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PubMed2006

Strategies for mitigating an influenza pandemic.

Development of strategies for mitigating the severity of a new influenza pandemic is now a top global public health priority. Influenza prevention and containment strategies can be considered under the broad categories of antiviral, vaccine and non-pharmaceutical (case isolation, household quarantine, school or workplace closure, restrictions on travel) measures. Mathematical models are powerful tools for exploring this complex landscape of intervention strategies and quantifying the potential costs and benefits of different options. Here we use a large-scale epidemic simulation to examine intervention options should initial containment of a novel influenza outbreak fail, using Great Britain and the United States as examples. We find that border restrictions and/or internal travel restrictions are unlikely to delay spread by more than 2-3 weeks unless more than 99% effective. School closure during the peak of a pandemic can reduce peak attack rates by up to 40%, but has little impact on overall attack rates, whereas case isolation or household quarantine could have a significant impact, if feasible. Treatment of clinical cases can reduce transmission, but only if antivirals are given within a day of symptoms starting. Given enough drugs for 50% of the population, household-based prophylaxis coupled with reactive school closure could reduce clinical attack rates by 40-50%. More widespread prophylaxis would be even more logistically challenging but might reduce attack rates by over 75%. Vaccine stockpiled in advance of a pandemic could significantly reduce attack rates even if of low efficacy. Estimates of policy effectiveness will change if the characteristics of a future pandemic strain differ substantially from those seen in past pandemics.

Antiviral Agents↗
PubMed2005

Antioxidant supplementation enhances antioxidant capacity and mitigates oxidative damage following acute ischaemic stroke.

OBJECTIVE: To test whether supplementary antioxidants immediately following acute ischaemic stroke will enhance antioxidant capacity and mitigate oxidative damage. DESIGN: A randomised controlled trial. SETTING: A university teaching hospital. SUBJECTS: A total of 48 acute ischaemic stroke patients within 12 h of symptom onset. INTERVENTION: Daily oral 800 IU (727 mg) of alpha-tocopherol and 500 mg of vitamin C (n = 24), or no treatment (n = 24) for 14 days. Treatment group and controls were matched for stroke subtype and age. MAIN OUTCOME MEASURES: alpha-Tocopherol, ascorbic acid, total antioxidant capacity (TAOC), plasma malondialdehyde (MDA) and C-reactive protein (CRP) before treatment, at day 7 and day 14 following recruitment. RESULTS: In all, 14 days of vitamin supplementation significantly improved plasma alpha-tocopherol and ascorbic concentrations in the treatment group compared with the decrease seen in the control group (P < 0.005 for difference in cumulative changes). TAOC increased significantly in the treatment group compared with controls (P < 0.003). There was a significant reduction in plasma MDA concentration in the treatment group, in contrast to the increase seen in the control group (P < 0.002). After adjusting for clinical complications CRP concentrations within 90 days postinfarct were significantly lower in the treatment group compared with controls. CONCLUSION: Supplementation with antioxidant vitamins within 12 h of onset of acute ischaemic stroke increased antioxidant capacity, reduced lipid peroxidation products and may have an anti-inflammatory effect. SPONSORSHIP: Sheffield Teaching Hospital NHS Trust.

Acute Disease↗
PubMed2003

Dystrophic phenotype of canine X-linked muscular dystrophy is mitigated by adenovirus-mediated utrophin gene transfer.

Utrophin is highly homologous and structurally similar to dystrophin, and in gene delivery experiments in mdx mice was able to functionally replace dystrophin. We performed mini-utrophin gene transfer in Golden Retriever dogs with canine muscular dystrophy (CXMD). Unlike the mouse model, the clinicopathological phenotype of CXMD is similar to that of Duchenne muscular dystrophy (DMD). We injected an adenoviral vector expressing a synthetic utrophin into tibialis anterior muscles of newborn dogs affected with CXMD and examined transgene expression by RNA and protein analysis at 10, 30 and 60 days postinjection in cyclosporin-treated and -untreated animals. Immunosuppression by cyclosporin was required to mitigate the immune response to viral and transgene antigens. RT-PCR analysis showed the presence of the exogenous transcript in the muscle of cyclosporin-treated and -untreated animals. The transgenic utrophin was efficiently expressed at the extrajunctional membrane in immunosuppressed dogs and this expression was stable for at least 60 days. We found reduced fibrosis and increased expression of dystrophin-associated proteins (DAPs) in association with muscle areas expressing the utrophin minigene, indicating that mini-utrophin can functionally compensate for lack of dystrophin in injected muscles. For this reason, utrophin transfer to dystrophin-deficient muscle appears as a promising therapeutic approach to DMD.

