Hydroxyl radical generation after the third hour following ischemia contributes to brain damage

The effects of 10 antiallergic drugs (astemizole, azelastine, ebastine, emedastine, epinastine, ketotifen, oxatomide, terfenadine, pemirolast and tranilast) on neuronal dopamine uptake were examined. Some drugs examined showed a concentration-dependent inhibition of [3H]dopamine uptake into synaptosomal preparations of the rat striatum. The inhibition constant (Ki) values were 231-876 nM for ebastine, terfenadine, oxatomide and astemizole. The specific binding of [3H] (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine) (GBR12935) to the rat striatal membranes was also inhibited by these antiallergic drugs. There was a good correlation between the degrees of inhibition of [3H]dopamine uptake and [3H]GBR12935 binding. Then, the behavioral excitement induced by L-DOPA (100 mg/kg, s.c.) plus pargyline hydrochloride (80 mg/kg, i.p.) in mice was significantly enhanced by i.p. treatment with ebastine (10 mg/kg) and astemizole (5 mg/kg). These results suggest that the neuronal dopamine uptake is inhibited by some antiallergic drugs, especially ebastine.     

Cerebral microembolism in patients with retinal ischemia

BACKGROUND AND PURPOSE: We investigated the frequency of cerebral microembolism detected by transcranial Doppler ultrasonography in patients with clinical evidence of retinal ischemia, including transient monocular blindness, central and branch retinal artery infarction, and ischemic oculopathy, and assessed its correlation with carotid artery stenosis. METHODS: Records of 331 consecutive patients examined during a 47-month period at the Neurovascular Laboratory were reviewed. Of the original 453 intracranial arteries, 186 middle cerebral arteries (MCAs) satisfied qualifying criteria that excluded patients with cardiac embolic sources. Forty-five MCAs ipsilateral to the symptomatic eye constituted the study group. The control group consisted of 141 asymptomatic MCAs. Microembolus detection studies were performed on transcranial Doppler instruments equipped with special software, and the degree of carotid artery stenosis was measured by cerebral or MR angiography or by color duplex studies. RESULTS: Microembolism was detected in 40.0% of study MCAs and 9.2% of controls (P < 0.001). In the study group, microembolic signals were detected in 61.9% of MCAs tested within a week of symptom onset and 20.8% of those tested afterward (P < 0.001). Severe (> or = 70%) carotid stenosis or occlusion was more frequent in the study group (P < 0.001). Microembolic signals were detected in 25.3% and 11.2%, respectively, of MCAs distal to carotid arteries with 70% to 100% and 0% to 69% stenosis (P = 0.013). CONCLUSIONS: In patients without cardiac embolic sources, cerebral microembolism is frequently present on the side of retinal ischemia, particularly during the week after onset of symptoms. It is often associated with severe stenosis or occlusion of the ipsilateral carotid artery.     

Fastigial stimulation increases ischemic blood flow and reduces brain damage after focal ischemia

Electrical stimulation of the cerebellar fastigial nucleus (FN) increases CBF and reduces brain damage after focal ischemia. We studied whether FN stimulation "protects" the brain from ischemic damage by increasing blood flow to the ischemic territory. Sprague-Dawley rats were anesthetized (halothane 1-3%) and artificially ventilated through a tracheal cannula inserted transorally. CBF was monitored by a laser-Doppler probe placed over the convexity at a site corresponding to the area spared from infarction by FN stimulation. Arterial pressure (AP), blood gases, and body temperature were controlled, and the electroencephalogram (EEG) was monitored. The stem of the middle cerebral artery (MCA) was occluded. After occlusion, the FN was stimulated for 60 min (100 microA; 50 Hz; 1 s on-1 s off) while AP was maintained at 97 +/- 11 mm Hg (mean +/- SD) by controlled hemorrhage. Rats were then allowed to recover, and infarct volume was determined 24 h later in thionin-stained sections. In unstimulated rats (n = 7), proximal MCA occlusion reduced CBF and the amplitude of the EEG. One day later, these rats had infarcts involving neocortex and striatum. FN stimulation after MCA occlusion (n = 12) enhanced CBF and EEG recovery [61 +/- 34 and 73 +/- 43%, respectively at 60 min; p < 0.05 vs. unstimulated group; analysis of variance (ANOVA)] and reduced the volume of the cortical infarct by 48% (p < 0.05). In contrast, hypercapnia (PCO2 = 64 +/- 4; n = 7) did not affect CBF and EEG recovery or infarct volume (p > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of the pathogenesis of glutamate neurotoxicity in retinal ischemia

