Thrombolysis with tissue plasminogen activator alters adhesion molecule expression in the ischemic rat brain.
(9/7625)
BACKGROUND AND PURPOSE: We tested the hypothesis that treatment of embolic stroke with recombinant human tissue plasminogen activator (rhtPA) alters cerebral expression of adhesion molecules. METHODS: Male Wistar rats were subjected to middle cerebral artery occlusion by a single fibrin-rich clot. P-selectin, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) immunoreactivity was measured at 6 or 24 hours after embolic stroke in control rats and in rats treated with rhtPA at 1 or 4 hours after stroke. To examine the therapeutic efficacy of combined rhtPA and anti-ICAM-1 antibody treatment at 4 hours after embolization, ischemic lesion volumes were measured in rats treated with rhtPA alone, rats treated with rhtPA and anti-ICAM-1 antibody, and nontreated rats. RESULTS: Administration of rhtPA at 1 hour after embolization resulted in a significant reduction of adhesion molecule vascular immunoreactivity after embolization in the ipsilateral hemisphere compared with corresponding control rats. However, when rhtPA was administered to rats at 4 hours after embolization, significant increases of adhesion molecule immunoreactivity in the ipsilateral hemisphere were detected. A significant increase of ICAM-1 immunoreactivity was also detected in the contralateral hemisphere at 24 hours after ischemia. A significant reduction in lesion volume was found in rats treated with the combination of rhtPA and anti-ICAM-1 antibody compared with rats treated only with rhtPA. CONCLUSIONS: The present study suggests that the time of initiation of thrombolytic therapy alters vascular immunoreactivity of inflammatory adhesion molecules in the ischemic brain and that therapeutic benefit can be obtained by combining rhtPA and anti-ICAM-1 antibody treatment 4 hours after stroke. (+info)
Continuing postischemic neuronal death in CA1: influence of ischemia duration and cytoprotective doses of NBQX and SNX-111 in rats.
(10/7625)
BACKGROUND AND PURPOSE: Transient forebrain ischemia results in a 24- to 72-hour delayed loss of CA1 neurons. Previous work has not assessed whether insult durations can vary the degree and maturation rate of CA1 injury and whether there are different ultrastructural features of death after brief or severe ischemia. We also tested whether known cytoprotective drugs achieve permanent or transient neuroprotection. METHODS: In the first experiment, ischemia was induced for 5, 15, or 30 minutes with the use of the 4-vessel occlusion rat model with 1- to 28-day survival. Others subjected to 5 or 15 minutes of ischemia and allowed to survive for 14 or 7 days, respectively, were examined with electron microscopy. Finally, we determined whether NBQX (30 mg/kg x3 at 0 or 6 hours after ischemia), an AMPA antagonist, and SNX-111 (5 mg/kg at 6 hours after ischemia), an N-type Ca2+ channel antagonist, provided enduring CA1 protection against 10 minutes of ischemia. RESULTS: CA1 damage was not detected at 24 hours. Thirty minutes of ischemia produced 47% and 84% CA1 damage at 2 and 3 days, respectively. A 15-minute occlusion yielded 11%, 74%, and 86% loss at 2, 3, and 7 days, respectively. Five minutes of ischemia produced an even slower progression with 24%, 52%, and 59% loss at 3, 7, and 14 days, respectively. Ultrastructural examination after 5 and 15 minutes of ischemia revealed necrosis with no morphological evidence of apoptosis. Both NBQX (P<0.021) and SNX-111 (P<0.001) significantly reduced CA1 death at 7 days (/=80%) compared with saline treatment ( approximately 79%). CONCLUSIONS: Brief forebrain ischemia results in a slower progression of CA1 loss than more severe insults. Nonetheless, neuronal injury had necrotic, not apoptotic, morphology. NBQX and SNX-111 only postponed CA1 injury. (+info)
Carotid endarterectomy and intracranial thrombolysis: simultaneous and staged procedures in ischemic stroke.
