Stroke is the third leading cause of death and disability in USA. Given that at least one third of stroke patients are hyperglycemic on admission, with most being diabetic, and 65 percent of diabetic patients die from some form of heart disease or stroke, the diabetic stroke patient provides opportunity for unique pharmacologic interventions to improve stroke outcome. Increased glucose supply post ischemic attack has also been associated with cellular acidosis and free radical generation which can exacerbate edema. Recent published and preliminary data from our lab suggest that blood-to-brain glucose transport in both the ischemic and diabetic brain is partially carried by the sodium dependent glucose cotransporter (SGLT1) in addition to the traditional glucose carrier (GLUT1). Blood-brain barrier activation of SGLT1 protein can have deleterious effects in brain ischemia since SGLT1 is known to transport 2Na+ and 210 water molecules for each glucose molecule transported, thus having the propensity to contribute to both vasogenic and cellular brain edema, a leading cause of stroke death. Our data suggests that SGLT1 inhibition, with phlorizin administration post ischemia, resulted in reduced SGLT1 substrate transport across the ischemic brain and improved neurodegeneration, free radical damage, and infarction and edema ratios. Thus we hypothesize that SGLT1 induction during ischemia/reperfusion (IR) and diabetes mellitus (DM) plays a central role in ischemic damage and edema formation. We will test this hypothesis in three specific aims using both in vitro and in vivo models of IR injury and a model of DM.
AIM 1 : Elucidate the functional """"""""transport"""""""" role of BBB SGLT1 using in vitro and in vivo models of brain ischemia and DM. Working Hypothesis: Brain endothelial cells subjected to high glucose (HG) and/or IR will increase SGLT1 mediated transport.
AIM 2 : Determine the regulatory mechanisms for SGLT1 activity at the BBB during conditions of both IR and HG. Working Hypothesis: Conditions of HG and IR will regulate SGLT1 activity by availability of Na and PKC control of SGLT1 membrane insertion.
AIM 3 : Evaluate the effects of SGLT1 inhibition on brain ECF [glucose], edema and infarction ratios, behavioral endpoints, and penumbral injury after in vivo focal ischemia with and without DM. Working Hypothesis: SGLT1 inhibition will decrease brain ECF [glucose] and improve stroke outcome in streptozotocin (STZ) treated mice and age matched controls. An understanding of altered blood-brain barrier SGLT1 function, regulation and neuroprotective effects of inhibition during stroke and DM is vital to provide a foundation for the development of phlorizin and other SGLT1 specific inhibitors as potential neuroprotective strategies to treat brain ischemia in both diabetic and non-diabetic stroke patients.

Public Health Relevance

We will investigate a mechanism associated with why people with diabetes have worse outcome during brain stroke. This mechanism may provide opportunities to improve brain damage for many stroke patients. If successful, this drug target could be utilized to improve brain recovery after stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS076012-03
Application #
8496151
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2011-09-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$283,525
Indirect Cost
$91,959
Name
Texas Tech University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Islam, Mohammad Rashedul; Yang, Li; Lee, Yeon Sun et al. (2016) Enkephalin-Fentanyl Multifunctional Opioids as Potential Neuroprotectants for Ischemic Stroke Treatment. Curr Pharm Des 22:6459-6468
Davis, Thomas P; Abbruscato, Thomas J; Egleton, Richard D (2015) Peptides at the blood brain barrier: Knowing me knowing you. Peptides 72:50-6
Shah, Kaushik K; Boreddy, Purushotham Reddy; Abbruscato, Thomas J (2015) Nicotine pre-exposure reduces stroke-induced glucose transporter-1 activity at the blood-brain barrier in mice. Fluids Barriers CNS 12:10
Yang, Li; Islam, Mohammad R; Karamyan, Vardan T et al. (2015) In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment. Brain Res 1609:1-11
Shah, Kaushik; Abbruscato, Thomas (2014) The role of blood-brain barrier transporters in pathophysiology and pharmacotherapy of stroke. Curr Pharm Des 20:1510-22
Shah, Kaushik K; Yang, Li; Abbruscato, Thomas J (2012) In vitro models of the blood-brain barrier. Methods Mol Biol 814:431-49
Shah, Kaushik; Desilva, Shanal; Abbruscato, Thomas (2012) The role of glucose transporters in brain disease: diabetes and Alzheimer’s Disease. Int J Mol Sci 13:12629-55
Yang, Li; Shah, Kaushik K; Abbruscato, Thomas J (2012) An in vitro model of ischemic stroke. Methods Mol Biol 814:451-66
Vemula, Sharanya; Roder, Karen E; Yang, Tianzhi et al. (2009) A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. J Pharmacol Exp Ther 328:487-95