PURPOSE: This study was carried out to examine the involvement of glutamate and nitric oxide neurotoxicity in ischemia/reperfusion-induced retinal injury in vivo. METHODS: We monitored glutamate release from in vivo cat retina during and after pressure-induced ischemia using a microdialysis technique. Morphometric studies were performed to study the effects of MK-801 (dizocilpine), L-NAME (N omega-nitro-L-arginine methyl ester), and D-NAME (N omega-nitro-D-arginine methyl ester) on the histological changes in the rat retina induced by ischemia or intravitreal injection of NMDA (N-methyl-D-aspartate; 200 nmol). RESULTS: A large release of glutamate occurred during ischemia, followed by a marked release after reperfusion. Histological changes occurred selectively in the inner part of the retina after ischemia as well as intravitreal injection of NMDA. Pretreatment with intravenous injection of MK-801 or L-NAME significantly inhibited the ischemic injury of the inner retina. Intravitreal injection of L-NAME inhibited NMDA-induced neurotoxicity in the retina. CONCLUSION: These findings indicate that nitric oxide mediates neurotoxic actions of glutamate which are responsible for ischemic injury in the retina.     

Microvascular permeability of the non-heart-beating rabbit lung after warm ischemia and reperfusion: role of neutrophil elastase

STUDY OBJECTIVES: Criteria used to define the respective roles of pulmonary mechanics and cardiovascular disease in limiting exercise performance are usually obtained at peak exercise, but are dependent on maximal patient effort. To differentiate heart from lung disease during a less effort-dependent domain of exercise, the predictive value of the breathing reserve index (BRI=minute ventilation [VE]/maximal voluntary ventilation [MVV]) at the lactate threshold (LT) was evaluated. DESIGN: Thirty-two patients with COPD and a pulmonary mechanical limit (PML) to exercise defined by classic criteria at maximum oxygen uptake (VO2max) were compared with 29 patients with a cardiovascular limit (CVL) and 12 normal control subjects. Expired gases and VE were measured breath by breath using a commercially available metabolic cart (Model 2001; MedGraphics Corp; St. Paul, Minn). Arterial blood gases, pH, and lactate were sampled each minute during exercise, and cardiac output (Q) was measured by first-pass radionuclide ventriculography (System 77; Baird Corp; Bedford, Mass) at rest and peak exercise. RESULTS: For all patients, the BRI at lactate threshold (BRILT) correlated with the BRI at VO2max (BRIMAX) (r=0.85, p<0.0001). The BRILT was higher for PML (0.73+/-0.03, mean+/-SEM) vs CVL (0.27+/-0.02, p<0.0001), and vs control subjects (0.24+/-0.03, p<0.0001). A BRILT > or = 0.42 predicted a PML at maximum exercise, with a sensitivity of 96.9%, a specificity of 95.1%, a positive predictive value of 93.9%, and a negative predictive value of 97.5%. CONCLUSIONS: The BRILT, a variable measured during the submaximal realm of exercise, can distinguish a PML from CVL.     

