NXY-059: a hopeful sign in the treatment of stroke.
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Animals↗
Biomedical subjects
David C Hess
Publications and source records attributed to David C Hess.
Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke.
BACKGROUND: Matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) are increased in the brain after experimental ischemic stroke in rats. These two proteases are involved with the degradation of the basal lamina and loss of stability of the blood brain barrier that occurs after ischemia and that is associated with thrombolytic therapy in ischemic stroke. Minocycline is a lipophilic tetracycline and is neuroprotective in several models of brain injury. Minocycline inhibits inflammation, apoptosis and extracellular matrix degradation. In this study we investigated whether delayed minocycline inhibits brain MMPs activated by ischemia in a model of temporary occlusion in Wistar rats. RESULTS: Both MMP-2 and MMP-9 were elevated in the ischemic tissue as compared to the contra-lateral hemisphere after 3 hours occlusion and 21 hours survival (p < 0.0001 for MMP-9). Intraperitoneal minocycline at 45 mg/kg concentration twice a day (first dose immediately after the onset of reperfusion) significantly reduced gelatinolytic activity of ischemia-elevated MMP-2 and MMP-9 (p < 0.0003). Treatment also reduced protein concentration of both enzymes (p < 0.038 for MMP-9 and p < 0.018 for MMP-2). In vitro incubation of minocycline in concentrations as low as 0.1 mug/ml with recombinant MMP-2 and MMP-9 impaired enzymatic activity and MMP-9 was more sensitive at lower minocycline concentrations (p < 0.05). CONCLUSION: Minocycline inhibits enzymatic activity of gelatin proteases activated by ischemia after experimental stroke and is likely to be selective for MMP-9 at low doses. Minocycline is a potential new therapeutic agent to acute treatment of ischemic stroke.
Animals↗
New hope for stroke patients: mobilization of endogenous stem cells.
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Cell Differentiation↗
Gene therapy, cell transplantation and stroke.
The use of neuroteratocarcinoma cells for transplantation therapy in stroke has emerged as a strategy for cell replacement therapy that has begun its transition from basic science laboratories to a clinical setting. Procurement logistics and novel neuroprotective functions associated with these cells allow neuroteratocarcinoma cells to serve as efficacious alternatives to using fetal cells as donor cell grafts for stroke therapy, although the optimal transplantation regimen must still be determined. In particular, the limitations of current stroke treatments and management reveal an urgent need to examine the efficacy of experimental treatments, such as neural transplantation, in order to develop better treatment therapies. This chapter will discuss the characteristics of NT2N cells, the role of the host brain microenvironment and NT2N cell grafts, laboratory research and clinical trials for the intracerebral transplantation of NT2N cells in stroke, the mechanisms underlying the grafts' effects, and NT2N cell grafts and the need for immunosuppression. This chapter will also highlight some of the most recent findings regarding NT2N cells.
Adult↗
Statin therapy for coronary heart disease and its effect on stroke.
Coronary heart disease (CHD) and stroke share common risk factors and are the leading causes of death and disability in the United States. Although the impact of elevated cholesterol on stroke risk has been disputed, numerous trials using 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) in patients with CHD have demonstrated a significant reduction in stroke incidence as a secondary endpoint. It is likely that statins are pleiotropic in stroke prevention, providing benefits through both cholesterol reduction and cholesterol-independent mechanisms. In this article, we review the relationship between cholesterol and stroke, randomized trials of statins in patients with CHD and high risk for CHD that have assessed stroke risk, and the putative mechanisms of stroke prevention by statins.
Coronary Disease↗
Telestroke: extending stroke expertise into underserved areas.
Telestroke systems offer the opportunity to extend stroke-care expertise into rural and underserved areas. These systems are being used to give alteplase to patients with stroke in previously underserved areas safely, effectively, and rapidly. Telestroke will probably play a large part in improving the quality of stroke care and in enrolling patients into clinical trials in rural and community hospitals. One such telestroke system, REACH (remote evaluation of acute ischaemic stroke), is a low-cost, web-based system that allows the consultant to access the system from work, home, or on the road. REACH is presently being used to give alteplase and guide acute stroke care in eight rural community hospitals in Georgia.
Female↗
Pathophysiology and treatment of stroke in sickle-cell disease: present and future.
Sickle-cell anaemia is the most common cause of stroke in children, and stroke is one of the most devastating complications of sickle-cell disease. Overt strokes are typically due to large-artery vasculopathy affecting the intracranial internal carotid arteries and proximal middle cerebral arteries, whereas silent strokes typically occur in the territory of penetrating arteries. The sickled red blood cell can contribute to the pathogenesis of stroke via abnormal adherence to the vascular endothelium and by haemolysis, which results in endothelial cell activation, a hypercoaguable state, and alterations in vasomotor tone. Red-blood-cell transfusion, the most common preventive measure for stroke in sickle-cell disease, is associated with iron overload in chronic disease. Therefore, interventions directed towards the potential mechanisms that promote vasculopathy and occlusion in sickle-cell anaemia should be investigated. Here we review the epidemiology, clinical spectrum, and pathophysiology of stroke in sickle-cell disease to identify potential therapeutic targets.
