Austin C Boese1, Auston Eckert1, Milton H Hamblin2, Jean-Pyo Lee3. 1. Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA. 2. Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA. 3. Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Brain Institute, Tulane University, New Orleans, LA 70112, USA. Electronic address: jeanpyoL@tulane.edu.
Abstract
INTRODUCTION: Clinically, significant stroke injury results from ischemia-reperfusion (IR), which induces a deleterious biphasic opening of the blood-brain barrier (BBB). Tissue plasminogen activator (tPA) remains the sole pharmacological agent to treat ischemic stroke. However, major limitations of tPA treatment include a narrow effective therapeutic window of 4.5 h in most patients after initial stroke onset and off-target non-thrombolytic effects (e.g., the risk of increased IR injury). We hypothesized that ameliorating BBB damage with exogenous human neural stem cells (hNSCs) would improve stroke outcome to a greater extent than treatment with delayed tPA alone in aged stroke mice. METHODS: We employed middle cerebral artery occlusion to produce focal ischemia with subsequent reperfusion (MCAO/R) in aged mice and administered tPA at a delayed time point (6 h post-stroke) via tail vein. We transplanted hNSCs intracranially in the subacute phase of stroke (24 h post-stroke). We assessed the outcomes of hNSC transplantation on pathophysiological markers of stroke 48 h post-stroke (24 h post-transplant). RESULTS: Delayed tPA treatment resulted in more extensive BBB damage and inflammation relative to MCAO controls. Notably, transplantation of hNSCs ameliorated delayed tPA-induced escalated stroke damage; decreased expression of proinflammatory factors (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6), decreased the level of matrix metalloprotease-9 (MMP-9), increased the level of brain-derived neurotrophic factor (BDNF), and reduced BBB damage. CONCLUSIONS: Aged stroke mice that received delayed tPA treatment in combination with hNSC transplantation exhibited reduced stroke pathophysiology in comparison to non-transplanted stroke mice with delayed tPA. This suggests that hNSC transplantation may synergize with already existing stroke therapies to benefit a larger stroke patient population.
INTRODUCTION: Clinically, significant stroke injury results from ischemia-reperfusion (IR), which induces a deleterious biphasic opening of the blood-brain barrier (BBB). Tissue plasminogen activator (tPA) remains the sole pharmacological agent to treat ischemic stroke. However, major limitations of tPA treatment include a narrow effective therapeutic window of 4.5 h in most patients after initial stroke onset and off-target non-thrombolytic effects (e.g., the risk of increased IR injury). We hypothesized that ameliorating BBB damage with exogenous human neural stem cells (hNSCs) would improve stroke outcome to a greater extent than treatment with delayed tPA alone in aged strokemice. METHODS: We employed middle cerebral artery occlusion to produce focal ischemia with subsequent reperfusion (MCAO/R) in aged mice and administered tPA at a delayed time point (6 h post-stroke) via tail vein. We transplanted hNSCs intracranially in the subacute phase of stroke (24 h post-stroke). We assessed the outcomes of hNSC transplantation on pathophysiological markers of stroke 48 h post-stroke (24 h post-transplant). RESULTS: Delayed tPA treatment resulted in more extensive BBB damage and inflammation relative to MCAO controls. Notably, transplantation of hNSCs ameliorated delayed tPA-induced escalated stroke damage; decreased expression of proinflammatory factors (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6), decreased the level of matrix metalloprotease-9 (MMP-9), increased the level of brain-derived neurotrophic factor (BDNF), and reduced BBB damage. CONCLUSIONS: Aged strokemice that received delayed tPA treatment in combination with hNSC transplantation exhibited reduced stroke pathophysiology in comparison to non-transplanted strokemice with delayed tPA. This suggests that hNSC transplantation may synergize with already existing stroke therapies to benefit a larger strokepatient population.
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