Ultrasound enhanced thrombolysis in experimental retinal vein occlusion in the rabbit

Live virus vaccines have in many cases proven to be an extremely effective tool for the prevention of viral diseases. However, the production of conventional live vaccines in eukaryotic cell cultures has many disadvantages, including the potential for contamination with adventitious agents and genetic alterations during propagation, making it necessary to do extensive testing before distribution. Based on results obtained with a flavivirus (tick-borne encephalitis virus) in an experimental animal system, we propose a novel live attenuated virus vaccination strategy consisting of the application of in vitro-synthesized infectious RNA instead of the live virus itself. When administered using the GeneGun, less than 1 ng of RNA was required to initiate replication of virus that was attenuated by a specifically engineered deletion and this induced a protective immunity in laboratory mice. Because this approach uses RNA, it does not have the potential drawbacks of DNA vaccines and thus combines the advantages of conventional live virus vaccines (for example, mimicking natural infection and inducing long-lasting immunity) with those of nucleic acid-based vaccines (for example, ease of production without a requirement for eukaryotic cell culture, stability and purity).     

Promoter analysis of RPE65, the gene encoding a 61-kDa retinal pigment epithelium-specific protein

OBJECTIVES: This study compared the long-term effects of complete atrioventricular junction (AVJ) ablation with those of AVJ modification in patients with medically refractory atrial fibrillation (AF). BACKGROUND: Comparisons between the long-term effects of AVJ ablation with those of AVJ modification in patients with medically refractory AF have not been systematically studied. METHODS: Sixty patients with medically refractory AF were randomly assigned to receive complete AVJ ablation with permanent pacing or AVJ modification. Subjective perception of quality of life (QOL) was assessed by a semiquantitative questionnaire before and 1 and 6 months after ablation. Cardiac performance was evaluated by echocardiography and radionuclide angiography within 24 h (baseline) and at 1 and 6 months after ablation. RESULTS: Both methods were associated with significant improvement in general QOL and a significant reduction in the frequency of major symptoms and symptoms during attacks. The frequency of hospital admission and emergency room visits and antiarrhythmic drug trials significantly decreased after ablation in both groups. However, patients after complete AVJ ablation had a significantly greater improvement in general QOL and a significantly reduced frequency of major symptoms and symptoms during attacks (including palpitation, dizziness, chest oppression, blurred vision and syncope). Left ventricular (LV) systolic function and the ability to perform activities of daily life significantly improved after ablation in patients with depressed LV function in both groups. All improvements after ablation or modification were maintained over the 6-month follow-up period. CONCLUSIONS: AVJ ablation with permanent pacing, as compared with AVJ modification, had a significantly greater ability to decrease the frequency of attacks and the extent of symptoms of AF, and the patients who received this procedure were more satisfied with their general well-being.     

Angiographic and histological evaluation of porcine retinal vascular damage and protection with perfluorocarbons after massive air embolism

BACKGROUND AND PURPOSE: We have previously shown that perfluorocarbon emulsions (PFEs) reduce the severity of cerebral injury (indicated by infarct, reduced blood flow, and depressed EEG) induced by air embolism during cardiopulmonary bypass (CPB). This study used retinal fluorescein angiography to define the mechanisms of cerebral injury and to determine the efficacy of PFEs in cerebral protection. These angiographic findings were correlated to previously reported histologic findings. METHODS: Twenty domestic pigs underwent CPB with a prime of standard crystalloid or PFE (5 mg/kg) and crystalloid. After 10 minutes on CPB, a single (5 mL/kg) or double (2x2.5 mL/kg) bolus of room air or saline (control) was delivered via the right carotid artery. Retinal fluorescein angiograms were captured at 4 time points: baseline, air insult, postbypass, and postreperfusion. Following euthanasia, both eyes were removed and the retinas isolated for histological analysis with horseradish peroxidase (HRP), as previously reported. RESULTS: In control pigs, postreperfusion angiograms showed small nonperfused areas, and retinal whole mounts demonstrated vascular damage as previously reported. In 5 PFE-primed animals, postreperfusion angiograms showed hyperfluorescence, but angiograms and HRP mounts were otherwise not significantly different from baseline. Severely hyperfluorescent vessels observed angiographically also showed a correlation with HRP extravasation but were not consistently indicative of severe vascular damage. CONCLUSIONS: Retinal fluorescein angiography and retinal staining with HRP indicate that mechanisms of cerebral air embolism include nonperfusion, vascular leakage and spasm, red blood cell sludging, and hemorrhage. Priming with PFE prevented many of the sequelae associated with air embolism.     