Adenoviridae↗
PubMed2005

Modulation of astrocytic activation by arundic acid (ONO-2506) mitigates detrimental effects of the apolipoprotein E4 isoform after permanent focal ischemia in apolipoprotein E knock-in mice.

Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4 (4/4)-knock-in (KI) mice, we have shown that delayed infarct expansion and reactive astrocytosis after permanent middle cerebral artery occlusion (pMCAO) were markedly exacerbated in 4/4-KI mice as compared with 2/2- or 3/3-KI mice. Here, we probed the putative causal relationship between enhanced astrocytic activation and exacerbation of brain damage in 4/4-KI mice using arundic acid (ONO-2506, Ono Pharmaceutical Co. Ltd), which is known to oppose astrocytic activation through its inhibitory action on S100B synthesis. In all of the KI mice, administration of arundic acid (10 mg/kg day, intraperitoneal, started immediately after pMCAO) induced significant amelioration of brain damage at 5 days after pMCAO in terms of infarct volumes (results expressed as the mean infarct volume (mm(3)) +/-1s.d. in 2/2-, 3/3-, or 4/4-KI mice in the vehicle groups: 16 +/- 2, 15 +/- 2, or 22 +/- 2; in the arundic acid groups: 11 +/- 2 (P < 0.001), 11 +/- 2 (P < 0.001), or 12 +/- 2 (P < 0.001), as compared with the vehicle groups), neurologic deficits, and S100/glial fibrillary acidic protein burden in the peri-infarct area. The beneficial effects of arundic acid were most pronounced in 4/4-KI mice, wherein delayed infarct expansion together with deterioration of neurologic deficits was almost completely mitigated. The above results support the notion that the apoE4 isoform exacerbates brain damage during the subacute phase of pMCAO through augmentation of astrocytic activation. Thus, pharmacological modulation of astrocytic activation may confer a novel therapeutic strategy for ischemic brain damage, particularly in APOE epsilon4 carriers.

Animals↗
PubMed2002

Use of Chlorella vulgaris for CO(2) mitigation in a photobioreactor.

Carbon dioxide (CO(2)) is a colorless gas that exists at a concentration of approximately 330 ppm in the atmosphere and is released in great quantities when fossil fuels are burned. The current flux of carbon out of fossil fuels is about 600 times greater than that into fossil fuels. With increased concerns about global warming and greenhouse gas emissions, there have been several approaches proposed for managing the levels of CO(2) emitted into the atmosphere. One of the most understudied methods for CO(2) mitigation is the use of biological processes in engineered systems such as photobioreactors. This research project describes the effectiveness of Chlorella vulgaris, used in a photobioreactor with a very short gas residence time, in sequestering CO(2) from an elevated CO(2) airstream. We evaluated a flow-through photobioreactor's operational parameters, as well as the growth characteristics of the C. vulgaris inoculum when exposed to an airstream with over 1850 ppm CO(2). When using dry weight, chlorophyll, and direct microscopic measurements, it was apparent that the photobioreactor's algal inoculum responded well to the elevated CO(2) levels and there was no build-up of CO(2) or carbonic acid in the photobioreactor. The photobioreactor, with a gas residence time of approximately 2 s, was able to remove up to 74% of the CO(2) in the airstream to ambient levels. This corresponded to a 63.9-g/m(3)/h bulk removal for the experimental photobioreactor. Consequently, this photobioreactor shows that biological processes may have some promise for treating point source emissions of CO(2) and deserve further study.

Bioreactors↗
PubMed2006

Mitigating peritoneal membrane characteristics in modern peritoneal dialysis therapy.

