benzofurans and Subarachnoid-Hemorrhage

The present paper reviews recent studies in monkey and man adding further to understanding of the role of perivascular peptides in the pathophysiology of subarachnoid haemorrhage. 1. The perivascular fibers, sympathetic fibers (storing noradrenaline, neuropeptide Y), parasympathetic fibers (storing acetylcholine, vasoactive intestinal peptide, peptide histidine methionine and neuropeptide Y) and sensory fibers (storing tachykinins, calcitonin gene-related peptide) were traced using True Blue in monkey. 2. Tracing studies of the monkey middle-cerebral artery (MCA) innervation confirmed earlier studies in rats and cats, with superior cervical and trigeminal ganglia as main immunostaining areas, and contralateral involvement in the superior cervical and trigeminal ganglia. Sphenopalatine immunostaining was scarce. 3. The release of neuropeptides in the external jugular vein in humans in the postoperative course after subarachnoid hemorrhage, using radioimmunoassay, was correlated to hemodynamical changes (vasoconstriction) monitored with Doppler ultrasound on middle cerebral (MCA) and internal carotid arteries (ICA)). 4. Neuropeptide Y-like immunoreactivity (NPY-LI) levels were increased compared to controls in patients with hemodynamic changes, and in some patients a relationship was found between velocities and NPY-LI. 5. Calcitonin gene-related peptide-LI levels were also increased in connection with vasospasm. In patients with MCA lesions a correlation of 0.61, p = 0.0002 was found between hemodynamic index (V MCA/V ICA) and CGRP-LI. The possible sympathetic and trigemino-cerebrovascular activation are discussed.

Topics: Animals; Benzofurans; Calcitonin Gene-Related Peptide; Cerebral Arteries; Cerebrovascular Circulation; Haplorhini; Hemodynamics; Humans; Ischemic Attack, Transient; Nerve Fibers; Neuropeptide Y; Neuropeptides; Subarachnoid Hemorrhage; Ultrasonography; Vasoconstriction

Salvianolic acid B (SalB), a natural polyphenolic compound extracted from the herb of Salvia miltiorrhiza, possesses antioxidant and neuroprotective properties and has been shown to be beneficial for diseases that affect vasculature and cognitive function. Here we investigated the protective effects of SalB against subarachnoid hemorrhage (SAH)-induced oxidative damage, and the involvement of underlying molecular mechanisms. In a rat model of SAH, SalB inhibited SAH-induced oxidative damage. The reduction in oxidative damage was associated with suppressed reactive oxygen species generation; decreased lipid peroxidation; and increased glutathione peroxidase, glutathione, and superoxide dismutase activities. Concomitant with the suppressed oxidative stress, SalB significantly reduced neurologic impairment, brain edema, and neural cell apoptosis after SAH. Moreover, SalB dramatically induced nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and increased expression of heme oxygenase-1 and NADPH: quinine oxidoreductase-1. In a mouse model of SAH, Nrf2 knockout significantly reversed the antioxidant effects of SalB against SAH. Additionally, SalB activated sirtuin 1 (SIRT1) expression, whereas SIRT1-specific inhibitor sirtinol pretreatment significantly suppressed SalB-induced SIRT1 activation and Nrf2 expression. Sirtinol pretreatment also reversed the antioxidant and neuroprotective effects of SalB. In primary cultured cortical neurons, SalB suppressed oxidative damage, alleviated neuronal degeneration, and improved cell viability. These beneficial effects were associated with activation of the SIRT1 and Nrf2 signaling pathway and were reversed by sirtinol treatment. Taken together, these in vivo and in vitro findings suggest that SalB provides protection against SAH-triggered oxidative damage by upregulating the Nrf2 antioxidant signaling pathway, which may be modulated by SIRT1 activation.

