = 7), 30% demonstrated no evidence of postischemic neuronal loss; the mean +/- SEM Viability Index scores for CA1, lateral cortex, and medial cortex were 1.6 +/- 0.6, 1.0 +/- 0.3, and 0.3 +/- 0.2, respectively. Of the animals selected by ophthalmoscopic criteria (n = 12), 100% had severe ischemic tissue damage to the ipsilateral hemisphere; the Viability Index scores for CA1, lateral cortex, and medial cortex were 3.5 +/- 0.1, 3.1 +/- 0.2, and 1.2 +/- 0.2, respectively; all scores were significantly larger than those observed in the behaviorally selected group. CONCLUSIONS: Selection of animals by ophthalmoscopic criteria provides a reliable, consistent method to predict animals with severe focal cerebral ischemia.     

Ischaemic brain damage in the gerbil in the absence of ''no-reflow''.

Approximately 40% of gerbils subjected to one hour of unilateral carotid artery occlusion displayed neurological abnormalities during that time. Most such animals were subsequently found to have ischaemic neuronal alterations within the territory of the ipsilateral middle cerebral artery. In contrast, impaired reperfusion ('no-reflow') rarely occurred and cannot therefore be implicated in the pathogenesis of ischaemic brain damage.     

Protection against oxidative damage to CNS by α-phenyl-tert-butyl nitrone (PBN) and other spin-trapping agents: A novel series of nonlipid free radical scavengers

Brain is extremely susceptible to oxidative damage. Utilizing a series of novel approaches, we have demonstrated that oxidative damage occurs during an ischemia/reperfusion insult (IRI) to brain. Thus, we have demonstrated that an IRI to Mongolian gerbil brain results in: (1) an enhanced rate of salicylate hydroxylation, implicating an increased flux of hydroxyl free radicals; (2) an enhanced flux of free radicals as determined by spintrapping; (3) an enhanced level of endogenous protein oxidation; (4) a decrease in glutamine synthetase (GS) activity, an enzyme very sensitive to oxidative damage; and (5) demonstration of protection from an IRI by administering the spin-trapping agent α-phenyl-tert-butyl nitrone (PBN). The novel observation that PBN offers protection from the lethality brought on by a brain IRI appears to be clearly linked to the ability of the administered spin-trap to inhibit oxidative damage as evidenced by the decreased amount of brain protein oxidation and the prevention of an IRI-mediated loss of GS activity in treated animals. Aged gerbils are more sensitive to the lethal action of a brain IRI than younger animals, but they are protected by PBN administration as are the younger animals. Older gerbils have a significantly higher level of oxidized protein in the brain. Older gerbils have decreased activities of GS and neutral protease, the enzyme that removes oxidized protein, than younger animals. Chronic twice daily administration of PBN (32 mg/kg) for 14 days to older animals significantly lowered brain oxidized protein levels and raised GS and neutral protease activity to those observed in younger animals. Cessation of PBN administration resulted in a time-dependent restoration of protein oxidation levels and enzyme activities back to those observed prior to spin-trap administration. Older gerbils exhibit significantly higher errors in a radial arm maze than younger animals, but older gerbils that had received chronic daily treatments of PBN (32 mg/kg) for 14 days committed significantly less errors than untreated controls. The errors committed in PBN-treated animals was decreased down to the level of those observed in younger animals. Clearly the spin-trapping agent, PBN, appears to have promise in: (1) elucidation of the role of oxidative damage in normal brain function during aging, (2) understanding the development of pathological conditions, and (3) development of treatment regimens for prevention of damage that occurs during the development of pathological conditions and in aging.     

Quantitative analysis of effects of kappa-opioid agonists on postischemic hippocampal CA1 neuronal necrosis in gerbils

The ability of the kappa-opioid receptor agonists U50488H and U62066E (spiradoline mesylate) compared with the non-kappa close structural analogue U54494A to affect postischemic necrosis of the selectively vulnerable hippocampal CA1 neurons was examined in male Mongolian gerbils. The gerbils were treated with either saline vehicle or 10 mg/kg i.p. of one of the test drugs 30 minutes before and again 2 hours after a 10-minute period of bilateral carotid artery occlusion or sham occlusion under light methoxyflurane anesthesia. Seven days after ischemia and reperfusion the brains were perfusion-fixed, and hippocampal CA1 cells were counted in a blind fashion. In ischemic gerbils that received only vehicle, there was a 78.9% loss of CA1 neurons compared with sham-occluded gerbils. In contrast, in U50488H-treated gerbils, mean cell loss was reduced to 33.9% (p less than 0.01 vs. vehicle-treated group). U62066E was even more effective in reducing postischemic CA1 degeneration to only 20.7% (p less than 0.0001 vs. vehicle-treated group). However, treatment with the non-kappa analogue U54494A did not cause any apparent protection; the gerbils in this group showed an 80.7% loss of CA1 neurons. Our results are consistent with the hypothesis that kappa-receptor stimulation is associated with improved postischemic neuronal preservation.