Is reperfusion injury an important cause of mucosal damage after porcine intestinal ischemia?

BACKGROUND: Intestinal ischemic injury is exacerbated by reperfusion in rodent and feline models because of xanthine oxidase-initiated reactive oxygen metabolite formation and neutrophil infiltration. Studies were conducted to determine the relevance of reperfusion injury in the juvenile pig, whose low levels of xanthine oxidase are similar to those of the human being. METHODS: Ischemia was induced by means of complete mesenteric arterial occlusion, volvulus, or hemorrhagic shock. Injury was assessed by means of histologic examination and measurement of lipid peroxidation. In addition, myeloperoxidase, as a marker of neutrophil infiltration, and xanthine oxidase-xanthine dehydrogenase were measured. RESULTS: Significant ischemic injury was evident after 0.5 to 3 hours of complete mesenteric occlusion or 2 hours of shock or volvulus. In none of these models was the ischemic injury worsened by reperfusion. To maximize superoxide production, pigs were ventilated on 100% O2, but only limited reperfusion injury (1.2-fold increase in histologic grade) was noted. Xanthine oxidase-xanthine dehydrogenase levels were negligible (0.4 +/- 0.4 mU/gm). CONCLUSIONS: Reperfusion injury may not play an important role in intestinal injury under conditions of complete mesenteric ischemia and low-flow states in the pig. This may result from low xanthine oxidase-xanthine dehydrogenase levels, which are similar to those found in the human being.     

Reperfusion injury: demonstration of brain damage produced by reperfusion after transient focal ischemia in rats

During reperfusion after ischemia, deleterious biochemical processes can be triggered that may antagonize the beneficial effects of reperfusion. Research into the understanding and treatment of reperfusion injury (RI) is an important objective in the new era of reperfusion therapy for stroke. To investigate RI, permanent and reversible unilateral middle cerebral artery/common carotid artery (MCA/CCA) occlusion (monitored by laser Doppler) of variable duration in Long-Evans (LE) and spontaneously hypertensive (SH) rats and unilateral MCA and bilateral CCA occlusion in selected LE rats was induced. In LE rats, infarct volume after 24 hours of permanent unilateral MCA/CCA occlusion was 31.1 +/- 34.6 mm3 and was only 28% of the infarct volume after 120 to 300 minutes of reversible occlusion plus 24 hours of reperfusion, indicating that 72% of the damage of ischemia/reperfusion is produced by RI. When reversible ischemia was prolonged to 480 and 1080 minutes, infarct volume was 39.6 mm3 and 16.6 mm3, respectively, being indistinguishable from the damage produced by permanent ischemia and significantly smaller than damage after 120 to 300 minutes of ischemia. Reperfusion injury was not seen in SH rats or with bilateral CCA occlusion in LE rats, in which perfusion is reduced more profoundly. Reperfusion injury was ameliorated by the protein synthesis inhibitor cycloheximide or spin-trap agent N-tert-butyl-alpha-phenylnitrone pretreatment.     

Development of cell markers in subretinal rabbit retinal transplants

Retinas from embryonic rabbits at day E15 were transplanted to the subretinal space in adult rabbits. After survival times between 7 and 193 days, the rabbits were killed, and the transplants were processed for immunohistochemistry. The results show that subretinal transplants from embryonic rabbit retinas develop many, if not all, retinal neuronal types. The cells show approximately normal morphology and express a variety of cell-type-specific markers: photoreceptor cells express visual pigment proteins as identified by antibodies against rhodopsin (R2-15), color-specific cone pigments (COS-1, OS-2) and the cone specific antigen 50-1B11, rod bipolar cells express PKC, horizontal cells HPC-1 antigen and neurofilament 160 kDa, amacrine cells HPC-1 antigen, GABA and neurofilament 160 kDa, and glial cells express vimentin and glial fibrillary acidic protein. The high degree of rosette formation seen in many young grafts, diminishes with time; many transplant cells disappear, and the remaining cells present a less prominent formation of rosettes.     

