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Pluta RM, Butman JA, Schatlo B, Johnson DL, Oldfield EH. Subarachnoid hemorrhage and the distribution of drugs delivered into the cerebrospinal fluid. Laboratory investigation. J Neurosurg 2009; 111:1001-7, 1-4. [PMID: 19374502 PMCID: PMC4762042 DOI: 10.3171/2009.2.jns081256] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT Investigators in experimental and clinical studies have used the intrathecal route to deliver drugs to prevent or treat vasospasm. However, a clot near an artery or arteries after subarachnoid hemorrhage (SAH) may hamper distribution and limit the effects of intrathecally delivered compounds. In a primate model of right middle cerebral artery (MCA) SAH, the authors examined the distribution of Isovue-M 300 and 3% Evans blue after infusion into the cisterna magna CSF. METHODS Ten cynomolgus monkeys were assigned to SAH and sham SAH surgery groups (5 in each group). Monkeys received CSF injections as long as 28 days after SAH and were killed 3 hours after the contrast/Evans blue injection. The authors assessed the distribution of contrast material on serial CT within 2 hours after contrast injection and during autopsy within 3 hours after Evans blue staining. RESULTS Computed tomography cisternographies showed no contrast in the vicinity of the right MCA (p < 0.05 compared with left); the distribution of contrast surrounding the entire right cerebral hemisphere was substantially reduced. Postmortem analysis demonstrated much less Evans blue staining of the right hemisphere surface compared with the left. Furthermore, the Evans blue dye did not penetrate into the right sylvian fissure, which occurred surrounding the left MCA. The authors observed the same pattern of changes and differences in contrast distribution between SAH and sham SAH animals and between the right and the left hemispheres on Days 1, 3, 7, 14, 21, and 28 after SAH. CONCLUSIONS Intrathecal drug distribution is substantially limited by SAH. Thus, when using intrathecal drug delivery after SAH, vasoactive drugs are unlikely to reach the arteries that are at the highest risk of delayed cerebral vasospasm.
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Affiliation(s)
- Ryszard M Pluta
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
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Lin CL, Shih HC, Dumont AS, Kassell NF, Lieu AS, Su YF, Hwong SL, Hsu C. The effect of 17β-estradiol in attenuating experimental subarachnoid hemorrhage–induced cerebral vasospasm. J Neurosurg 2006; 104:298-304. [PMID: 16509505 DOI: 10.3171/jns.2006.104.2.298] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Object
Sex differences in the outcome of aneurysmal subarachnoid hemorrhage (SAH) are controversial, and the potential influence of estradiol on vasodilation is unclear. In the present study the authors evaluate the effect and possible mechanism of 17β-estradiol (E2) on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH.
Methods
A 30-mm Silastic tube filled with E2 in corn oil (0.3 mg/ml) was subcutaneously implanted in male rats. Serum levels of E2 were measured on Days 0, 1, 2, 3, 4, and 7 postimplantation. The degree of vasospasm was determined by averaging the cross-sectional areas of the basilar artery (BA) 7 days after the first SAH. Expressions of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) in the BA were also evaluated.
Serum levels of E2 in the E2-treated rats were at physiological levels (56–92 pg/ml) and were significantly higher than those in the control and vehicle-treated groups. Treatment with E2 significantly (p < 0.01) attenuated SAH-induced vasospasm. Induction of iNOS messenger (m)RNA and protein in the BA by SAH was significantly diminished by the E2 treatment but not by vehicle treatment. The SAH-induced suppression of eNOS mRNA and protein was relieved by E2 treatment.
Conclusions
These results suggest that continuous treatment with E2 at physiological levels prevents cerebral vasospasm following SAH. The beneficial effect of E2 may be in part related to the prevention of augmentation of iNOS expression and the preservation of normal eNOS expression after SAH. Treatment with E2 holds therapeutic promise in the treatment of cerebral vasospasm following SAH and merits further investigation.
