• Adaptive Cerebral Neovascularization in a Model of Type 2 Diabetes

      Schreihofer, Derek A.; Fagan, Susan C.; Ergul, Adviye; Li, Weiguo; Prakash, Roshini; Kelley-Cobbs, Aisha I.; Ogbi, Safia; Kozak, Anna; El-Remessy, Azza B.; Department of Physiology; et al. (2010-01200)
      OBJECTIVE: The effect of diabetes on neovascularization varies between different organ systems. While excessive angiogenesis complicates diabetic retinopathy, impaired neovascularization contributes to coronary and peripheral complications of diabetes. However, how diabetes influences cerebral neovascularization is not clear. Our aim was to determine diabetes-mediated changes in the cerebrovasculature and its impact on the short-term outcome of cerebral ischemia.
    • Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats.

      Xu, Lin; Fagan, Susan C.; Waller, Jennifer L.; Edwards, David; Borlongan, Cesar V; Zheng, Jianqing; Hill, William D; Feuerstein, Giora; Hess, David C.; Department of Neurology; et al. (2004-05-19)
      BACKGROUND: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. The aim of this study was to determine if minocycline was effective at reducing infarct size in a Temporary Middle Cerebral Artery Occlusion model (TMCAO) when given at lower intravenous (IV) doses that correspond to human clinical exposure regimens. METHODS: Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats. RESULTS: Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose. CONCLUSIONS: The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4-5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke.
    • Vascular Protection by Angiotensin Receptor Antagonism Involves Differential VEGF Expression in Both Hemispheres after Experimental Stroke

      Guan, Weihua; Somanath, Payaningal R.; Kozak, Anna; Goc, Anna; El-Remessy, Azza B.; Ergul, Adviye; Johnson, Maribeth H.; Alhusban, Ahmed; Soliman, Sahar; Fagan, Susan C.; et al. (2011-09-1)
      We identified that the angiotensin receptor antagonist, candesartan, has profound neurovascular protective properties when administered after ischemic stroke and was associated with a proangiogenic state at least partly explained by vascular endothelial growth factor A (VEGFA). However, the spatial distribution of vascular endothelial growth factor (VEGF) isoforms and their receptors remained unknown. Protein analysis identified a significant increase in vascular endothelial grow factor B (VEGFB) in the cerebrospinal fluid (CSF) and the ischemic hemispheres (with increased VEGF receptor 1 activation) of treated animals (p<0.05) which was co-occurring with an increase in protein kinase B (Akt) phosphorylation (p<0.05). An increase in VEGFA protein in the contralesional hemisphere corresponded to a significant increase in vascular density at seven days (p<0.01) after stroke onset