Membrane function at the start of peritoneal dialysis (PD) treatment, measured as solute transport rate and ultrafiltration capacity, varies considerably between individuals. Although this can be correlated to clinical factors such as age and body habitus, this accounts for little of the variance seen. It is increasingly clear, however, that this variability in membrane function does impact on clinical outcomes. Specifically, high solute transport increases mortality risk, independent of other known factors such as age, comorbidity, and residual renal function. High solute transport causes earlier loss of the osmotic gradient when a low molecular weight osmolyte such as glucose is used. This will result in an earlier and lower peak in the ultrafiltration achieved combined with a higher fluid absorption rate once the osmotic gradient is lost. It is therefore quite plausible that the worse clinical outcomes associated with high transport reflect less good ultrafiltration, although other explanations must be considered, including higher peritoneal protein losses and a possible association with systemic inflammation. Strategies now exist to mitigate the effects of high transport on fluid removal. These include optimization of the short dwell lengths using automated PD (APD) combined with icodextrin which will result in sustained ultrafiltration and thus prevention of reabsorption in the long dwell. Survival analysis of APD patients, especially in cohorts in which icodextrin has been used, would suggest that high transport status is not a risk factor, although some of these data are only preliminary. In contrast, low ultrafiltration capacity of the membrane seems to be more important in these patients, especially if anuric. Here the best strategy would seem to be prevention as patients who develop low ultrafiltration capacity are not easily treated on PD. Avoiding excessive hypertonic glucose exposure and preserving residual renal function offers the best available approach.

Dialysis Solutions↗
PubMed2004

B-group vitamin supplementation mitigates oxidative damage after acute ischaemic stroke.

Evidence shows that there is a rapid increase in the production of markers of oxidative damage immediately following acute stroke and that endogenous antioxidant defences are rapidly depleted, thus permitting further tissue damage. Several studies point to an antioxidant effect of B-group vitamins and a pro-oxidant effect of elevated plasma tHcy (total homocysteine). In the present study, we assessed whether supplementary B-group vitamins during this critical period will enhance antioxidant capacity and mitigate oxidative damage. Forty-eight patients with acute ischaemic stroke within 12 h of symptom onset were assigned to receive daily oral supplements of B-group vitamins comprising 5 mg of folate, 5 mg of vitamin B2, 50 mg of vitamin B6 and 0.4 mg of vitamin B12 (n=24) or no supplements (n=24) for 14 days. The treatment group and controls were matched for stroke subtype and age. Blood samples were obtained before intervention and also at 7 and 14 days post-recruitment for measurement of the following biomarkers: red cell folate (whole blood folate corrected with haematocrit), erythrocyte glutathione reductase activity coefficient (EGRAC; measure of vitamin B2 status), plasma pyridoxal phosphate (vitamin B6 status), plasma vitamin B12, plasma alpha-tocopherol, plasma ascorbic acid, plasma TAOC (total antioxidant capacity), plasma MDA (malondialdehyde), plasma tHcy and CRP (C-reactive protein). Supplementation for 14 days with B-group vitamins significantly increased the plasma concentrations of pyridoxal phosphate and red blood cell folate and improved a measure of B2 status compared with the control group (P<0.05). Plasma tHcy decreased in both groups albeit less in the control group, but differences in cumulative changes were not significant. There was, however, a decrease in plasma MDA concentration in the treatment group, in contrast with the increase seen in the control group and these differences were significant (P=0.05). CRP concentration, a marker of tissue inflammation, was significantly lower in the treatment group compared with controls (P<0.05). In conclusion, B-group vitamin supplementation immediately post-infarct may have antioxidant and anti-inflammatory effects in stroke disease independent of a homocysteine-lowering effect.

Aged↗
PubMed2001

Mitigation of stress-induced suppression of contact hypersensitivity by odorant inhalation.

BACKGROUND: Various skin functions are affected by stress. We have previously shown that odorant inhalation can regulate skin immune reactions. OBJECTIVES: To test the hypothesis that certain odorants can mitigate the effects of stress on skin immune reactions. METHODS: Contact hypersensitivity (CH) reactions were elicited in C57BL/6 mice. Mice were subjected to immobilization stress and were exposed to odorants for 2 days. Epidermal sheets were stained for I-A antigens and analysed by confocal laser scanning microscopy. Serum corticosterone levels were assayed by radioimmunoassay. RESULTS: Exposure of mice to 1,3-dimethoxy-5-methylbenzene (DMMB) had no effect on the intact CH reaction, but it upregulated the reaction suppressed by immobilization stress. Other odorants, including terpinyl acetate and valerian oil, had minor effects on the CH reaction. Suppression of I-A-positive cells was prevented by DMMB inhalation. Valerian oil, but not DMMB, downregulated stress-induced plasma corticosterone levels. CONCLUSIONS: Results suggest that odorant inhalation modulates various physiological pathways, some of which result in regulation of skin function.