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Affiliation(s)
- Chih-Lung Lin
- Department of Neurosurgery, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China
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Zhou BR, Gumenscheimer M, Freudenberg MA, Galanos C. Lethal effect and apoptotic DNA fragmentation in response of D-GalN-treated mice to bacterial LPS can be suppressed by pre-exposure to minute amount of bacterial LPS: Dual role of TNF receptor 1. World J Gastroenterol 2005; 11:3398-404. [PMID: 15948245 PMCID: PMC4315994 DOI: 10.3748/wjg.v11.i22.3398] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether induction of tolerance of mice to lipopolysaccharide (LPS) was able to inhibit apoptotic reaction in terms of characteristic DNA fragmentation and protect mice from lethal effect.
METHODS: Experimental groups of mice were pretreated with non-lethal amount of LPS (0.05 μg). Both control and experimental groups simultaneously were challenged with LPS plus D-GalN for 6-7 h. The evaluations of both DNA fragmentations from the livers and the protection efficacy against lethality to mice through induction of tolerance to LPS were conducted.
RESULTS: In the naive mice challenge with LPS plus D-GalN resulted in complete death in 24 h, whereas a characteristic apoptotic DNA fragmentation was exclusively seen in the livers of mice receiving LPS in combination with D-GalN. The mortality in the affected mice was closely correlated to the onset of DNA fragmentation. By contrast, in the mice pre-exposed to LPS, both lethal effect and apoptotic DNA fragmentation were suppressed when challenged with LPS/D-GalN. In addition to LPS, the induction of mouse tolerance to TNF also enabled mice to cross-react against death and apoptotic DNA fragmentation when challenged with TNF and/or LPS in the presence of D-GalN. Moreover, this protection effect by LPS could last up to 24 h. TNFR1 rather than TNFR2 played a dual role in signaling pathway of either induction of tolerance to LPS for the protection of mice from mortality or inducing morbidity leading to the death of mice.
CONCLUSION: The mortality of D-GalN-treated mice in response to LPS was exceedingly correlated to the onset of apoptosis in the liver, which can be effectively suppressed by brief exposure of mice to a minute amount of LPS. The induced tolerance status was mediated not only by LPS but also by TNF. The developed tolerance to either LPS or TNF can be reciprocally cross-reacted between LPS and TNF challenges, whereas the signaling of induction of tolerance and promotion of apoptosis was through TNFR1, rather than TNFR2.
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MESH Headings
- Animals
- DNA Fragmentation/drug effects
- Drug Tolerance
- Endotoxemia/drug therapy
- Endotoxemia/mortality
- Endotoxemia/pathology
- Galactosamine/pharmacology
- Lipopolysaccharides/pharmacology
- Mice
- Mice, Inbred C57BL
- Mice, Mutant Strains
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type I/metabolism
- Receptors, Tumor Necrosis Factor, Type II/genetics
- Receptors, Tumor Necrosis Factor, Type II/metabolism
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Affiliation(s)
- Bing-Rong Zhou
- Department of Microbiology, Second Military Medical University, Shanghai, China
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Vatter H, Zimmermann M, Weyrauch E, Lange BN, Setzer M, Raabe A, Seifert V. Cerebrovascular characterization of the novel nonpeptide endothelin-A receptor antagonist LU 208075. Clin Neuropharmacol 2003; 26:73-83. [PMID: 12671526 DOI: 10.1097/00002826-200303000-00006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Enhanced cerebrovascular resistance under pathologic conditions, like cerebral vasospasm after subarachnoid hemorrhage, seems to be caused by the vasocontractile effect of endothelin-1 (ET-1). Therefore, the effect of the novel and ET(A) receptor selective antagonist LU 208075 was characterized by the contraction and relaxation induced by ET-1 and bigET-1 on rat basilar artery. Basilar artery ring segments with (E+) and without (E-) functionally intact endothelium were prepared to measure the isometric force. Concentration-effect curves were constructed by cumulative application