Anemia, Sickle Cell↗
Hypertension after experimental cerebral ischemia: candesartan provides neurovascular protection.
BACKGROUND: After ischemic stroke, hypertension increases the risk of recurrence, hemorrhage and fatal cerebral edema, but blood pressure (BP) lowering in the acute stroke period is controversial due to fears of infarct extension and worsened outcomes. OBJECTIVE: To determine whether BP lowering with candesartan, initiated at reperfusion, can reduce neurovascular damage and improve outcome in a model of hypertension after experimental ischemic stroke. METHODS: Male Wistar rats (280-305 g) underwent 3 h of middle cerebral artery occlusion (MCAO). At reperfusion, either saline (n = 18) or candesartan 1 mg/kg (n = 18) was administered intravenously. BP was measured by telemetry for 2 days before and 24 h after MCAO. Neurologic function was assessed and sacrifice occurred at 24 h after occlusion. Brain tissue was analyzed for infarct size, hemoglobin content and edema. RESULTS: Mean BP increased from 96 to 124 mmHg immediately upon MCAO and decreased to 114 mmHg after reperfusion, remaining elevated for 24 h (P < 0.001) in the saline group. Candesartan reduced BP back to baseline and BP remained lower than in saline-treated animals until sacrifice (P < 0.001). Infarct size (54 versus 38%, P = 0.01) and hemoglobin content (23.4 versus 10.0 microg/g tissue; P = 0.03) and edema (17.97 versus 11.33%, P < 0.0001) were lower in the candesartan group. In addition, neurologic function at 24 h was improved (P = 0.0036) in the candesartan group. CONCLUSIONS: Candesartan administered after reperfusion in acute ischemic stroke reduces neurovascular damage and improves outcome.
Animals↗
Ammonium toxicity and potassium limitation in yeast.
DNA microarray analysis of gene expression in steady-state chemostat cultures limited for potassium revealed a surprising connection between potassium and ammonium: potassium limits growth only when ammonium is the nitrogen source. Under potassium limitation, ammonium appears to be toxic for Saccharomyces cerevisiae. This ammonium toxicity, which appears to occur by leakage of ammonium through potassium channels, is recapitulated under high-potassium conditions by over-expression of ammonium transporters. Although ammonium toxicity is well established in metazoans, it has never been reported for yeast. To characterize the response to ammonium toxicity, we examined the filtrates of these cultures for compounds whose excretion might serve to detoxify the ammonium (such as urea in mammals). Using liquid chromatography-tandem mass spectrometry to assay for a wide array of metabolites, we detected excreted amino acids. The amounts of amino acids excreted increased in relation to the severity of growth impairment by ammonium, suggesting that amino acid excretion is used by yeast for ammonium detoxification.
Amino Acids↗
Transplantation of cryopreserved human bone marrow-derived multipotent adult progenitor cells for neonatal hypoxic-ischemic injury: targeting the hippocampus.
There is currently no treatment for neonatal hypoxic-ischemic (HI) injury. Although limited clinical trials of stem cell therapy have been initiated in a number of neurological disorders, the preclinical evidence of a cell-based therapy for neonatal HI injury remains in its infancy. Stem cell therapy, via stimulation of endogenous stem cells or transplantation of exogenous stem cells, has targeted neurogenic sites, such as the hippocampus, for brain protection and repair. The hippocampus has also been shown to secrete growth factors, especially during the postnatal period, suggesting that this brain region presents a highly conducive microenvironment for cell survival. Based on its neurogenic and neurotrophic factor-secreting features, the hippocampus stands as an appealing target for stem cell therapy. In the present study, we investigated the efficacy of intrahippocampal transplantation of multipotent adult progenitor cells (MAPCs), which are pluripotent progenitor cells with the ability to differentiate into a neuronal lineage. Seven-day old Sprague-Dawley rats were initially subjected to unilateral HI injury, that involved permanent ligation of the right common carotid artery and subsequent exposure to hypoxic environment. At day 7 after HI
Animals↗
Statins in stroke: prevention, protection and recovery.