Animals↗
PubMed2002

Endothelin ETA receptor-subtype specific antagonism does not mitigate the acute systemic or renal effects of exogenous angiotensin II in humans.

BACKGROUND: Angiotensin II (Ang II) is assumed to play a pathophysiological role in a variety of vascular diseases. Animal studies indicate that these effects are partly attributed to stimulation of endothelin-1 (ET-1) release. The aim of the present study was to investigate whether the acute effects of Ang II on systemic and renal haemodynamics in healthy subjects can be influenced by endothelin ET(A)-receptor blockade. DESIGN: The study design was balanced, randomized, placebo-controlled, double blind, two-way cross-over, in 10 healthy male subjects. METHODS: Subjects received stepwise increasing intravenous doses of Ang II (0.65, 1.25, 2.5, 5 ng kg(-1) min(-1) for 15 min per dose level) in the presence or absence of BQ-123 (60 microg min(-1)), a specific ETA-receptor antagonist. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate and inulin plasma clearance method, respectively. Renal vascular resistance (RVR) was calculated from mean arterial pressure (MAP) and renal plasma flow. RESULTS: Ang II decreased RPF by 34% and GFR by 9% and increased RVR by 94% and MAP by 27% (ANOVA, P < 0.001 vs. baseline, for all parameters). BQ-123 did not alter these renal and systemic haemodynamic responses to a significant degree. In addition, BQ-123 had no significant haemodynamic effect under baseline conditions. CONCLUSIONS: Short-term increase of circulating Ang II levels causes systemic and renal pressor effects, which are not mitigated by endothelin ETA-receptor blockade. This suggests that the pressor response to Ang II cannot be accounted for by the acute release of vasoactive ET-1.

Adult↗
PubMed2002

Mitigation of avian reproductive tract function by Salmonella enteritidis producing high-molecular-mass lipopolysaccharide.

Hens were infected with a wild-type Salmonella enteritidis and its wzz mutant, which lacked the ability to make high-molecular-mass lipopolysaccharide (LPS), in six experiments paired by dosage and route of exposure. Involution of the reproductive tract occurred in 86% of hens that were injected subcutaneously with 108 cfu of the wild-type strain, but none did so when injected with the wzz mutant. In spite of the lack of a specific effect on the reproductive tract, infection of hens with the mutant produced more contaminated eggs and heterophilic granulomas in developing ova (yolks) than wild type; thus, overall, the mutant appeared to be more virulent except after intravenous injection. The mutant also decreased shell quality more often than wild type, regardless of dosage or route of infection. These results suggest that egg-contaminating Salmonella enteritidis that produces high-molecular-mass LPS mitigates signs of illness in poultry by altering the response of the avian reproductive tract to infection, but without altering the incidence of egg contamination following bacteraemia. Further research is warranted to determine whether analyses of shell quality might aid in identification of flocks at risk of producing contaminated eggs.

Animals↗
PubMed1999

Mitigation of delayed-type hypersensitivity reactions by a CD44 variant isoform v3-specific antibody: blockade of leukocyte egress.

In allergic alterations of human skin the majority of infiltrated leukocytes express CD44v3, but no other CD44 variant isoform. Vessel endothelium, too, is brightly stained with a CD44v3-specific antibody. Being concerned about therapeutic intervention, it became of importance to define whether expression of CD44v3 on the endothelial cells or on the leukocytes or on both is of functional importance. As expression of CD44v3 in the mouse on activated endothelium and on subpopulations of activated CD4+ cells, B cells and monocytes was similar to the expression in the human, we answered the question in a mouse delayed-type hypersensitivity model. The effect of anti-CD44v3 was compared with the effect of anti-CD44s and anti-CD44v10, both known to suppress delayed-type hypersensitivity reactions. Anti-CD44v3 mitigated the delayed-type hypersensitivity reaction in dinitrofluorobenzene sensitized and challenged mice comparable with anti-CD44s and anti-CD44v10. The seemingly similar effects of CD44 isoform-specific antibodies, however, resulted from a distinct modulation of response. Anti-CD44s mainly suppressed T cell activation and interleukin-2 as well as interferon-gamma expression. Anti-CD44v10 inhibited the activation of monocytes in the draining lymph nodes and in the infiltrate, which led to a strong reduction in the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-12 and in edema formation. Anti-CD44v3 had only a weak effect on cytokine expression by isolated subpopulations of leukocytes, but suppressed cytokine production by helper T cells when cocultured with antigen-presenting cells, i.e., blocked an interaction between antigen-presenting cells and helper T cells. The dominating effect of anti-CD44v3, however, relied on a blockade of leukocyte extravasation. As leukocytes transferred into dinitrofluorobenzene sensitized, anti-CD44v3-treated and lethally irradiated mice did not infiltrate the sensitized skin, anti-CD44v3 most likely prevented leukocyte extravasation by blocking CD44v3 on endothelial cells.