of ET-1 or bigET-1 in the presence of LU 208075 (10(-7)M, 10(-6)M, and 10(-5)M). The effect of LU 208075 was determined by the pA(2) value. The contraction by ET-1 and bigET-1 was inhibited by LU 208075 in a dose-dependent manner. The pA(2) values for ET-1 and for bigET-1 were 6.51 +/- 0.39 (E+) and 6.67 +/- 0.43 (E-), and 7.03 +/- 0.32 (E+) and 7.24 +/- 0.31 (E-) respectively. The E(max) values for bigET-1 but not for ET-1 were reduced significantly in the presence of LU 208075. A significant relaxation by ET-1 or bigET-1 was observed only in the presence of LU 208075. This relaxation was inhibited by LU 208075 in higher concentrations, with pA(2) values of 5.68 +/- 0.05 (ET-1) and 5.50 +/- 0.39 (bigET-1). The current data correlate with a competitive inhibition of ET(A) receptor-mediated contraction and relaxation, caused by ET(B) receptor activation on cerebral vessels by LU 208075. The selectivity for the ET(A) receptor was approximately sevenfold. Furthermore, the results may suggest an inhibition of the functional ET-converting enzyme activity by LU 208075.
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Affiliation(s)
- Hartmut Vatter
- Department of Neurosurgery, Johann Wolfgang Goethe-University, Schleusenweg 2-16, D-60528 Frankfurt am Main, Germany.
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Bagdatoglu C, Guleryuz A, Unlu A, Kanik A, Berk C, Ozdemir C, Koksel T, Egemen N. Resolution of cerebral vasospasm with trapidil; an animal model. J Clin Neurosci 2002; 9:429-32. [PMID: 12217673 DOI: 10.1054/jocn.2001.1009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Cerebral vasospasm and rebleeding are important clinical phenomena associated with a high mortality rate. Therefore, any promising finding in the laboratory deserves assessment in clinical practice. The present study was designed to examine the possible effects of trapidil on the basilar artery of the rabbit through a cerebral vasospasm model. This experimental study was carried out on 26 adult New Zealand albino rabbits of both sexes weighing 2.5-3.0 kg. A transclival exposure was performed. Vasospasm was produced by an intracisternal injection of autologous blood. After observation of the vasospasm, trapidil was locally applied in increasing concentrations (10(-5)-10(-4) M). The effect of each concentration was measured independently after 10 minutes for each application and was extended to three hours. Trapidil was shown to have a clear spasmolytic effect on the rabbit's basilar artery. These data suggest that trapidil can have a potential use in the treatment of patients suffering from cerebral vasospasm.
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Mizuno Y, Azuma H, Ito Y, Isotani E, Ohno K, Hirakawa K. Inhibitory effect of activated protein C on cerebral vasospasm after subarachnoid hemorrhage in the rabbit. J Cardiovasc Pharmacol 2002; 39:729-38. [PMID: 11973417 DOI: 10.1097/00005344-200205000-00014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
This study investigated whether activated protein C (APC) improves the cerebral vasospasm in an experimental subarachnoid hemorrhage that was produced by the intracisternal injection of autologous blood. Male rabbits were divided into the following four groups: APC 0.1-and 0.5-mg groups, in which 0.1 and 0.5 mg APC were injected into the cisterna magna, respectively; a placebo group, in which saline was injected instead of APC; and a sham operation group that did not get injections of autologous blood, APC, and saline. On day 2, amount of clot in the basal cistern was significantly (p < 0.01) decreased in the APC 0.5-mg group. Percent diameter of the basilar artery on day 2 to that before injecting the blood was angiographically determined as 97.1 +/- 3.8% in the APC 0.5-mg group, which was significantly (p < 0.001) greater than the corresponding value in the placebo group (74.8 +/- 3.4%). The impaired endothelium-dependent relaxation following subarachnoid hemorrhage was normalized in the APC 0.5-mg group (p < 0.0001). These results suggest that APC would improve cerebral vasospasm following subarachnoid hemorrhage, possibly by decreasing the amount of subarachnoid clot and normalizing the impaired nitric oxide production/release.
