Transforming growth factor-alpha acting at the epidermal growth factor receptor reduces infarct volume after permanent middle cerebral artery occlusion in rats.
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Transforming growth factor-alpha (TGF-alpha) is a ligand for the epidermal growth factor (EGF) receptor (EGFR), and is more abundant than EGF in the brain. The authors studied whether administration of exogenous TGF-alpha into the brain can protect neurons against ischemia in a model of permanent middle cerebral artery (MCA) occlusion in the rat, and whether any effect of TGF-alpha was mediated by EGFR by administering 4,5-dianilinophthalimide (DAPH), a protein-tyrosine kinase inhibitor with high selectivity for EGFR. Rats received either TGF-alpha (10 or 25 ng), DAPH (100 ng), DAPH plus TGF-alpha (25 ng), or vehicle in the ipsilateral first ventricle. Drugs were administered twice: 30 minutes before and 30 minutes after MCA occlusion, and infarct volume was evaluated 24 hours later. Transforming growth factor-alpha at the dose of 25 ng caused a statistically significant reduction of infarct volume (60%) in relation to ischemic rats administered vehicle. This reduction was no longer seen when TGF-alpha was administered in combination with DAPH. The present results show that TGF-alpha can protect neurons from ischemic damage, and that this effect is mediated by EGFR. It is suggested that activation of EGFR-mediated intracellular signalling pathways contributes to the survival of neural cells susceptible to ischemic injury. (+info)
Synergistic protective effects of antioxidant and nitric oxide synthase inhibitor in transient focal ischemia.
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Both nitric oxide synthase (NOS) inhibitors and free radical scavengers have been shown to protect brain tissue in ischemia-reperfusion injury. Nitric oxide and superoxide anion act via distinct mechanisms and react together to form the highly deleterious peroxynitrite. Therefore the authors examined the effects and the interaction between the NOS inhibitor, NG nitro-L-arginine (LNA) and the antioxidant/superoxide scavenger, di-tert-butyl-hydroxybenzoic acid (DtBHB) in the rat submitted to 2 hours of middle cerebral artery occlusion. Posttreatment was initiated 4 hours after the onset of ischemia and infarct volume was measured at 48 hours. The dose-related effect of LNA resulted in a bell-shaped curve: 15, 56, 65, and 33% reduction of total infarct for 0.03, 0.1, 0.3, and 1 mg/kg (intravenously [IV]) respectively and 11% increase in infarct volume for 3 mg/kg (IV). Whereas DtBHB (20 mg/kg; intraperitoneally [IP]) was ineffective, the dose of 60 mg/kg produced 65% protection in infarct volume. The combination of a subthreshold dose of LNA (0.03 mg/kg; IV) and DtBHB (20 mg/kg; IP) resulted in significant reduction (49%) in infarct volume. These results show that LNA and DtBHB act synergistically to provide a consistent neuroprotection against ischemic injury when administered 4 hours after ischemia. This suggests that nitric oxide and free radicals are involved and interact in synergy in ischemia-reperfusion injury. (+info)
N-Acetylaspartate distribution in rat brain striatum during acute brain ischemia.
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Brain N-acetylaspartate (NAA) can be quantified by in vivo proton magnetic resonance spectroscopy (1H-MRS) and is used in clinical settings as a marker of neuronal density. It is, however, uncertain whether the change in brain NAA content in acute stroke is reliably measured by 1H-MRS and how NAA is distributed within the ischemic area. Rats were exposed to middle cerebral artery occlusion. Preischemic values of [NAA] in striatum were 11 mmol/L by 1H-MRS and 8 mmol/kg by HPLC. The methods showed a comparable reduction during the 8 hours of ischemia. The interstitial level of [NAA] ([NAA]e) was determined by microdialysis using [3H]NAA to assess in vivo recovery. After induction of ischemia, [NAA]e increased linearly from 70 micromol/L to a peak level of 2 mmol/L after 2 to 3 hours before declining to 0.7 mmol/L at 7 hours. For comparison, [NAA]e was measured in striatum during global ischemia, revealing that [NAA]e increased linearly to 4 mmol/L after 3 hours and this level was maintained for the next 4 h. From the change in in vivo recovery of the interstitial space volume marker [14C]mannitol, the relative amount of NAA distributed in the interstitial space was calculated to be 0.2% of the total brain NAA during normal conditions and only 2 to 6% during ischemia. It was concluded that the majority of brain NAA is intracellularly located during ischemia despite large increases of interstitial [NAA]. Thus, MR quantification of NAA during acute ischemia reflects primarily changes in intracellular levels of NAA. (+info)
Early diagnosis of central nervous system aspergillosis with combination use of cerebral diffusion-weighted echo-planar magnetic resonance image and polymerase chain reaction of cerebrospinal fluid.