Topics: Animals; Antioxidants; Apoptosis; Benzofurans; Cell Survival; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sirtuin 1; Subarachnoid Hemorrhage

Endothelin converting Enzyme-1 (ECE-1) is essential for the production of Endothelin-1 (ET-1), which is associated with vasospasm following subarachnoid hemorrhage (SAH). We have previously demonstrated the presence of a catalytically active soluble form of ECE-1 in the media of endothelial cells. We aimed to determine if this form of ECE-1 exists in vivo, in cerebrospinal fluid (CSF) of SAH patients. We examined CSF taken from SAH subjects for the presence of soluble ECE-1 using a bradykinin based quenched fluorescent substrate assay. We obtained further confirmation by characterizing the CSF mediated cleavage products of BigET-1 and BigET₁₈₋₃₄ (6 μg/ml) using mass spectrometry. The specificity of cleavage was confirmed using the ECE-1 inhibitor CGS35066 5 nmol/L. SAH CSF samples had mean ECE-1 activity of 0.127 ± 0.037 μmols of substrate cleaved/μl of CSF/24 h. The C-terminal peptides generated upon the cleavage of BigET-1 and BigET₁₈₋₃₄ were detected 48 h after incubation of these substrates with CSF. Cleavage of these substrates was inhibited by CGS35066. Results of Western blots also produced strong evidence for the presence of truncated soluble ECE-1 in CSF. These results strongly suggest the presence of a truncated but catalytically active form of ECE-1 in the CSF of SAH subjects. Further studies are necessary to determine the biological significance of soluble ECE-1 in CSF of SAH subjects, including an association with vasospasm after SAH.

Topics: Aspartic Acid Endopeptidases; Benzofurans; Bradykinin; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Humans; Hydrocephalus; Mass Spectrometry; Metalloendopeptidases; Organophosphonates; Subarachnoid Hemorrhage

Endothelin-1, a potent vasoconstrictive peptide, has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). The goal of this study was to evaluate the effect of continuous intravenous infusion of a highly selective endothelin-converting enzyme-1 inhibitor, CGS 35066, on the prevention and reversal of cerebral vasospasm following SAH. New Zealand white rabbits were subjected to SAH by injecting autologous arterial blood into the cisterna magna. Infusion of CGS 35066 at dosages of 1, 3, or 10 mg/kg/ day was initiated either 1 hr and 24 hrs later in the prevention and reversal protocols, respectively. Animals were sacrificed by perfusion-fixation 48 hrs after SAH induction. The cross-sectional areas of basilar arteries were measured using computer-assisted videomicroscopy. Ultrastructural changes in basilar arteries were determined using electron microscopy. CGS 35066 significantly prevented and reversed the arterial narrowing after SAH in all three groups. The mean cross-sectional areas of arteries from animals in both the prevention and reversal protocol groups that received 10 mg/kg/day of CGS 35066 did not differ significantly from those of the healthy controls. Histological studies of the basilar artery in the 10 mg/kg/day treatment group did not show pathomorphological changes, such as corrugation of the endothelium seen at 2 days after SAH induction or vacuole formation in the endothelial cells noted in the vehicle-treated SAH group. These findings suggest that CGS 35066 is a promising therapeutic agent for the prevention and reversal of cerebral vasospasm after SAH. It also prevents the pathological changes in vascular walls due to SAH.

Topics: Animals; Basilar Artery; Benzofurans; Infusions, Intravenous; Male; Organophosphonates; Protease Inhibitors; Rabbits; Subarachnoid Hemorrhage; Vasospasm, Intracranial

CGS 26303, a dual inhibitor of endothelin-converting enzyme-1 (ECE-1) and neutral endopeptidase 24.11, was previously shown to prevent and reverse vasospasm in an experimental model of subarachnoid hemorrhage (SAH). However, reversal of the vasospastic response was not very efficacious. This study was designed to examine the effects of a highly selective ECE-1 inhibitor, CGS 35066, on SAH-induced cerbrovasospasm. Experimental SAH was induced in New Zealand white rabbits by injecting autogenous blood into cisterna magna and CGS 35066 was injected i.v. twice daily, either at 1 h (prevention protocol) or 24 h (reversal protocol) after SAH. Treatment with CGS 35066 significantly attenuated basilar arterial narrowing at a dose of 1 mg/kg in both protocols. These findings provide support for the use of selective ECE-1 inhibitors for the treatment of SAH-induced vasospasm even after the process of arterial narrowing has begun.