(11/7625)
PURPOSE: The feasibility and safety of combining carotid surgery and thrombolysis for occlusions of the internal carotid artery (ICA) and the middle cerebral artery (MCA), either as a simultaneous or as a staged procedure in acute ischemic strokes, was studied. METHODS: A nonrandomized clinical pilot study, which included patients who had severe hemispheric carotid-related ischemic strokes and acute occlusions of the MCA, was performed between January 1994 and January 1998. Exclusion criteria were cerebral coma and major infarction established by means of cerebral computed tomography scan. Clinical outcome was assessed with the modified Rankin scale. RESULTS: Carotid reconstruction and thrombolysis was performed in 14 of 845 patients (1.7%). The ICA was occluded in 11 patients; occlusions of the MCA (mainstem/major branches/distal branch) or the anterior cerebral artery (ACA) were found in 14 patients. In three of the 14 patients, thrombolysis was performed first, followed by carotid enarterectomy (CEA) after clinical improvement (6 to 21 days). In 11 of 14 patients, 0.15 to 1 mIU urokinase was administered intraoperatively, ie, emergency CEA for acute ischemic stroke (n = 5) or surgical reexploration after elective CEA complicated by perioperative intracerebral embolism (n = 6). Thirteen of 14 intracranial embolic occlusions and 10 of 11 ICA occlusions were recanalized successfully (confirmed with angiography or transcranial Doppler studies). Four patients recovered completely (Rankin 0), six patients sustained a minor stroke (Rankin 2/3), two patients had a major stroke (Rankin 4/5), and two patients died. In one patient, hemorrhagic transformation of an ischemic infarction was detectable postoperatively. CONCLUSION: Combining carotid surgery with thrombolysis (simultaneous or staged procedure) offers a new therapeutic approach in the emergency management of an acute carotid-related stroke. Its efficacy should be evaluated in interdisciplinary studies. (+info)
Lamotrigine attenuates cortical glutamate release during global cerebral ischemia in pigs on cardiopulmonary bypass.
(12/7625)
BACKGROUND: The dose-response effects of pretreatment with lamotrigine (a phenyltriazine derivative that inhibits neuronal glutamate release) in a porcine cerebral ischemia model during cardiopulmonary bypass were studied. METHODS: Sagittal sinus catheters and cortical microdialysis catheters were inserted into anesthetized pigs. Animals undergoing normothermic cardiopulmonary bypass were pretreated with lamotrigine 0, 10, 25, or 50 mg/kg (n = 10 per group). Fifteen minutes of global cerebral ischemia was produced, followed by 40 min of reperfusion and discontinuation of cardiopulmonary bypass. Cerebral oxygen metabolism was calculated using cerebral blood flow (radioactive microspheres) and arterial-venous oxygen content gradients. Concentrations of microdialysate glutamate and aspartate were quantified; electroencephalographic signals were recorded. After cardiopulmonary bypass, blood and cerebrospinal fluid were sampled for S-100B protein, and a biopsy was performed on the cerebral cortex for metabolic profile. RESULTS: Lamotrigine caused dose-dependent reductions in systemic vascular resistance so that additional fluid was required to maintain venous return. Concentrations of glutamate and aspartate did not change during reperfusion after 50 mg/kg lamotrigine in contrast to fivefold and twofold increases, respectively, with lower doses. There were no intergroup differences in cerebral metabolism, electroencephalographic scores, cortical metabolites, brain lactate, or S-100B protein concentrations in the cerebrospinal fluid and blood. CONCLUSIONS: Lamotrigine 50 mg/kg significantly attenuated excitatory neurotransmitter release during normothermic cerebral ischemia during cardiopulmonary bypass without improving other neurologic parameters. Lamotrigine caused arterial and venous dilation, which limits its clinical usefulness. (+info)
Sympathetic ganglionic blockade masks beneficial effect of isoflurane on histologic outcome from near-complete forebrain ischemia in the rat.
(13/7625)
BACKGROUND: Isoflurane-anesthetized rats have better outcome from global cerebral ischemia than rats anesthetized with fentanyl and nitrous oxide. The authors wanted to determine whether circulating catecholamine concentrations depend on the anesthetic agent and whether sympathetic ganglionic blockade affects anesthetic-mediated differences in outcome from near-complete forebrain ischemia. METHODS: For two different experiments, normothermic Sprague-Dawley rats that had fasted were assigned to one of four groups and subjected to 10 min of 30 mm Hg mean arterial pressure and bilateral carotid occlusion. Rats were anesthetized with 1.4% isoflurane or fentanyl (25 microg x kg(-1) x h(-1)) and 70% nitrous oxide, with or without preischemic trimethaphan (2.5 mg given intravenously). In experiment 1, arterial plasma catecholamine concentrations were measured before, at 2 and 8 min during, and after ischemia (n = 5-8). In experiment 2, animals (n = 15) underwent histologic analysis 5 days after ischemia. RESULTS: In experiment 1, intraischemic increases in plasma norepinephrine and epinephrine levels were 28 and 12 times greater in the fentanyl-nitrous oxide group than in the isoflurane group (P<0.01). Trimethaphan blocked all changes in plasma catecholamine concentrations (P<0.02). In experiment 2, isoflurane reduced the mean +/- SD percentage of dead hippocampal CA1 neurons compared with fentanyl-nitrous oxide (43+/-22% vs. 87+/-10%; P<0.001). Trimethaphan abolished the beneficial effects of isoflurane (91+/-6%; P<0.001). Similar observations were made in the cortex. CONCLUSIONS: Isoflurane attenuated the peripheral sympathetic response to ischemia and improved histologic outcome compared with fentanyl and nitrous oxide. This outcome benefit was reversed by sympathetic ganglionic blockade. The beneficial effects of isoflurane may result from a neuroprotective influence of an intermediate sympathetic response that is abolished by trimethaphan. (+info)
Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning.