Stroke is the third most common cause of death and the leading cause of neurological disability in the USA. While some risk factors for stroke, such as hypertension and cigarette smoking, are well defined, the role of cholesterol in stroke pathogenesis is debated. However, numerous studies in the past decade have shown that medications that reduce cholesterol via 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition (statins) reduce the incidence of ischemic stroke in patients who are known to have, or be at high risk of, coronary artery disease. In addition, statins may have benefits in neuroprotection and recovery after stroke. The mechanisms by which statins protect against, and improve outcome after, stroke probably extend beyond lipid lowering.
Cholesterol↗
Minocycline for short-term neuroprotection.
Minocycline is a widely used tetracycline antibiotic. For decades, it has been used to treat various gram-positive and gram-negative infections. Minocycline was recently shown to have neuroprotective properties in animal models of acute neurologic injury. As a neuroprotective agent, the drug appears more effective than other treatment options. In addition to its high penetration of the blood-brain barrier, minocycline is a safe compound commonly used to treat chronic infections. Its several mechanisms of action in neuroprotection -- antiinflammatory and antiapoptotic effects, and protease inhibition -- make it a desirable candidate as therapy for acute neurologic injury, such as ischemic stroke. Minocycline is ready for clinical trials of acute neurologic injury.
Animals↗
Behavioral and histological characterization of intrahippocampal grafts of human bone marrow-derived multipotent progenitor cells in neonatal rats with hypoxic-ischemic injury.
Children born with hypoxic-ischemic (HI) brain injury account for a significant number of live births wherein no clinical treatment is available. Limited clinical trials of stem cell therapy have been initiated in a number-of neurological disorders, but the preclinical evidence of a cell-based therapy for neonatal HI injury remains in its infancy. One major postulated mechanism underlying therapeutic benefits of stem cell therapy involves stimulation of endogenous neurogenesis via transplantation of exogenous stem cells. To this end, transplantation has targeted neurogenic sites, such as the hippocampus, for brain protection and repair. The hippocampus has been shown to secrete growth factors, especially during the postnatal period, suggesting that this brain region presents as highly conducive microenvironment for cell survival. Based on its neurogenic and neurotrophic factor-secreting features, the hippocampus stands as an appealing target for stem cell therapy. Here, we investigated the efficacy of intrahippocampal transplantation of multipotent progenitor cells (MPCs), which are pluripotent progenitor cells with the ability to differentiate into a neuronal lineage. Seven-day-old Sprague-Dawley rats were initially subjected to unilateral HI injury, which involved permanent ligation of the right common carotid artery and subsequent exposure to hypoxic environment. At day 7 after HI injury, animals received stereotaxic hippocampal injections of vehicle or cryopre-served MPCs (thawed just prior to transplantation) derived either from Sprague-Dawley rats (syngeneic) or Fisher rats (allogeneic). All animals were treated with daily immunosuppression throughout the survival period. Behavioral tests were conducted on posttransplantation days 7 and 14 using the elevated body swing test and the rotarod to reveal general and coordinated motor functions. MPC transplanted animals exhibited reduced motor asymmetry and longer time spent on the rotarod than those that received the vehicle infusion. Both syngeneic and allogeneic MPC transplanted injured animals did not significantly differ in their behavioral improvements at both test periods. Immunohistochemical evaluations of graft survival after behavioral testing at day 14 posttransplantation revealed that syngeneic and allogeneic transplanted MPCs survived in the hippocampal region. These results demonstrate for the first time that transplantation of MPCs ameliorated motor deficits associated with HI injury. In view of comparable behavioral recovery produced by syngeneic and allogeneic MPC grafts, allogeneic transplantation poses as a feasible and efficacious cell replacement strategy with direct clinical application. An equally major finding is the observation lending support to the hippocampus as an excellent target brain region for stem cell therapy in treating HI injury.
Animals↗
The neuroblast and angioblast chemotaxic factor SDF-1 (CXCL12) expression is briefly up regulated by reactive astrocytes in brain following neonatal hypoxic-ischemic injury.
BACKGROUND: Stromal cell-derived factor 1 (SDF-1 or CXCL12) is chemotaxic for CXCR4 expressing bone marrow-derived cells. It functions in brain embryonic development and in response to ischemic injury in helping guide neuroblast migration and vasculogenesis. In experimental adult stroke models SDF-1 is expressed perivascularly in the injured region up to 30 days after the injury, suggesting it could be a therapeutic target for tissue repair strategies. We hypothesized that SDF-1 would be expressed in similar temporal and spatial patterns following hypoxic-ischemic (HI) injury in neonatal brain. RESULTS: Twenty-five 7-day-old C57BL/J mice underwent HI injury. SDF-1 expression was up regulated up to 7 days after the injury but not at the later time points. The chief sites of SDF-1 up regulation were astrocytes, their foot processes along blood vessels and endothelial cells. CONCLUSION: The localization of SDF-1 along blood vessels in the HI injury zone suggests that these perivascular areas are where chemotaxic signaling for cellular recruitment originates and that reactive astrocytes are major mediators of this process. The associated endothelium is likely to be the site for vascular attachment and diapedesis of CXCR4 receptor expressing cells to enter the injured tissue. Here we show that, relative to adults, neonates have a significantly smaller window of opportunity for SDF-1 based vascular chemotaxic recruitment of bone marrow-derived cells. Therefore, without modification, following neonatal HI injury there is only a narrow period of time for endogenous SDF-1 mediated chemotaxis and recruitment of reparative cells, including exogenously administered stem/progenitor cells.