Adult↗
PubMed2004

Inhaling to mitigate exhaled bioaerosols.

Humans commonly exhale aerosols comprised of small droplets of airway-lining fluid during normal breathing. These "exhaled bioaerosols" may carry airborne pathogens and thereby magnify the spread of certain infectious diseases, such as influenza, tuberculosis, and severe acute respiratory syndrome. We hypothesize that, by altering lung airway surface properties through an inhaled nontoxic aerosol, we might substantially diminish the number of exhaled bioaerosol droplets and thereby provide a simple means to potentially mitigate the spread of airborne infectious disease independently of the identity of the airborne pathogen or the nature of any specific therapy. We find that some normal human subjects expire many more bioaerosol particles than other individuals during quiet breathing and therefore bear the burden of production of exhaled bioaerosols. Administering nebulized isotonic saline to these "high-producer" individuals diminishes the number of exhaled bioaerosol particles expired by 72.10 +/- 8.19% for up to 6 h. In vitro and in vivo experiments with saline and surfactants suggest that the mechanism of action of the nebulized saline relates to modification of the physical properties of the airway-lining fluid, notably surface tension.

Administration, Inhalation↗
PubMed2006

Topical interests and the mitigation of search engine bias.

Search engines have become key media for our scientific, economic, and social activities by enabling people to access information on the web despite its size and complexity. On the down side, search engines bias the traffic of users according to their page ranking strategies, and it has been argued that they create a vicious cycle that amplifies the dominance of established and already popular sites. This bias could lead to a dangerous monopoly of information. We show that, contrary to intuition, empirical data do not support this conclusion; popular sites receive far less traffic than predicted. We discuss a model that accurately predicts traffic data patterns by taking into consideration the topical interests of users and their searching behavior in addition to the way search engines rank pages. The heterogeneity of user interests explains the observed mitigation of search engines' popularity bias.

Journal Article↗
PubMed2001

The current biodiversity extinction event: scenarios for mitigation and recovery.

The current massive degradation of habitat and extinction of species is taking place on a catastrophically short timescale, and their effects will fundamentally reset the future evolution of the planet's biota. The fossil record suggests that recovery of global ecosystems has required millions or even tens of millions of years. Thus, intervention by humans, the very agents of the current environmental crisis, is required for any possibility of short-term recovery or maintenance of the biota. Many current recovery efforts have deficiencies, including insufficient information on the diversity and distribution of species, ecological processes, and magnitude and interaction of threats to biodiversity (pollution, overharvesting, climate change, disruption of biogeochemical cycles, introduced or invasive species, habitat loss and fragmentation through land use, disruption of community structure in habitats, and others). A much greater and more urgently applied investment to address these deficiencies is obviously warranted. Conservation and restoration in human-dominated ecosystems must strengthen connections between human activities, such as agricultural or harvesting practices, and relevant research generated in the biological, earth, and atmospheric sciences. Certain threats to biodiversity require intensive international cooperation and input from the scientific community to mitigate their harmful effects, including climate change and alteration of global biogeochemical cycles. In a world already transformed by human activity, the connection between humans and the ecosystems they depend on must frame any strategy for the recovery of the biota.

Ecosystem↗
PubMed2003

Hepatocyte growth factor preserves beta cell mass and mitigates hyperglycemia in streptozotocin-induced diabetic mice.