Topics: Animals; Aspartic Acid Endopeptidases; Basilar Artery; Benzofurans; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelin-Converting Enzymes; Enzyme Inhibitors; Injections, Intravenous; Male; Metalloendopeptidases; Organophosphonates; Rabbits; Subarachnoid Hemorrhage; Vasospasm, Intracranial

To investigate the effect of dl-3-n-butylphthalide (dl-NBP) on experimental subarachnoid hemorrhage (SAH) in rats.. SAH was induced by injection of autologous artery blood 0.35 mL into lateral ventricle. Regional cerebral blood flow (rCBF) in caudate nucleus was determined by hydrogen clearance method.. A rapid and marked decrease in rCBF in caudate nucleus was observed 15 min after SAH and the rCBF remained at low level (about 50% pre-SAH value) within 180 min. dl-NBP (50, 100 mg.kg-1, i.g.) increased rCBF 30-180 min after the onset of SAH without significant effect on mean artery blood pressure. dl-NBP 100 mg.kg-1 increased rCBF in caudate nucleus by 26% at 15 min and by 36% at 180 min respectively after SAH. d-NBP but not l-NBP (10 mg.kg-1, i.p.) increased rCBF.. dl-NBP improves rCBF in caudate nucleus of rats subjected to SAH.

Topics: Animals; Benzofurans; Caudate Nucleus; Male; Neuroprotective Agents; Rats; Rats, Wistar; Regional Blood Flow; Subarachnoid Hemorrhage

To investigate the therapeutic effects of dl-3-n-butylphthalide (dl-NBP) on regional cerebral blood flow impairment and blood-brain barrier damage induced by subarachnoid hemorrhage (SAH) in rats.. SAH was induced by an injection of 0.35 ml autologous blood into the lateral ventricle. The regional cerebral blood flow in caudate nucleus was determined by hydrogen clearance method. Permeability of blood-brain barrier was measured by extravasation of the protein bound Evans blue dye to brain tissue.. SAH produced a marked decrease in both caudate blood flow and blood-brain barrier damage which showed increased extravasation of protein bound Evans blue dye to brain tissue. dl-NBP (5-20 mg/kg, given 5 min after the onset of SAH) and nimodipine (0.25 mg/kg) significantly increased the regional cerebral blood flow in caudate nucleus within 3 hours of SAH. Moreover, dl-NBP (10 mg/kg) and nimodipine (0.25 mg/kg, given 5 min and 3 h after SAH) significantly reduced the brain extravasation of Evans blue dye which increased after 6 hours of SAH.. By improving the regional cerebral blood flow and blood-brain barrier, dl-NBP has therapeutic effects on experimental SAH.

Topics: Animals; Benzofurans; Blood-Brain Barrier; Caudate Nucleus; Male; Neuroprotective Agents; Rats; Rats, Wistar; Regional Blood Flow; Subarachnoid Hemorrhage

Effects of dl-3-n-butylphthalide(dl-NBP) on changes of regional cerebal blood flow (rCBF) and blood-brain barrier of rats subjected to subarachnoid hemorrhage (SAH) were investigated. Regional CBF was determined by hydrogen clearance method at 15 min before, 15 and 30 min thereafter once every 30 min up to 180 min after the beginning of SAH. The results showed that SAH produced a significant decrease in rCBF in caudate nucleus and blood-brain barrier damage which displayed increased extravasation of Evans blue to brain tissue. Both dl-NBP (5-20 mg.kg-1 given intraperitoneally 5 min after the onset of SAH) and nimodipine (0.25 mg.kg-1) were shown to increase rCBF in caudate nucleus through 3 h of SAH. Moreover, dl-NBP 10 mg.kg-1 and nimodipine 0.25 mg.kg-1, given 5 min and 3 h, respectively, after SAH, significantly reduced the brain extravasation of Evans blue 6 h after SAH, indicating that both dl-NBP and nimodipine has protective effects on blood-brain barrier. These results suggest that dl-NBP has therapeutic effects on SAH.

Topics: Animals; Benzofurans; Blood-Brain Barrier; Cerebrovascular Circulation; Drugs, Chinese Herbal; Male; Neuroprotective Agents; Rats; Rats, Wistar; Subarachnoid Hemorrhage