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We treated a patient diagnosed as central nervous system (CNS) aspergillosis with the combined use of cerebral diffusion-weighted echo-planar magnetic resonance imaging (DWI) and polymerase chain reaction of the cerebrospinal fluid (CSF-PCR). DWI, a cutting-edge imaging modality to reveal the earliest changes of cerebral infarction, detected cerebral fungal embolization when the conventional computed tomographic scan and magnetic resonance imaging failed to reveal it. CSF-PCR demonstrated the presence of Aspergillus-specific DNA in the specimen, when the conventional examination and culture of CSF were nonspecific or negative. These diagnostic methods could be useful in the early diagnosis of CNS aspergillosis. (+info)
Delayed increase in infarct volume after cerebral ischemia: correlations with thrombolytic treatment and clinical outcome.
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BACKGROUND AND PURPOSE: Growing experimental evidence indicates that the development of cerebral ischemic damage is slower than previously believed. The aims of this work were (1) to study the evolution of CT hypoattenuation between 24 to 36 hours and 7 days in ischemic stroke patients; (2) to evaluate whether thrombolytic treatment given within 6 hours of stroke affects delayed infarction evolution; and (3) to investigate possible correlations between lesion volume changes over time and clinical outcome. METHODS: Of 620 patients included in the European Cooperative Acute Stroke Study 1 (ECASS1), we selected 450 patients whose control CT scans at day 1 (CT1) and day 7 (CT7) were available. They had been randomly divided into 2 groups: 206 patients had been treated with rtPA and 244 with placebo. CT1 and CT7 were classified according to the location of the infarct. The volume of CT hypoattenuation was measured using the formula AxBxC/2 for irregular volumes. The 95% confidence interval of inter- and intrarater variability was used to determine whether significant changes in lesion volume had occurred between CT1 and CT7. Clinical severity was evaluated by means of the Scandinavian Stroke Scale (SSS) at entry (SSS0) and at day 30 (SSS30). RESULTS: Mean lesion volumes were significantly (P<0.0001) higher at day 7 than at day 1 in all the subgroups of patients and particularly in patients with a subcortical lesion. Of the 450 patients studied, 287 (64%) did not show any significant change in lesion volume between CT1 and CT7, 143 (32%) showed a significant increase and the remaining 20 (4%) a significant decrease. No significant correlation was observed between treatment and lesion evolution between CT1 and CT7. Both clinical scores (SSS0 and SSS30) and degree of neurological recovery were significantly (P<0.05) lower in the subgroup of patients with a significant lesion volume increase than in the other 2 groups. CONCLUSIONS: In approximately two thirds of patients, infarct size is established 24 to 36 hours after stroke onset, whereas in the remaining one third, changes in lesion volume may occur later than the first 24 to 36 hours. Many factors may be responsible for delayed infarct enlargement and for a lower degree of clinical recovery, both of which may occur despite early recombinant tissue plasminogen activator treatment. (+info)
Carotid endarterectomy and intracranial thrombolysis: simultaneous and staged procedures in ischemic stroke.
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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)
An 18-mer peptide fragment of prosaposin ameliorates place navigation disability, cortical infarction, and retrograde thalamic degeneration in rats with focal cerebral ischemia.
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It was previously reported that prosaposin possesses neurotrophic activity that is ascribed to an 18-mer peptide comprising the hydrophilic sequence of the rat saposin C domain. To evaluate the effect of the 18-mer peptide on ischemic neuronal damage, the peptide was infused in the left lateral ventricle immediately after occlusion of the left middle cerebral artery (MCA) in stroke-prone spontaneously hypertensive (SP-SH) rats. The treatment ameliorated the ischemia-induced space navigation disability and cortical infarction and prevented secondary thalamic degeneration in a dose-dependent manner. In culture experiments, treatment with the 18-mer peptide attenuated free radical-induced neuronal injury at low concentrations (0.002 to 2 pg/mL), and the peptide at higher concentrations (0.2 to 20 ng/mL) protected neurons against hypoxic insult. Furthermore, a saposin C fragment comprising the 18-mer peptide bound to synaptosomal fractions of the cerebral cortex, and this binding decreased at the 1st day after MCA occlusion and recovered to the preischemic level at the 7th day after ischemia. These findings suggest that the 18-mer peptide ameliorates neuronal damage in vivo and in vitro through binding to the functional receptor, although the cDNA encoding prosaposin receptor has not been determined yet. (+info)
Factor V Leiden and antibodies against phospholipids and protein S in a young woman with recurrent thromboses and abortion.
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We describe the case of a 39-year-old woman who suffered two iliofemoral venous thromboses, a cerebral ischemic infarct and recurrent fetal loss. Initial studies showed high levels of antiphospholipid antibodies (APAs) and a moderate thrombocytopenia. After her second miscarriage, laboratory diagnosis revealed that the woman was heterozygous for the factor V Leiden mutation and had a functional protein S deficiency as well as anti-protein S and anti-beta 2-glycoprotein I antibodies. The impairment of the protein C pathway at various points could well explain the recurrent thromboses in the patient and supports the role of a disturbed protein C system in the pathophysiology of thrombosis in patients with APAs. (+info)