(14/7625)
Neuroprotection against cerebral ischemia can be realized if the brain is preconditioned by previous exposure to a brief period of sublethal ischemia. The present study was undertaken to test the hypothesis that nitric oxide (NO) produced from the neuronal isoform of NO synthase (NOS) serves as a necessary signal for establishing an ischemia-tolerant state in brain. A newborn rat model of hypoxic preconditioning was used, wherein exposure to sublethal hypoxia (8% oxygen) for 3 hours renders postnatal day (PND) 6 animals completely resistant to a cerebral hypoxic-ischemic insult imposed 24 hours later. Postnatal day 6 animals were treated 0.5 hour before preconditioning hypoxia with the nonselective NOS inhibitor L-nitroarginine (2 mg/kg intraperitoneally). This treatment, which resulted in a 67 to 81% inhibition of calcium-dependent constitutive NOS activity 0.5 to 3.5 hours after its administration, completely blocked preconditioning-induced protection. However, administration of the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg intraperitoneally) before preconditioning hypoxia, which decreased constitutive brain NOS activity by 58 to 81%, was without effect on preconditioning-induced cerebroprotection, as was pretreatment with the inducible NOS inhibitor aminoguanidine (400 mg/kg intraperitoneally). The protective effects of preconditioning were also not blocked by treating animals with competitive [3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate; 5 mg/kg intraperitoneally] or noncompetitive (MK-801; 1 mg/kg intraperitoneally) N-methyl-D-aspartate receptor antagonists prior to preconditioning hypoxia. These findings indicate that NO production and activity are critical to the induction of ischemic tolerance in this model. However, the results argue against the involvement of the neuronal NOS isoform, activated secondary to a hypoxia-induced stimulation of N-methyl-D-aspartate receptors, and against the involvement of the inducible NOS isoform, but rather suggest that NO produced by the endothelial NOS isoform is required to mediate this profound protective effect. (+info)
Changes in the diffusion of water and intracellular metabolites after excitotoxic injury and global ischemia in neonatal rat brain.
(15/7625)
The reduction of the apparent diffusion coefficient (ADC) of brain tissue water in acute cerebral ischemia, as measured by diffusion-weighted magnetic resonance imaging, is generally associated with the development of cytotoxic edema. However, the underlying mechanism is still unknown. Our aim was to elucidate diffusion changes in the intracellular environment in cytotoxic edematous tissue. The ADC of intracellular metabolites was measured by use of diffusion-weighted 1H-magnetic resonance spectroscopy after (1) unilateral N-methyl-D-aspartate (NMDA) injection and (2) cardiac arrest-induced global ischemia in neonatal rat brain. The distinct water ADC drop early after global ischemia was accompanied by a significant reduction of the ADC of all measured metabolites (P < 0.01, n = 8). In the first hours after excitotoxic injury, the ADC of water and the metabolites taurine and N-acetylaspartate dropped significantly (P < 0.05, n = 8). At 24 and 72 hours after NMDA injection brain metabolite levels were diminished and metabolite ADC approached contralateral values. Administration of the NMDA-antagonist MK-801 1.5 hours after NMDA injection completely normalized the water ADC but not the metabolite ADC after 1 to 2 hours (n = 8). No damage was detected 72 hours later and, water and metabolite ADC had normal values (n = 8). The contribution of brain temperature changes (calculated from the chemical shift between the water and N-acetylaspartate signals) and tissue deoxygenation to ischemia-induced intracellular ADC changes was minor. These data lend support to previous suggestions that the ischemia-induced brain water ADC drop may partly be caused by reduced diffusional displacement of intracellular water, possibly involving early alterations in intracellular tortuosity, cytoplasmic streaming, or intracellular molecular interactions. (+info)
Transcriptional activation following cerebral ischemia in mice of a promoter-deleted nitric oxide synthase-2 gene.
(16/7625)
Nitric oxide synthase (NOS)-2 is transcriptionally activated in a wide variety of injurious conditions, including cerebral ischemia, and the resulting nitric oxide is implicated both in tissue damage and recovery. Studies in vitro suggest that the proximal region of the NOS-2 promoter is obligatory for gene activation by proinflammatory cytokines. However, following cerebral ischemia in a NOS-2 gene-deficient mouse in which this region and exons 1-4 have been deleted, we find temporal and spatial expression, identical to wild-type, from a previously unidentified promoter region. The resulting protein is predicted to lack the first 113 amino acids and is NOS-2-incompetent. Fortuitously, this gene-deficient mouse presents a unique opportunity to determine more about the mechanisms of NOS-2 gene regulation in vivo. (+info)