David C. Hess

Background and Purpose—: Primary stroke centers (PSCs) are associated with greater rates of tissue plasminogen activator use and improved outcomes. The American Stroke Association has advocated for the preferential transport of stroke patients to PSCs. We investigated the impact of PSC certification on hospital stroke discharge patterns in Georgia communities with a choice between PSC and non-PSC. Methods—: We analyzed data from the Georgia Discharge Data System before (2004) and after stroke certification (2009). Only Metropolitan Statistical Areas containing ≥1 PSC and ≥1 non-PSC were included in the analysis. We calculated the odds of acute stroke discharge from a PSC in 2009 compared with 2004. Results—: In Georgia Metropolitan Statistical Areas with at least 1 PSC and 1 non-PSC hospital, the percent of patients discharged from a subsequently designated PSC increased from 50.2% to 56.6% between 2004 and 2009 (OR, 1.29; P <0.0001). In 4 Metropolitan Statistical Areas, the proportion of stroke discharges from PSCs increased, whereas in 2 Metropolitan Statistical Areas, there was no significant increase, and in 1, there was a trend toward less stroke discharges from PSCs. Conclusions—: Although there has been an overall increase in stroke discharges from PSCs, the impact of stroke certification on patient destination was small and inconsistent across the state suggesting that local factors influence the location of hospitalization.

Background and Purpose— Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ischemic stroke. Methods— Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days. Results— Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65±13.7 years), race (83% white), and sex (47% female) were consistent across the doses. The mean baseline National Institutes of Health Stroke Scale score was 8.5±5.8 and 60% received tissue plasminogen activator. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10-mg/kg dose. No severe hemorrhages occurred in tissue plasminogen activator-treated patients. Pharmacokinetic analysis (n=22) revealed a half-life of approximately 24 hours and linearity of parameters over doses. Conclusions— Minocycline is safe and well tolerated up to doses of 10 mg/kg intravenously alone and in combination with tissue plasminogen activator. The half-life of minocycline is approximately 24 hours, allowing every 24-hour dosing. Minocycline may be an ideal agent to use with tissue plasminogen activator.

Tissue plasminogen activator (tPA) is the only drug approved by the United States Food and Drug Administration for treatment of acute ischemic stroke. Because the drug must be used soon after symptom onset and is associated with intracerebral hemorrhage, tPA remains underutilized. Research has therefore focused on identifying other drugs that can be used concomitantly with tPA to improve the odds of a favorable recovery and to reduce the risk of intracerebral hemorrhage. Minocycline is a broad‐spectrum antibiotic that has been found to be a neuroprotective agent in preclinical ischemic stroke models. Minocycline inhibits matrix metalloproteinase‐9, a biomarker for intracerebral hemorrhage associated with tPA use. Minocycline is also an antiinflammatory agent and inhibits poly(ADP‐ribose) polymerase‐1. Minocycline has been safe and well tolerated in clinical trials. Additional safety and efficacy data are needed, and a phase III trial of minocycline with tPA in patients experiencing acute ischemic stroke is planned.

Background: Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, has been shown to promote therapeutic benefits in experimental stroke. However, equally compelling evidence demonstrates that the drug exerts variable and even detrimental effects in many neurological disease models. Assessment of the mechanism underlying minocycline neuroprotection should clarify the drug's clinical value in acute stroke setting. Results: Here, we demonstrate that minocycline attenuates both in vitro (oxygen glucose deprivation) and in vivo (middle cerebral artery occlusion) experimentally induced ischemic deficits by direct inhibition of apoptotic-like neuronal cell death involving the anti-apoptotic Bcl-2/cytochrome c pathway. Such anti-apoptotic effect of minocycline is seen in neurons, but not apparent in astrocytes. Our data further indicate that the neuroprotection is dose-dependent, in that only low dose minocycline inhibits neuronal cell death cascades at the acute stroke phase, whereas the high dose exacerbates the ischemic injury. Conclusion: The present study advises our community to proceed with caution to use the minimally invasive intravenous delivery of low dose minocycline in order to afford neuroprotection that is safe for stroke.

Cell-based therapy for stroke represents a third wave of therapeutics for stroke and one focused on restorative processes with a longer time window of opportunity than neuroprotective therapies. An...

Abstract.  Cells of the central nervous system were once thought to be incapable of regeneration. This dogma has been challenged in the last decade with studies showing new, migrating stem cells in the brain in many rodent injury models and findings of new neurones in the human hippocampus in adults. Moreover, there are reports of bone marrow‐derived cells developing neuronal and vascular phenotypes and aiding in repair of injured brain. These findings have fuelled excitement and interest in regenerative medicine for neurological diseases, arguably the most difficult diseases to treat. There are numerous proposed regenerative approaches to neurological diseases. These include cell therapy approaches in which cells are delivered intracerebrally or are infused by an intravenous or intra‐arterial route; stem cell mobilization approaches in which endogenous stem and progenitor cells are mobilized by cytokines such as granulocyte colony stimulatory factor (GCSF) or chemokines such as SDF‐1; trophic and growth factor support, such as delivering brain‐derived neurotrophic factor (BDNF) or glial‐derived neurotrophic factor (GDNF) into the brain to support injured neurones; these approaches may be used together to maximize recovery. While initially, it was thought that cell therapy might work by a ‘cell replacement’ mechanism, a large body of evidence is emerging that cell therapy works by providing trophic or ‘chaperone’ support to the injured tissue and brain. Angiogenesis and neurogenesis are coupled in the brain. Increasing angiogenesis with adult stem cell approaches in rodent models of stroke leads to preservation of neurones and improved functional outcome. A number of stem and progenitor cell types has been proposed as therapy for neurological disease ranging from neural stem cells to bone marrow derived stem cells to embryonic stem cells. Any cell therapy approach to neurological disease will have to be scalable and easily commercialized if it will have the necessary impact on public health. Currently, bone marrow‐derived cell populations such as the marrow stromal cell, multipotential progenitor cells, umbilical cord stem cells and neural stem cells meet these criteria the best. Of great clinical significance, initial evidence suggests these cell types may be delivered by an allogeneic approach, so strict tissue matching may not be necessary. The most immediate impact on patients will be achieved by making use of the trophic support capability of cell therapy and not by a cell replacement mechanism.

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 μg/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.

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.