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Affiliation(s)
- Yusuke Mizuno
- Department of Neurosurgery, School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
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Didion SP, Hathaway CA, Faraci FM. Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD. Am J Physiol Heart Circ Physiol 2001; 281:H1697-703. [PMID: 11557560 DOI: 10.1152/ajpheart.2001.281.4.h1697] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The goal of this study was to examine the role of endogenous copper/zinc (CuZn)-superoxide dismutase (SOD) on superoxide levels and on responses of cerebral blood vessels to stimuli that are mediated by nitric oxide (acetylcholine) and cyclooxygenase-dependent mechanisms (bradykinin and arachidonic acid). Levels of superoxide in the rabbit basilar artery were measured using lucigenin-enhanced chemiluminescence (5 microM lucigenin). Diethyldithiocarbamate (DDC; 10 mM), an inhibitor of CuZn-SOD, increased superoxide levels by approximately 2.4-fold (P < 0.05) from a baseline value of 1.0 +/- 0.2 relative light units x min(-1) x mm(-2) (means +/- SE). The diameter of cerebral arterioles (baseline diameter, 99 +/- 3 microm) was also measured using a closed cranial window in anesthetized rabbits. Topical application of DDC attenuated responses to acetylcholine, bradykinin, and arachidonate, but not nitroprusside. For example, 10 microM arachidonic acid dilated cerebral arterioles by 40 +/- 5 and 2 +/- 2 microm under control conditions and after DDC, respectively (P < 0.05). These inhibitory effects of DDC were reversed by the superoxide scavenger 4,5-dihydroxy-1,3-benzenedisulfonic acid (10 mM). Arachidonate increased superoxide levels in the basilar artery moderately under normal conditions and this increase was greatly augmented in the presence of DDC. These findings suggest that endogenous CuZn-SOD limits superoxide levels under basal conditions and has a marked influence on increases in superoxide in vessels exposed to arachidonic acid. The results also suggest that nitric oxide- and cyclooxygenase-mediated responses in the cerebral microcirculation are dependent on normal activity of CuZn-SOD.
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Affiliation(s)
- S P Didion
- Department of Internal Medicine, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa 52242-1081, USA
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Bordet R, Deplanque D, Maboudou P, Puisieux F, Pu Q, Robin E, Martin A, Bastide M, Leys D, Lhermitte M, Dupuis B. Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J Cereb Blood Flow Metab 2000; 20:1190-6. [PMID: 10950379 DOI: 10.1097/00004647-200008000-00004] [Citation(s) in RCA: 110] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
A low dose (0.5 mg/kg) of lipopolysaccharide (LPS), administered 72 hours before 60-minute middle cerebral artery occlusion, induced a delayed neuroprotection proven by the significant decrease (-35%) of brain infarct volume in comparison with control, whereas infarct volumes remained unchanged in rats treated 12, 24, or 168 hours before ischemia. This delayed neuroprotective effect of LPS was induced only with low doses (0.25 to 1 mg/kg), whereas this effect disappeared with a higher dose (2 mg/kg). The delayed neuroprotection of LPS was induced in the cortical part of the infarcted zone, not in the subcortical part. The beneficial effect of LPS on consequences of middle cerebral artery occlusion was suppressed by dexamethasone (3 mg/kg) and indomethacin (3 mg/ kg) administered 1 hour before LPS, whereas both drugs had no direct effect on infarct volume by themselves, suggesting that activation of inflammatory pathway is involved in the development of LPS-induced brain ischemic tolerance. Preadministration of cycloheximide, an inhibitor of protein synthesis, also blocked LPS-induced brain ischemic tolerance suggesting that a protein synthesis is also necessary as a mediating mechanism. Superoxide dismutase (SOD) could be one of the synthesized proteins because lipopolysaccharide increased SOD brain activity 72 hours, but not 12 hours, after its administration, which paralleled the development of brain ischemic tolerance. In contrast, catalase brain activity remained unchanged after LPS administration. The LPS-induced delayed increase in SOD brain content was suppressed by a previous administration of indomethacin. These data suggest that the delayed neuroprotective effect of low doses of LPS is mediated by an increased synthesis of brain SOD that could be triggered by activation of inflammatory pathway.