Ischemic damage and subsequent proliferation of oligodendrocytes in focal cerebral ischemia

In order to achieve a better understanding of the pathophysiology of ischemic white matter lesions, oligodendrocytic degeneration and subsequent proliferation were examined in the mouse model of middle cerebral artery occlusion. In situ hybridization histochemistry for proteolipid protein messenger RNA was employed as a sensitive and specific marker of oligodendrocytes, and immunohistochemistry for myelin basic protein was used as a compact myelin marker. Immunohistochemistry for microtubule-associated protein 2 and albumin was employed to monitor neuronal degeneration and the breakdown of the blood brain barrier, respectively. In the ischemic core of the caudoputamen, the immunoreactivity for microtubule-associated protein 2 disappeared and massive albumin extravasation occurred several hours after vessel occlusion, while proteolipid protein messenger RNA signals remained relatively strong at this time. The messenger RNA signals began to attenuate 12 h after ischemia and were hardly detectable 24 h after ischemia in the whole ischemic lesion. In situ end-labeling of fragmented DNA showed some cells with proteolipid protein messenger RNAs to have DNA fragmentation at this period. In contrast to proteolipid protein messenger RNA signals, the immunoreactivity for myelin basic protein was detected as long as five days after ischemia. An apparent increase in the cells possessing strong proteolipid protein messenger RNA signals was found five days after ischemia, mainly in the corpus callosum and the cortex bordering the infarcted areas. A double simultaneous procedure with in situ hybridization for proteolipid protein messenger RNA and immunohistochemistry for glial fibrillary acid protein or lectin histochemistry for macrophages/microglia showed proliferating oligodendrocytes to be co-localized with reactive astrocytes and macrophages/microglia. These findings show that oligodendrocytic damage occurred following ischemic neuronal damage and the breakdown of the blood brain barrier, but preceded the breakdown of myelin proteins in the ischemic lesion, that an apoptosis-like process was involved in ischemic oligodendrocytic death, and that surviving oligodendrocytes responded and proliferated in the outer border of the infarcted area.     

In vivo evaluation of leukocyte dynamics in retinal ischemia reperfusion injury

PURPOSE: To evaluate quantitatively leukocyte dynamics in vivo in the rat retinal microcirculation during ischemia reperfusion injury with the use of acridine orange digital fluorography. METHODS: Retinal ischemia was induced in anesthetized pigmented rats by a temporary ligation of the optic nerve. After 60 minutes of ischemia, leukocyte behavior in the retinal microcirculation was evaluated, with acridine orange digital fluorography--consisting of a scanning laser ophthalmoscope and the fluorescent nuclear dye, acridine orange--during reperfusion at 1, 2, 4, 6, 12, 24, 48, 96, and 168 hours. The obtained images were recorded on videotape and analyzed with a computer-assisted image analysis system. RESULTS: Rolling leukocytes along the major retinal veins were observed in treated rats during the reperfusion period; no rolling leukocytes were observed in the control rats. The number of rolling leukocytes gradually increased and peaked at 102 +/- 40 cells/minute 12 hours after reperfusion; few rolling leukocytes were observed at 96 hours. The velocity of rolling leukocytes at 12 hours (19.1 +/- 3.5 microns/second; P < 0.05) was significantly lower than that at the other three times. No rolling leukocytes were observed along the arterial walls throughout the experiments. The number of accumulated leukocytes increased as time elapsed, peaked at 931 +/- 187 cells/mm2 24 hours after reperfusion, and decreased thereafter. CONCLUSIONS: Leukocyte dynamics in the retinal microcirculation can be quantitatively evaluated during ischemia reperfusion injury.     