Type I diabetes is an autoimmune disease that results in destructive depletion of the insulin-producing beta cells in the islets of Langerhans in pancreas. With the knowledge that hepatocyte growth factor (HGF) is a potent survival factor for a wide variety of cells, we hypothesized that supplementation of HGF may provide a novel strategy for protecting pancreatic beta cells from destructive death and for preserving insulin production. In this study, we demonstrate that expression of the exogenous HGF gene preserved insulin excretion and mitigated hyperglycemia of diabetic mice induced by streptozotocin. Blood glucose levels were significantly reduced in mice receiving a single intravenous injection of naked HGF gene at various time points after streptozotocin administration. Consistently, HGF concomitantly increased serum insulin levels in diabetic mice. Immunohistochemical staining revealed a marked preservation of insulin-producing beta cells by HGF in the pancreatic islets of the diabetic mice. This beneficial effect of HGF was apparently mediated by both protection of beta cells from death and promotion of their proliferation. Delivery of HGF gene in vivo induced pro-survival Akt kinase activation and Bcl-xL expression in the pancreatic islets of diabetic mice. These findings suggest that supplementation of HGF to prevent beta cells from destructive depletion and to promote their proliferation might be an effective strategy for ameliorating type I diabetes.

Animals↗
PubMed1990

Children's understanding of the mitigating function of disclaimers.

Despite earlier work indicating young children's competence in the use and understanding of retrospective "facework strategies" such as apologies, justifications, and excuses, it was hypothesized that an understanding of the disclaimer, a prospective strategy, would be relatively late appearing. An experiment is reported in which 144 British children between the ages of 5 and 11 years were presented with stories concerning an actor who had brought about certain negative consequences, having either previously issued, or not, a disclaimer. Children were asked to indicate and justify whether they felt the actor should be punished. Broadly consistent with the hypothesis guiding the present study, significant reductions in punishment recommendations following the provision of a disclaimer were found only among the 11-year-old subjects. However, from subjects' justifications for the decision not to punish, it was noted that nearly 50% of the 8-year-olds and 25% of the 5-year-olds provided evidence of understanding the mitigating function of disclaimers.

Child↗
PubMed2006

A traditional Japanese medicine mitigates TNBS-induced colitis in rats.

OBJECTIVE: Differences in dietary habits may be one of the reasons that the incidence of inflammatory bowel disease has remained lower in Japan than in Western countries. We investigated whether a traditional Japanese medicine (Strong Wakamto), based on Aspergillus oryzae koji, would exert any effect on experimental colitis in rats. MATERIAL AND METHODS: Colitis was induced using an enema of trinitrobenzene sulfonic acid (TNBS) and ethanol. Strong Wakamto was administered for 28 days before induction of colitis and for 7 days thereafter, and the effect of this medicine was evaluated. RESULTS: Treatment with 5% Strong Wakamto improved loss of body-weight, increased colon weight and significantly decreased the histological damage score for colon mucosa. Decreases in faecal Lactobacillus sp., superoxide dismutase activity and zinc concentrations, and the increased IL-1beta expression in colonic tissue after TNBS enema were improved when Strong Wakamto was given. The present in vitro studies indicate that administration of Strong Wakamto prevents lipopolysaccharide-induced TNF-alpha production in human macrophages. CONCLUSIONS: Oral administration of Strong Wakamto mitigates experimental inflammatory bowel disease induced by TNBS enema in rats. The beneficial effects seem attributable to a combination of balancing microflora, immunomodulatory effects on gut macrophages, and enhancement of anti-superoxide activity in colonic tissues.

Animals↗
PubMed1991

Intraventricular infusion of the selective sigma-agonist 1,3-di-ortho-tolylguanidine (DTG) mitigates ischaemic brain damage in the hippocampus.

Experimental evidence suggests that neuronal pharmacologic sites termed sigma (sigma) may be related, but not identical to PCP sites in the ion channel linked to NMDA excitatory receptors. These receptors may play a role in schizophreniform psychoses, and clinical trials of putative sigma-ligands have begun. Because of this, and because of the relationship of sigma-ligands to NMDA receptors, we studied the effect of the most selective presently available sigma-ligand on ischaemic neuronal death throughout the rat brain after transient forebrain ischaemia. Ventricular delivery of DTG at 0.5 mumol/h via an osmotic minipump was chosen to allow continuous access of the drug to brain tissue, control animals receiving artificial CSF. After one week survival, selective neuronal necrosis was reduced in the hippocampus, but not in the neocortex or striatum, contrasting with our previous findings in this model with pure NMDA antagonists. The results indicate that ischaemic neuronal necrosis in the hippocampus may be mitigated by sigma-agonists, possibly via an interaction with NMDA receptors.

Animals↗