# Mechanisms and therapeutic targets of neurovascular injury in hyperglycemic stroke

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $332,500

## Abstract

Although 30% of patients with stroke are diabetic, and over 50% develop post-stroke hyperglycemia (HG), the
clinical benefit of glucose normalization in the acute stroke setting is problematic controversial due to the risk of
hypoglycemia. Moreover, both diabetes and HG are associated with worse neurological outcomes, lower
reperfusion therapies efficacy, and aggravated vascular complications. Hence, there is an urgent need to
identify novel targets for the development of treatments that mitigate these risks. Our long-term goal is to
identify suitable drug targets to aid in the discovery of novel and clinically applicable therapies for improving
stroke outcome. The objective of this application is to determine the role of endothelial-TXNIP in hyperglycemic
stroke-induced neurovascular damage. Thioredoxin-interacting protein (TXNIP), a major intracellular regulator
of redox/ glucose induced stress and inflammation, now known to be upregulated in stroke, presents a
promising therapeutic target. In preliminary studies, we have demonstrated that HG mice have higher TXNIP
expression and increased hemorrhage after an embolic stroke compared to wild type (WT) controls. These
exciting findings have suggested that TXNIP as a promising therapeutic target in cerebral stroke. However,
there are definite knowledge gaps concerning the specific contribution of vascular TXNIP to the inflammatory
response in ischemia and reperfusion (tPA) injury. Therefore, our central hypothesis is that HG/ reperfusion-
induced TXNIP expression sustains neurovascular injury through activation of NLRP3-inflammasome, vascular
endothelial growth factor (VEGF), and matrix metalloproteinase (MMP) after stroke. This hypothesis will be
tested in three specific: Aim 1: Test the hypothesis that HG exacerbates reperfusion injury by activating the
TXNIP-NLRP3 inflammasome after stroke. Aim 2: Test the hypothesis that hyperglycemic stroke-induced
TXNIP triggers VEGF and MMP mediated neurovascular damage. Aim 3: Test the hypothesis that a novel
TXNIP inhibitor attenuates hyperglycemic stroke-induced neurovascular damage and functional deficits.
Expected outcomes of the proposed research include: (1) Identification of hyperglycemic stroke induced-
TXNIP as a key mediator of NLRP3 inflammasome formation, and (2) demonstration that hyperglycemic stroke
induced-TXNIP-NLRP3 triggers VEGF and MMP-mediated neurovascular damage, using endothelial specific
(EC)-TXNIP-/- mice, a specific NLRP3, MMP-9/2 and VEGF inhibitors, and reperfusion with IV-tPA (1.5 h). (3)
Our study will be the first to use of the newly created specific inhibitors for TXNIP and NLRP3 to address
whether therapeutic inhibition of TXNIP will improve long-term recovery and extent of the ischemic penumbra
by using MRI-diffusion tensor imaging (DTI) in an embolic stroke. These studies may have far-reaching
translational implications as the identification of vascular TXNIP, as key mediators of secondary injury will
provide novel targe...

## Key facts

- **NIH application ID:** 9923011
- **Project number:** 5R01NS097800-05
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Tauheed Ishrat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $332,500
- **Award type:** 5
- **Project period:** 2016-07-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923011

## Citation

> US National Institutes of Health, RePORTER application 9923011, Mechanisms and therapeutic targets of neurovascular injury in hyperglycemic stroke (5R01NS097800-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9923011. Licensed CC0.

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