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Affiliation(s)
- R Bordet
- Laboratoire de Pharmacologie, Faculté de Médecine, Lille, France
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Jain KK. Nicaraven for the treatment of cerebral vasospasm in subarachnoid haemorrhage. Expert Opin Investig Drugs 2000; 9:859-70. [PMID: 11060715 DOI: 10.1517/13543784.9.4.859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Cerebral vasospasm is a complication of subarachnoid haemorrhage and can cause cerebral ischaemia. Antivasospastic agents are used to relieve vasospasm after subarachnoid haemorrhage. A large number of agents with varying modes of action currently being investigated are reviewed. Pharmacology and clinical trials of nicaraven are discussed. The drug has been found to have both antivasospastic as well as neuroprotective effects. Clinically, the most documented efficacy of nicaraven is in the management of vasospasm associated with subarachnoid haemorrhage based on its free radical scavenging effect. Other potential areas for application are cerebral oedema associated with intracerebral haemorrhage and for neuroprotection in cerebral infarction. Nicaraven is in pre-registration by Chugai Pharma Ltd. in Japan for the treatment of vasospasm following subarachnoid haemorrhage. The regulatory atmosphere in Japan regarding the approval of neuroprotectives is reviewed and nicaraven is likely to be approved by the year 2001 when the patent on it expires.
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Affiliation(s)
- K K Jain
- Jain PharmaBiotech, Bläsiring 7, CH-4057 Basel, Switzerland.
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Toyoda T, Kassell NF, Lee KS. Induction of tolerance against ischemia/reperfusion injury in the rat brain by preconditioning with the endotoxin analog diphosphoryl lipid A. J Neurosurg 2000; 92:435-41. [PMID: 10701530 DOI: 10.3171/jns.2000.92.3.0435] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT Inflammatory responses and oxygen free radicals have increasingly been implicated in the development of ischemic brain injury. In some cases, an attenuation of inflammation or free-radical injury can provide tissue protection. Diphosphoryl lipid A (DPL) is a detoxified derivative of a lipopolysaccharide (endotoxin) of Salmonella minnesota strain R595, which is capable of stimulating the immune system without eliciting direct toxic effects. In this study the authors examined the influence of preconditioning with DPL on ischemia/reperfusion injury in rats. METHODS Sprague-Dawley rats were injected intravenously with either DPL or vehicle. Twenty-four hours later, some animals were tested for superoxide dismutase (SOD) activity. Others were subjected to a 3-hour period of focal cerebral ischemia and, after a reperfusion period of 24 hours, were killed. Infarction volume, SOD activity, and myeloperoxidase (MPO) activity were assayed in the postischemic animals. Pretreatment with DPL produced significant reductions in cerebral infarction and MPO activity in the ischemic penumbra. A significant enhancement of basal SOD activity was observed 24 hours after DPL treatment (that is, before ischemia), and a further enhancement of SOD activity was seen in the ischemic penumbra 24 hours after reperfusion. CONCLUSIONS These data provide the first evidence of a neuroprotective effect of preconditioning with DPL in an in vivo model of cerebral ischemia. Although the precise mechanisms through which DPL exerts its neuroprotective influence remain to be established, an inhibition of the complex inflammatory response to ischemia and an enhancement of endogenous antioxidant activity are leading candidates.
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Affiliation(s)
- T Toyoda
- Department of Neuroscience, University of Virginia Health Sciences Center, Charlottesville 22908, USA
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