Postischemic application of lipid peroxidation inhibitor U-101033E reduces neuronal damage after global cerebral ischemia in rats

BACKGROUND AND PURPOSE: The lipid peroxidation inhibitor U-101033E was examined for effects on cerebral blood flow (CBF), cortical tissue hemoglobin oxygen saturation (HbSo2), and neuronal damage. METHODS: Fifteen minutes of global cerebral ischemia was induced by two-vessel occlusion and hypobaric hypotension. Wistar rats (n = 25) were randomized to receive vehicle (n = 9) or 40 mg/kg U-101033E (n = 9) intraperitoneally during 2 hours of reperfusion. A sham group (n = 7) had neither ischemia nor therapy. Histology was evaluated 7 days after ischemia. RESULTS: During late hyperperfusion (at 17 minutes), vehicle-treated animals had a higher (P = 0.044) cortical tissue HbSo2 (72.0 +/- 1.4%) than did U-101033E-treated animals (65.8 +/- 2.5%). Neuronal counts in the superficial cortex layer found after 7 days correlated negatively with rCBF (r = -0.76; P < 0.001) or cortical tissue HbSo2 (r = -0.56; P = 0.028) assessed during the late hyperperfusion phase. U-101033E reduced neuronal damage in hippocampal CA1 from 64.3 +/- 9.2% to 31.2 +/- 8.4% (P = 0.020), as well as in the superficial cortical layer from 53.5 +/- 14.6% to 12.8 +/- 11.7% (P = 0.046). While animals in the vehicle group had reduced counts in all four examined cortex layers (P < 0.05 versus sham group), there was significant cortical neuron loss in the U-101033E group in only one of four areas. U-101033E had no effect on resting CBF or CO2 reactivity. CONCLUSIONS: Postischemic application of U-101033E protects hippocampal CA1 and cortical neurons after 15 minutes of global cerebral ischemia. The results indicate that free radical-induced lipid peroxidation contributes to reperfusion injury, a process that can be inhibited by antioxidants such as U-101033E.     

The melatonin antagonist luzindole protects retinal photoreceptors from light damage in the rat

PURPOSE: Systemic administration of melatonin can increase retinal light damage in the rat. The role of retinal melatonin receptors in modulating light-damage susceptibility was investigated by intravitreally injecting the melatonin receptor antagonist luzindole into rats. METHODS: Nine Sprague-Dawley albino rats 8 to 9 weeks of age were kept in 50 lux cyclic light for at least 7 days before receiving an intravitreal injection of 1 microl 1 mM luzindole in one eye and 1 microl vehicle in the other eye. The injection was given just before the beginning of the normal 12-hour dark phase. At the end of this dark period, animals were exposed to constant light of 2500 lux for 48 hours. Animals were returned to dim cyclic light for 7 days, and dark-adapted electroretinograms (ERGs) were then recorded from the two eyes simultaneously. The eyes were processed for retinal morphology. Photoreceptor nuclei were counted in the outer nuclear layer (ONL), and the thickness of the ONL and that of the rod outer-segment plus inner-segment layer were measured at several points along sections through the vertical meridian. Two age-matched control rats were maintained in dim cyclic light but received no injections. RESULTS: Luzindole-treated eyes had ERG b-wave thresholds of 2.7 +/- 0.5 (mean +/- SEM) log candela (cd)/m2 lower than the fellow eyes injected with vehicle (P < 0.001), and the maximum b-wave amplitude was 1.0 +/- 0.2 log microV greater in luzindole-treated eyes (P < 0.001). Thresholds of the scotopic threshold response were 0.5 +/- 0.1 log cd/m2 lower than those in vehicle-injected eyes (P < 0.05). Luzindole-treated eyes on average had twice as many photoreceptor cells remaining (P < 0.005). In some areas, several rows of photoreceptor nuclei and outer segments remained in the luzindole-treated eye, whereas the fellow control eye showed cells only occasionally and no outer segments. CONCLUSIONS: Eyes pretreated with the melatonin receptor competitive antagonist luzindole before the dark phase preceding constant light exposure were substantially protected from light damage to the retinal photoreceptors. These results implicate the intraocular melatonin-dopamine system in the regulation of light-damage susceptibility.     