Age Factors↗
REACH: clinical feasibility of a rural telestroke network.
BACKGROUND AND PURPOSE: Development of stroke networks is critical to bringing guideline-driven stroke care to rural, underserved areas. METHODS: A Web-based telestroke tool, REACH, was developed to provide a foundation for a rural stroke network that delivered acute stroke consults 24 hours per day 7 days per week to 8 rural community hospitals in Georgia. RESULTS: There were 194 acute stroke consults delivered. Thirty patients were treated with tissue plasminogen activator (tPA). The mean National Institutes of Health Stroke Score (NIHSS) was 15.4, and the median NIHSS was 12.5. The mean onset to treatment time (OTT) was 122 minutes. The OTT dropped from 143 minutes in the first 10 patients treated to 111 minutes in last 20 patients. Of the 30 patients treated with tPA, 23% (7) were treated in < or =90 minutes and 60% (18) were treated within 2 hours. There were no symptomatic intracerebral hemorrhages. CONCLUSIONS: The REACH telestroke system permits the rapid and safe use of tPA in rural community hospitals. Over time, the system became more efficient and OTT decreased.
Aged↗
Limitations of intravenous human bone marrow CD133+ cell grafts in stroke rats.
We examined the effects of timing and routes of transplantation on survival and functional benefits of human bone-marrow-derived CD133+ cells in experimentally stroke Sprague-Dawley rats. At day 7 post-stroke, both immediate and delayed intracerebral transplantation resulted in similar graft survival (7%) that was localized within the original transplant site and reduction of motor (27%) and neurological (40%) deficits. In contrast, graft survival (0.01-0.04%) was only detected in delayed intravenous transplantation, characterized by cell migration throughout the ipsilateral stroke hemisphere. Behavioral improvement, however, was limited to neurological response and only apparent in immediate intravenous transplantation. Reduction of cerebral infarct (25%) was only noted in intracerebral transplantation. Intravenous transplantation requires optimization for improved therapeutic outcome of CD133+ cell grafts in stroke.
AC133 Antigen↗
Statins and stroke prevention.
Data from studies on the benefits of statins in coronary artery disease patients in preventing recurrent primary and secondary cardiac endpoints, as well as ischemic strokes, imply the potential value of statins in recurrent ischemic stroke prevention without coronary artery disease symptoms or, by extension, primary ischemic stroke prevention. However, data on the latter are lacking, although the ongoing Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study is designed to answer that question. Until these data become available, clinicians are justified in using statins to avert recurrent ischemic strokes due to atherosclerosis, especially if elevated total cholesterol, increased low-density lipoprotein cholesterol, and/or reduced high-density lipoprotein cholesterol, as specified in the National Cholesterol Education Program Third Adult Treatment Panel, are present. This article reviews the pathophysiology of atherosclerosis, particularly the major components of atheromas of cholesterol, smooth muscle cells, inflammation, "foam cells," and connective tissue elements. Emphasis is placed on the first three and the results of statin trials in coronary artery disease, as well as the beneficial pleiotrophic effects of statins in ischemic strokes.
Atherosclerosis↗
Transplantation of carotid body cells in the treatment of neurological disorders.
Laboratory and clinical studies have shown that intracerebral transplantation of carotid body (CB) cells ameliorate Parkinsonian deficits. The recent clinical study by Arjona and colleagues indicated that CB autograft transplantation is a relatively simple, safe, and viable treatment for PD patients. In particular, Espejo and colleagues demonstrated that the therapeutic efficacy of intracerebral transplantation of the CB in PD was likely obtained through secretion of neurotrophic factors rather than the local release of dopamine, which suggests it possible and reasonable to extend the use of the CB as an efficacious graft source for neural transplantation. Thus, we transplanted CB cell suspensions into the ischemic penumbra within 1h after stroke surgery. The results revealed that CB transplantation also significantly reduced stroke-induced behavioral deficits and cerebral infarction. In this review, we focus on summarizing the physiological properties of the CB related to transplantation, describing briefly possible mechanisms responsible for the effect of CB transplantation, and introducing recent studies of the CB as a donor source for neural transplantation.
Animals↗