More than 7% of the US population who have diabetes are at a 2 to 6-fold higher risk for having ischemic stroke and suffer from unfavorable stroke outcome and poor recovery. Reperfusion therapy with tissue plasminogen activator (tPA) is the only therapy for ischemic stroke;however, this treatment increases the risk of bleeding into the brain (hemorrhagic transformation, HT), especially in diabetics. A critical barrier to progress in the development of new therapeutic strategies, as well as the proper use of tPA in high-risk populations, is the lack of understanding on how bleeding influences the repair and recovery after stroke. Our goal is to identify new targets for prevention and treatment of stroke i patients with preexisting vascular disease and develop new neurovascular protection strategies. Our objective is to address this critical barrier and clinical problem by defining the impact and mechanisms by which HT impairs neurovascular repair after ischemic stroke in diabetes. Our central hypothesis is that bleeding into the brain, petechial OR space- occupying, impairs neurovascular restoration and worsens outcome in diabetes via the activation of toll like receptor (TLR)-4 by excess iron, a novel damage associated molecular pattern (DAMP). This hypothesis will be tested in 3 Specific Aims: 1. Test the hypothesis that petechial nonspace-occupying HT impairs neurovascular restorative repair and worsens neurological deficits in diabetes. We will determine the extent to which HT impairs neurovascular repair and functional outcome in multiple models of stroke and diabetes;2. Test the hypothesis that iron deposition resulting from greater HT in diabetes impairs neurovascular plasticity and worsens outcome of ischemic stroke. We will determine the role of iron on neurovascular restoration and functional outcome after embolic stroke in Type 2 diabetes;and 3. Test the hypothesis that HT stimulates TLR4 signaling/inflammation worsening repair and recovery after diabetic ischemic stroke. We will determine the mechanisms by which HT impairs functional recovery after embolic stroke in Type 2 diabetes. The outcomes of our translational studies include: 1) demonstrating that any bleeding into the brain is detrimental by impairing vascular and neuronal repair (this challenges the existing paradigm that only space-occupying HT worsens outcomes);2) generating new and important data related to mechanisms of how diabetes attenuates neuronal and endothelial repair processes by using combinations of animal models of diabetes or stroke to recapitulate the clinical condition, and 3) identification of iron as a new DAMP and show that iron chelation and/or downstream TLR4 inhibition are promising therapeutic targets in stroke treatment/recovery. This project will have a significant positive impact on stroke research and human health because it will 1) identify neurovascular protection and restoration strategies to improve stroke outcomes, 2) advance our knowledge of the role of the cerebral vasculature in stroke repair, and 3) provide specific information on stroke recovery in diabetes which occurs in more than 30% of the 800,000 annual stroke victims.

Public Health Relevance

More than 7% of the US population has diabetes. Diabetic patients suffer from stroke injury to a greater extent, especially bleeding into the brain, and als experience poor recovery after stroke. However, we do not know the impact of bleeding on stroke recovery. This project will determine the mechanisms how bleeding affect the repair of the brain after stroke in diabetes.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Koenig, James I
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Georgia Regents University
Schools of Medicine
United States
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Hardigan, Trevor; Ward, Rebecca; Ergul, Adviye (2016) Cerebrovascular complications of diabetes: focus on cognitive dysfunction. Clin Sci (Lond) 130:1807-22
Hardigan, Trevor; Yasir, Abdul; Abdelsaid, Mohammed et al. (2016) Linagliptin treatment improves cerebrovascular function and remodeling and restores reduced cerebral perfusion in Type 2 diabetes. Am J Physiol Regul Integr Comp Physiol 311:R466-77
Abdelsaid, Mohammed; Williams, Raeonda; Hardigan, Trevor et al. (2016) Linagliptin attenuates diabetes-induced cerebral pathological neovascularization in a blood glucose-independent manner: Potential role of ET-1. Life Sci 159:83-9
Alhusban, Ahmed; Kozak, Anna; Eldashan, Wael et al. (2016) Artery reopening is required for the neurorestorative effects of angiotensin modulation after experimental stroke. Exp Transl Stroke Med 8:4
Alhusban, Ahmed; Kozak, Anna; Eldahshan, Wael et al. (2016) Erratum to: Artery reopening is required for the neurorestorative effects of angiotensin modulation after experimental stroke. Exp Transl Stroke Med 8:5
Hardigan, Trevor; Abdul, Yasir; Ergul, Adviye (2016) Linagliptin reduces effects of ET-1 and TLR2-mediated cerebrovascular hyperreactivity in diabetes. Life Sci 159:90-6
Ward, Rebecca; Ergul, Adviye (2016) Relationship of endothelin-1 and NLRP3 inflammasome activation in HT22 hippocampal cells in diabetes. Life Sci 159:97-103
Yasir, Abdul; Hardigan, Trevor; Ergul, Adviye (2016) Diabetes-mediated middle cerebral artery remodeling is restored by linagliptin: Interaction with the vascular smooth muscle cell endothelin system. Life Sci 159:76-82
Ergul, Adviye; Hafez, Sherif; Fouda, Abdelrahman et al. (2016) Impact of Comorbidities on Acute Injury and Recovery in Preclinical Stroke Research: Focus on Hypertension and Diabetes. Transl Stroke Res 7:248-60
Coucha, Maha; Abdelsaid, Mohammed; Li, Weiguo et al. (2016) Nox4 contributes to the hypoxia-mediated regulation of actin cytoskeleton in cerebrovascular smooth muscle. Life Sci 163:46-54

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