Comparison of metoprolol and carvedilol pharmacology and cardioprotection in rabbit ischemia and reperfusion model

Carvedilol, a selective alpha1 and non-selective beta-adrenoceptor antagonist and antioxidant, has been shown to provide significant cardiac protection in animal models of myocardial ischemia. To further explore the mechanisms contributing to carvedilol cardioprotection efficacy, the effects of carvedilol on hemodynamic variables, infarct size and myeloperoxidase activity (an index of neutrophil accumulation) were compared with a beta1-selective adrenoceptor antagonist, metoprolol. Carvedilol (1 mg/kg) or metoprolol (1 mg/kg or 1 mg/kg + 0.5 mg/kg 90 min later) was given intravenously 5 min before reperfusion. In vehicle-treated rabbits, ischemia (60 min) and reperfusion (180 min) resulted in significant increments in left ventricular end diastolic pressure, large infarcts (59+/-2.6% of area-at-risk) and marked increase in myeloperoxidase activity (0.59+/-0.09 U/100 mg tissue). Carvedilol treatment resulted in sustained reduction of pressure-rate-index and significantly smaller infarcts (22.0+/-2.5%, P < 0.01 vs. vehicle) as well as decreased myeloperoxidase activity (0.186+/-0.056 U/100 mg tissue, P < 0.01 vs. vehicle). The highest dose of metoprolol, 1 mg/kg + 0.5 mg/kg, that resulted in pressure-rate-index comparable to that of 1.0 mg/kg carvedilol, failed to reduce myeloperoxidase activity in the ischemic myocardial tissue, and the infarct size (35+/-3.1%) was significantly larger than in carvedilol-treated animals. Taken together, this study suggests that the superior cardioprotection of carvedilol over metoprolol is not a consequence of hemodynamic variances but possibly the result of the additional pharmacological properties of carvedilol such as the antioxidant and anti-neutrophil effects.     

Amelioration by cyclosporin A of brain damage in transient forebrain ischemia in the rat

The immunosuppressant drug cyclosporin A (CsA) is considered to be inherently protective in conditions of ischemia, e.g. in hepatic and cardiac tissue. However, investigations of effects of CsA on neuronal tissue have been contradictory, probably because the blood-brain barrier (BBB) is virtually impermeable to CsA. In the present study, we exploited the finding that the insertion of a syringe needle into brain parenchyma obviously disrupts the BBB and allows influx of CsA, and explored whether CsA, given as intraperitoneal injections daily for 1 week before and 1 week after forebrain ischemia of 7 or 10 min duration, ameliorates the damage incurred to the hippocampal CA 1 sector. In other experiments, the needle insertion and the first i.p. injection of CsA were made 30 min after the start of recirculation, with continued daily administration of CsA during the postinsult week. In animals which were injected with CsA in daily doses of 10 mg kg-1, but in which no needle was inserted, the drug failed to ameliorate CA1 damage, whether the ischemia had a duration of 7 or 10 min. Likewise, needle insertion had no effect on CA1 damage if CsA was not administered. In contrast, when CsA was given to animals with a needle insertion, CA1 damage was dramatically ameliorated, whether treatment was initiated 1 week before ischemia, or 30 min after the start of recirculation. The effect of CsA seemed larger than that of any other drug proposed to have an anti-ischemic effect in forebrain/global ischemia. Injection of tritiated CsA in one animal with BBB disruption lead to detectable radioactivity throughout the ventricular system, suggesting a generalised increase of the entry of CsA across the BBB. The results demonstrate that immunosuppressants of the type represented by CsA markedly ameliorate delayed neuronal damage after transient forebrain ischemia, provided that they can pass the BBB. It is discussed whether the effect of the drug is one involving calcineurin, a protein phosphatase, or if CsA counteracts a permeability transition of the inner mitochondrial membrane, assumed to occur in response to adverse conditions, e.g. gradual accumulation of Ca2+ in the mitochondria in the postischemic period.